Goto, Yukiori, O'Donnell, Patricio
Synchronous Activity in the Hippocampus and Nucleus Accumbens In Vivo
J. Neurosci. 2001 21: 131-
"The hippocampus is one of the brain regions involved in cognitive functions, including learning and memory. Extensive studies have unveiled how information is processed within this system. However, the mechanisms by which hippocampal activity is translated into action remain unsolved. One important target of hippocampal projections is the nucleus accumbens, which has been described as the motivation-to-action interface. Previous experiments indicate that these projections can control information processing in this region by setting neurons into a depolarized state. Here, we report that membrane potential transitions in nucleus accumbens neurons are correlated with electrical activity in the ventral hippocampus, suggesting that hippocampal neural activity can determine ensembles of active accumbens neurons." [Full Text]

Kitano, Katsunori, Cateau, Hideyuki, Kaneda, Katsuyuki, Nambu, Atsushi, Takada, Masahiko, Fukai, Tomoki
Two-State Membrane Potential Transitions of Striatal Spiny Neurons as Evidenced by Numerical Simulations and Electrophysiological Recordings in Awake Monkeys
J. Neurosci. 2002 0: 20026482-230
"Spontaneous membrane potential fluctuations of striatal spiny projection neurons play a crucial role in their spike generation. Previous intracellular recording studies in anesthetized rats have shown that the membrane potential of striatal spiny neurons shifts between the depolarized "up" state and the hyperpolarized "down" state. Here we report evidence for the occurrence of such two-state membrane potential transitions by numerical simulations and electrophysiological recordings in awake monkeys. Data from our simulations of a striatal spiny neuron model demonstrated that spike latency histograms of the model neuron displayed two separate (i.e., early and late) peaks in response to excitatory cortical input, corresponding to neuronal activity in the up or down state, respectively. Then, we addressed experimentally whether the latency distribution of cortically induced spike firing of striatal spiny neurons might show dual peaks. Striatal neuron activity was extracellularly recorded in response to electrical stimulation in the two cortical motor-related areas, the primary motor cortex and the supplementary motor area, of awake monkeys. Analysis of spike latency histograms has defined that striatal spiny neurons typically exhibit two temporally distinct peaks, as obtained by the numerical simulations. Thus, the membrane potential shifts between the up and down states appear to occur in striatal spiny neurons of the behaving animal." [Full Text]

Goto, Yukiori, O'Donnell, Patricio
Network Synchrony in the Nucleus Accumbens In Vivo
J. Neurosci. 2001 21: 4498-4504
"Nucleus accumbens neurons show membrane potential fluctuations between a very negative resting membrane potential and periodical plateau depolarizations. Because action potential firing occurs only during the depolarized state, the control of transitions between states is important for information processing within this region, with an impact on accumbens-related behaviors. It has been proposed that ensembles of active neurons in the nucleus accumbens could be based on a population of cells depolarizing simultaneously into the UP state. In this study, in vivo intracellular recordings from accumbens neurons were performed simultaneously with local field potential recordings to examine whether the nucleus accumbens can exhibit synchronization of membrane potential states in a population of neurons. These simultaneous recordings indicated that local field potential shifts occurred synchronously with transitions to the UP state. Furthermore, manipulations that evoked prolonged plateau depolarizations also evoked field potentials of similar duration. Such signals likely occurred because of simultaneous membrane potential changes in a population of neurons. Together with our previous studies, these results suggest that membrane potential states in the nucleus accumbens can be synchronized by synaptic inputs from the hippocampus." [Full Text]

O'DONNELL, PATRICIO, GREENE, JENNIFER, PABELLO, NINA, LEWIS, BARBARA L., GRACE, ANTHONY A.
Modulation of Cell Firing in the Nucleus Accumbens
Ann NY Acad Sci 1999 877: 157-175
"Pennartz et al. have proposed that functions of the nucleus accumbens (NA) are subserved by the activity of ensembles of neurons rather than by an overall neuronal activation. Indeed, the NA is a site of convergence for a large number of inputs from limbic structures that may modulate the flow of prefrontal cortical information and contribute to defining such ensembles, as exemplified in the ability of hippocampal input to gate cortical throughput in the nucleus accumbens. NA neurons exhibit a bistable membrane potential, characterized by a very negative resting membrane potential (down state), periodically interrupted by plateau depolarizations (up state), during which the cells may fire in response to cortical inputs. A dynamic ensemble can be the result of a distributed set of neurons in their up state, determined by the moment-to-moment changes in the spatial distribution of hippocampal inputs responsible for transitions to the up state. Ensembles may change as an adaptation to the contextual information provided by the hippocampal input. Furthermore, for dynamic ensembles to be functionally relevant, the model calls for near synchronous transitions to the up state in a group of neurons. This can be accomplished by the cell-to-cell transfer of information via gap junctions, a mechanism that can allow for a transfer of slow electrical signals, including "up" events between coupled cells. Furthermore, gap junction permeability is tightly modulated by a number of factors, including levels of dopamine and nitric oxide, and cortical inputs, allowing for fine-tuning of this synchronization of up events. The continuous selection of such dynamic ensembles in the NA may be disputed in schizophrenia, resulting in an inappropriate level of activity of thalamocortical systems." [Full Text]

EA Stern, D Jaeger, and CJ Wilson
Membrane potential synchrony of simultaneously recorded striatal spiny neurons in vivo.
Nature, Jul 1998; 394(6692): 475-8.
"The basal ganglia are an interconnected set of subcortical regions whose established role in cognition and motor control remains poorly understood. An important nucleus within the basal ganglia, the striatum, receives cortical afferents that convey sensorimotor, limbic and cognitive information. The activity of medium-sized spiny neurons in the striatum seems to depend on convergent input within these information channels. To determine the degree of correlated input, both below and at threshold for the generation of action potentials, we recorded intracellularly from pairs of spiny neurons in vivo. Here we report that the transitions between depolarized and hyperpolarized states were highly correlated among neurons. Within individual depolarized states, some significant synchronous fluctuations in membrane potential occurred, but action potentials were not synchronized. Therefore, although the mean afferent signal across fibres is highly correlated among striatal neurons, the moment-to-moment variations around the mean, which determine the timing of action potentials, are not. We propose that the precisely timed, synchronous component of the membrane potential signals activation of cell assemblies and enables firing to occur. The asynchronous component, with low redundancy, determines the fine temporal pattern of spikes." [Abstract]

J. R. Wickens, and C. J. Wilson
Regulation of Action-Potential Firing in Spiny Neurons of the Rat Neostriatum In Vivo
J Neurophysiol 79: 2358-2364, 1998. [Full Text]

Rahman, Shafiqur, McBride, William J.
D1-D2 dopamine receptor interaction within the nucleus accumbens mediates long-loop negative feedback to the ventral tegmental area (VTA)
J Neurochem 2001 77: 1248-1255
"The objective of the present study was to examine the effects of perfusion of dopamine (DA) D1- and D2-like receptor agonists in the nucleus accumbens (ACB) on the long-loop negative feedback regulation of mesolimbic somatodendritic DA release in the ventral tegmental area (VTA) of Wistar rats employing ipsilateral dual probe in vivo microdialysis. Perfusion of the ACB for 60 min with the D1-like receptor agonist SKF 38393 (SKF, 1–100 µM) dose-dependently reduced the extracellular levels of DA in the ACB, whereas the extracellular levels of DA in the VTA were not changed. Similarly, application of the D2-like receptor agonist quinpirole (Quin, 1–100 µM) through the microdialysis probe in the ACB reduced the extracellular levels of DA in the ACB in a concentration-dependent manner, whereas extracellular levels of DA in the VTA were not altered. Co-application of SKF (100 µM) and Quin (100 µM) produced concomitant reductions in the extracellular levels of DA in the ACB and VTA. The reduction in extracellular levels of DA in the ACB and VTA produced by co-infusion of SKF and Quin was reversed in the presence of either 100 µM SCH 23390 (D1-like antagonist) or 100 µM sulpiride (D2-like antagonist). Overall, the results suggest that (a) activation of dopamine D1- or D2-like receptors can independently regulate local terminal DA release in the ACB, whereas stimulation of both subtypes is required for activation of the negative feedback pathway to the VTA." [Abstract]

Svingos AL, Colago EE, Pickel VM.
Vesicular acetylcholine transporter in the rat nucleus accumbens shell: Subcellular distribution and association with micro-opioid receptors.
Synapse 2001 Jun 1;40(3):184-192
"Cholinergic interneurons in the nucleus accumbens shell (AcbSh) are implicated in the reinforcing behaviors that develop in response to opiates active at micro-opioid receptors (MOR). We examined the electron microscopic immunocytochemical localization of the vesicular acetylcholine transporter (VAChT) and MOR to determine the functional sites for storage and release of acetylcholine (ACh), and potential interactions involving MOR in this region of rat brain. VAChT was primarily localized to membranes of small synaptic vesicles in axon terminals. Less than 10% of the VAChT-labeled terminals were MOR-immunoreactive. In contrast, 35% of the cholinergic terminals formed symmetric or punctate synapses with dendrites showing an extrasynaptic plasmalemmal distribution of MOR. Membranes of tubulovesicles in other selective dendrites were also VAChT-labeled, and almost half of these dendrites displayed plasmalemmal MOR immunoreactivity. The VAChT-labeled dendritic tubulovesicles often apposed unlabeled axon terminals that formed symmetric synapses. Our results indicate that in the AcbSh MOR agonists can modulate the release of ACh from vesicular storage sites in axon terminals as well as in dendrites where the released ACh may serve an autoregulatory function involving inhibitory afferents. These results also suggest, however, that many of the dendrites of spiny projection neurons in the AcbSh are dually influenced by ACh and opiates active at MOR, thus providing a cellular substrate for ACh in the reinforcement of opiates." [Abstract]

Rahman, Shafiqur, McBride, William J
Involvement of GABA and cholinergic receptors in the nucleus accumbens on feedback control of somatodendritic dopamine release in the ventral tegmental area
J Neurochem 2002 80: 646-654
"The objectives of the present study were to examine the involvement of GABA and cholinergic receptors within the nucleus accumbens (ACB) on feedback regulation of somatodendritic dopamine (DA) release in the ventral tegmental area (VTA). Adult male Wistar rats were implanted with ipsilateral dual guide cannulae for in vivo microdialysis studies. Activation of the feedback system was accomplished by perfusion of the ACB with the DA uptake inhibitor GBR 12909 (GBR; 100 µm). To assess the involvement of GABA and cholinergic receptors in regulating this feedback system, antagonists (100 µm) for GABAA (bicuculline, BIC), GABAB (phaclofen, PHAC), muscarinic (scopolamine, SCOP), and nicotinic (mecamylamine, MEC) receptors were perfused through the probe in the ACB while measuring extracellular DA levels in the ACB and VTA. Local perfusion of the ACB with GBR significantly increased (500% of baseline) the extracellular levels of DA in the ACB and produced a concomitant decrease (50% of baseline) in the extracellular DA levels in the VTA. Perfusion of the ACB with BIC or PHAC alone produced a 200–400% increase in the extracellular levels of DA in the ACB but neither antagonist altered the levels of DA in the VTA. Co-perfusion of either GABA receptor antagonist with GBR further increased the extracellular levels of DA in the ACB to 700–800% of baseline. However, coperfusion with BIC completely prevented the reduction in the extracellular levels of DA in the VTA produced by GBR alone, whereas PHAC partially prevented the reduction. Local perfusion of the ACB with either MEC or SCOP alone had little effect on the extracellular levels of DA in the ACB or VTA. Co-perfusion of either cholinergic receptor antagonist with GBR markedly reduced the extracellular levels of DA in the ACB and prevented the effects of GBR on reducing DA levels in the VTA. Overall, the results of this study suggest that terminal DA release in the ACB is under tonic GABA inhibition mediated by GABAA (and possibly GABAB ) receptors, and tonic cholinergic excitation mediated by both muscarinic and nicotinic receptors. Activation of GABAA (and possibly GABAB ) receptors within the ACB may be involved in the feedback inhibition of VTA DA neurons. Cholinergic interneurons may influence the negative feedback system by regulating terminal DA release within the ACB." [Abstract]

James M. Brundege, and John T. Williams
Differential Modulation of Nucleus Accumbens Synapses
J Neurophysiol 88: 142-151, 2002.
"The nucleus accumbens (NAcc) is a brain region involved in functions ranging from motivation and reward to feeding and drug addiction. The NAcc is typically divided into two major subdivisions, the shell and the core. The primary output neurons of both of these areas are medium spiny neurons (MSNs), which are quiescent at rest and depend on the relative input of excitatory and inhibitory synapses to determine when they fire action potentials. These synaptic inputs are, in turn, regulated by a number of neurochemical signaling agents that can ultimately influence information processing in the NAcc. The present study characterized the ability of three major signaling pathways to modulate synaptic transmission in NAcc MSNs and compared this modulation across different synapses within the NAcc. The opioid [Met]5enkephalin (ME) inhibited excitatory postsynaptic currents (EPSCs) in shell MSNs, an effect mediated primarily by µ-opioid receptors. Forskolin, an activator of adenylyl cyclase, potentiated shell EPSCs. An analysis of miniature EPSCs indicated a primarily presynaptic site of action, although a smaller postsynaptic effect may have also contributed to the potentiation. Adenosine and an adenosine A1-receptor agonist inhibited shell EPSCs, although no significant tonic inhibition by endogenous adenosine was detected. The effects of these signaling agents were then compared across four different synapses in the NAcc: glutamatergic EPSCs and GABAergic inhibitory postsynaptic currents (IPSCs) in both the core and shell subregions. ME inhibited all four of these synapses but produced a significantly greater inhibition of shell IPSCs than the other synapses. Forskolin produced an increase in transmission at each of the synapses tested. However, analysis of miniature IPSCs in the shell showed no sign of a postsynaptic contribution to this potentiation, in contrast to the shell miniature EPSCs. Tonic inhibition of synaptic currents by endogenous adenosine, which was not observed in shell EPSCs, was clearly present at the other three synapses tested. These results indicate that neuromodulation can vary between the different subregions of the NAcc and between the different synapses within each subregion. This may reflect differences in neuronal interconnections and functional roles between subregions and may contribute to the effects of drugs acting on these systems." [Abstract]

Sesack SR, Pickel VM.
Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area.
J Comp Neurol 1992 Jun 8;320(2):145-60
"Physiological and pharmacological studies indicate that descending projections from the prefrontal cortex modulate dopaminergic transmission in the nucleus accumbens septi and ventral tegmental area. We investigated the ultrastructural bases for these interactions in rat by examining the synaptic associations between prefrontal cortical terminals labeled with anterograde markers (lesion-induced degeneration or transport of Phaseolus vulgaris leucoagglutinin; PHA-L) and neuronal processes containing immunoreactivity for the catecholamine synthesizing enzyme, tyrosine hydroxylase. Prefrontal cortical terminals in the nucleus accumbens and ventral tegmental area contained clear, round vesicles and formed primarily asymmetric synapses on spines or small dendrites. In the ventral tegmental area, these terminals also formed asymmetric synapses on large dendrites and a few symmetric axodendritic synapses. In the nucleus accumbens septi, degenerating prefrontal cortical terminals synapsed on spiny dendrites which received convergent input from terminals containing peroxidase immunoreactivity for tyrosine hydroxylase, or from unlabeled terminals. In single sections, some tyrosine hydroxylase-labeled terminals formed thin and punctate symmetric synapses with dendritic shafts, or the heads and necks of spines. Close appositions, but not axo-axonic synapses, were frequently observed between degenerating prefrontal cortical afferents and tyrosine hydroxylase-labeled or unlabeled terminals. In the ventral tegmental area, prefrontal cortical terminals labeled with immunoperoxidase for PHA-L were in synaptic contact with dendrites containing immunogold reaction product for tyrosine hydroxylase, or with unlabeled dendrites. These results suggest that: (1) catecholaminergic (mainly dopaminergic) and prefrontal cortical terminals in the nucleus accumbens septi dually synapse on common spiny neurons; and (2) dopaminergic neurons in the ventral tegmental area receive monosynaptic input from prefrontal cortical afferents. This study provides the first ultrastructural basis for multiple sites of cellular interaction between prefrontal cortical efferents and mesolimbic dopaminergic neurons." [Abstract]

Finch DM, Gigg J, Tan AM, Kosoyan OP.
Neurophysiology and neuropharmacology of projections from entorhinal cortex to striatum in the rat.
Brain Res 1995 Jan 30;670(2):233-47
"We studied projections from the entorhinal cortex (Ent) to the striatum in anesthetized rats using extra- and intracellular recording and multibarrel iontophoresis. The majority of recording were from the caudate-putamen (CPu) and core of the nucleus accumbens (AcbC). Electrical stimulation of the Ent evoked synaptic responses in 77% of tests with AcbC neurons and 48% of tests with CPu neurons. In the case of AcbC neurons, 61% of these tests proved to be excitatory and were often followed by inhibitory phases. In contrast to this, only 18% of tests from CPu neurons were excitatory. Intracellular HRP labeling showed that responsive cells were medium spiny neurons. During iontophoretic experiments, application of the glutamatergic AMPA antagonist DNQX could selectively decrease or block excitatory responses. The GABAA antagonist bicuculline methiodide increased cellular firing rates and could reveal excitatory responses, suggesting block of a short-latency, short-duration inhibitory component. Ejection of the GABAB antagonist CGP-35348 could attenuate a later, longer-duration component of inhibition. The results indicate that the Ent excites striatal neurons at least in part by glutamatergic receptors and suggest that this excitation is followed by secondary prolonged GABAergic inhibition." [Abstract]

Johnson LR, Aylward RL, Hussain Z, Totterdell S.
Input from the amygdala to the rat nucleus accumbens: its relationship with tyrosine hydroxylase immunoreactivity and identified neurons.
Neuroscience 1994 Aug;61(4):851-65
"Both tyrosine hydroxylase-positive fibres from the mesolimbic dopamine system and amygdala projection fibres from the basolateral nucleus are known to terminate heavily in the nucleus accumbens. Caudal amygdala fibres travelling dorsally via the stria terminalis project densely to the nucleus accumbens shell, especially in the dopamine rich septal hook. The amygdala has been associated with the recognition of emotionally relevant stimuli while the mesolimbic dopamine system is implicated with reward mechanisms. There is behavioural and electrophysiological evidence that the amygdala input to the nucleus accumbens is modulated by the mesolimbic dopamine input, but it is not known how these pathways interact anatomically within the nucleus accumbens. Using a variety of neuroanatomical techniques including anterograde and retrograde tracing, immunocytochemistry and intracellular filling, we have demonstrated convergence of these inputs on to medium-sized spiny neurons. The terminals of the basolateral amygdala projection make asymmetrical synapses predominantly on the heads of spines which also receive on their necks or adjacent dendrites, symmetrical synaptic input from the mesolimbic dopamine system. Some of these neurons have also been identified as projection neurons, possibly to the ventral pallidum. We have shown a synaptic level how dopamine is positioned to modulate excitatory limbic input in the nucleus accumbens." [Abstract]

Roitman MF, Na E, Anderson G, Jones TA, Bernstein IL.
Induction of a salt appetite alters dendritic morphology in nucleus accumbens and sensitizes rats to amphetamine.
J Neurosci 2002 Jun 1;22(11):RC225
"Sensitization to drugs, such as amphetamine, is associated with alterations in the morphology of neurons in the nucleus accumbens, a brain region critical to motivation and reward. The studies reported here indicate that a strong natural motivator, sodium depletion and associated salt appetite, also leads to alterations in neurons in nucleus accumbens. Medium spiny neurons in the shell of the nucleus accumbens of rats that had experienced sodium depletions had significantly more dendritic branches and spines than controls. In addition, a history of sodium depletions was found to have cross-sensitization effects, leading to enhanced psychostimulant responses to amphetamine. Thus, neuronal alterations common to salt and drug sensitization may provide a general mechanism for enhanced behavioral responses to subsequent exposures to these challenges." [Abstract]

Cabeza de Vaca, Soledad, Carr, Kenneth D.
Food Restriction Enhances the Central Rewarding Effect of Abused Drugs
J. Neurosci. 1998 18: 7502-7510
"Chronic food restriction increases the systemic self-administration and locomotor-stimulating effect of abused drugs. However, it is not clear whether these behavioral changes reflect enhanced rewarding potency or a CNS-based modulatory process. The purpose of this study was to determine whether food restriction specifically increases the rewarding potency of drugs, as indexed by their threshold-lowering effect on lateral hypothalamic self-stimulation, and whether any such effect can be attributed to an enhanced central response rather than changes in drug disposition. When drugs were administered systemically, food restriction potentiated the threshold-lowering effect of amphetamine (0.125, 0.25, and 0.5 mg/kg, i.p.), phencyclidine (1.0, 2.0, and 3.0 mg/kg, i.p.), and dizocilpine (MK-801) (0.0125, 0.05, and 0.1 mg/kg, i.p.) but not nicotine (0.15, 0.3, 0.45 mg/kg, s.c.). When amphetamine (25.0, 50.0, and 100.0 µg) and MK-801 (5.0, 10.0, and 20.0 µg) were administered via the intracerebroventricular route, food restriction again potentiated the threshold-lowering effects and increased the locomotor-stimulating effects of both drugs. These results indicate that food restriction increases the sensitivity of neural substrates for rewarding and stimulant effects of drugs. In light of work that attributes rewarding effects of MK-801 to blockade of NMDA receptors on medium spiny neurons in nucleus accumbens, the elements affected by food restriction may lie downstream from the mesoaccumbens dopamine neurons whose terminals are the site of amphetamine-rewarding action. Possible metabolic-endocrine triggers of this effect are discussed, as is the likelihood that mechanisms mediating the modulatory effect of food restriction differ from those mediating sensitization by intermittent drug exposure." [Full Text]

Kelley AE, Bakshi VP, Haber SN, Steininger TL, Will MJ, Zhang M.
Opioid modulation of taste hedonics within the ventral striatum.
Physiol Behav 2002 Jul;76(3):365-77
"There is a long-standing interest in the role of endogenous opioid peptides in feeding behavior and, in particular, in the modulation of food reward and palatability. Since drugs such as heroin, morphine, alcohol, and cannabinoids, interact with this system, there may be important common neural substrates between food and drug reward with regard to the brain's opioid systems. In this paper, we review the proposed functional role of opioid neurotransmission and mu opiate receptors within the nucleus accumbens and surrounding ventral striatum. Opioid compounds, particularly those selective for the mu receptor, induce a potent increase in food intake, sucrose, salt, saccharin, and ethanol intake. We have explored this phenomenon with regard to macronutrient selection, regional specificity, role of output structures, Fos mapping, analysis of motivational state, and enkephalin gene expression. We hypothesize that opioid-mediated mechanisms within ventral striatal medium spiny neurons mediate the affective or hedonic response to food ('liking' or food 'pleasure'). A further refinement of this hypothesis is that activation of ventral striatal opioids specifically encodes positive affect induced by tasty and/or calorically dense foods (such as sugar and fat), and promotes behaviors associated with this enhanced palatability. It is proposed that this brain mechanism was beneficial in evolutionary development for ensuring the consumption of relatively scarce, high-energy food sources. However, in modern times, with unlimited supplies of high-calorie food, it has contributed to the present epidemic of obesity." [Abstract]

Robinson TE, Kolb B.
Morphine alters the structure of neurons in the nucleus accumbens and neocortex of rats.
Synapse 1999 Aug;33(2):160-2
"Rats were given repeated injections of 10 mg/kg of morphine and were then left undisturbed for 24-25 days before their brains were processed for Golgi-Cox staining. Prior exposure to morphine decreased the complexity of dendritic branching and the number of dendritic spines on medium spiny neurons in the shell of the nucleus accumbens and on pyramidal cells in the prefrontal and parietal cortex. It is suggested that some of the long-term behavioral consequences of repeated exposure to morphine may be due to its ability to reorganize patterns of synaptic connectivity in the forebrain." [Abstract]

Williams, John T., Christie, MacDonald J., Manzoni, Olivier
Cellular and Synaptic Adaptations Mediating Opioid Dependence
Physiol. Rev. 2001 81: 299-343 [Full Text]

Martin, Gilles, Nie, Zhiguo, Siggins, George Robert
µ-Opioid Receptors Modulate NMDA Receptor-Mediated Responses in Nucleus Accumbens Neurons
J. Neurosci. 1997 17: 11-22 [Full Text]

Svingos AL, Clarke CL, Pickel VM.
Localization of the delta-opioid receptor and dopamine transporter in the nucleus accumbens shell: implications for opiate and psychostimulant cross-sensitization.
Synapse 1999 Oct;34(1):1-10
"Opiate- and psychostimulant-induced modulation of dopamine transmission in the nucleus accumbens shell (AcbSh) is thought to play a key role in their potent reinforcing and locomotor effects. To investigate the cellular basis for potential functional interactions involving opiates active at the delta-opioid receptor (DOR) and psychostimulants that bind selectively to the dopamine transporter (DAT), we examined the electron microscopic localization of their respective antisera in rat AcbSh. DOR immunoperoxidase labeling was seen primarily, and DAT immunogold particles exclusively, in axon terminals. In these terminals, DOR immunoreactivity was prominently associated with discrete segments of the plasma membrane and the membranes of nearby small synaptic and large dense core vesicles. DAT immunogold particles were almost exclusively distributed along nonsynaptic axonal plasma membranes. Thirty-nine percent DOR-labeled profiles (221/566) either apposed DAT-immunoreactive terminals or also contained DAT. Of these 221 DOR-labeled profiles, 13% were axon terminals containing DAT and 15% were dendritic spines apposed to DAT-immunoreactive terminals. In contrast, 70% were morphologically heterogeneous axon terminals and small axons apposed to DAT-immunoreactive terminals. Our results indicate that DOR agonists in the AcbSh can directly modulate the release of dopamine, as well as postsynaptic responses in spiny neurons that receive dopaminergic input, but act principally to control the presynaptic secretion of other neurotransmitters whose release may influence or be influenced by extracellular dopamine. Thus, while opiates and psychostimulants mainly have differential sites of action, cross-sensitization of their addictive properties may occur through common neuronal targets." [Abstract]

Svingos AL, Chavkin C, Colago EE, Pickel VM.
Major coexpression of kappa-opioid receptors and the dopamine transporter in nucleus accumbens axonal profiles.
Synapse 2001 Dec 1;42(3):185-92
"The behavioral effects of psychostimulants, which are produced at least in part through inhibition of the dopamine transporter (DAT), are modulated by kappa-opioid receptors (KOR) in the nucleus accumbens (Acb). Using electron microscopic immunocytochemistry, we reveal that in the Acb KOR labeling is mainly, and DAT immunoreactivity is exclusively, presynaptic. From 400 KOR-labeled presynaptic structures, including axon terminals, intervaricosities, and small axons, 51% expressed DAT and 29% contacted another population of terminals exclusively labeled for DAT. Within axonal profiles that contained both antigens, DAT and KOR were prominently localized to plasma membrane segments that showed overlapping distributions of the respective immunogold-silver and immunoperoxidase markers. KOR labeling was also localized to membranes of small synaptic vesicles in terminals with or without DAT immunoreactivity. In addition, from 24 KOR-immunoreactive dendritic spines 42% received convergent input from DAT-containing varicosities and unlabeled terminals forming asymmetric, excitatory-type synapses. Our results provide the first ultrastructural evidence that in the Acb, KOR is localized to strategic sites for involvement in the direct presynaptic release and/or reuptake of dopamine. These data also suggest a role for KOR in the presynaptic modulation of other neurotransmitters and in the postsynaptic excitatory responses of single spiny neurons in the Acb. Dual actions on dopamine terminals and their targets in the Acb may account for KOR-mediated attenuation of drug reinforcement and sensitization." [Abstract]

Svingos, Adena L., Colago, Eric E. O., Pickel, Virginia M.
Cellular Sites for Dynorphin Activation of kappa -Opioid Receptors in the Rat Nucleus Accumbens Shell
J. Neurosci. 1999 19: 1804-1813 [Full Text]

Gregory O. Hjelmstad, and Howard L. Fields
Kappa Opioid Receptor Inhibition of Glutamatergic Transmission in the Nucleus Accumbens Shell
J Neurophysiol 85: 1153-1158, 2001. [Full Text]

Schwarzer C, Berresheim U, Pirker S, Wieselthaler A, Fuchs K, Sieghart W, Sperk G.
Distribution of the major gamma-aminobutyric acid(A) receptor subunits in the basal ganglia and associated limbic brain areas of the adult rat.
J Comp Neurol 2001 May 14;433(4):526-49
"Within the basal ganglia, gamma-aminobutyric acid (GABA) exerts a fundamental role as neurotransmitter of local circuit and projection neurons. Its fast hyperpolarizing action is mediated through GABA(A) receptors. These ligand-gated chloride channels are assembled from five subunits, which derive from multiple genes. Using immunocytochemistry, we investigated the distribution of 12 major GABA(A) receptor subunits (alpha1-5, beta1-3, gamma1-3, and delta) in the basal ganglia and associated limbic brain areas of the rat. Immunoreactivity for an additional subunit (subunit alpha6) was not observed. The striatum, the nucleus accumbens, and the olfactory tubercle displayed strong, diffuse staining for the subunits alpha2, alpha4, beta3, and delta presumably located on dendrites of the principal medium spiny neurons. Subunit alpha1-, beta2-, and gamma2-immunoreactivities were apparently mostly restricted to interneurons of these areas. In contrast, the globus pallidus, the entopeduncular nucleus, the ventral pallidum, the subthalamic nucleus, and the substantia nigra pars reticulata revealed dense networks of presumable dendrites of resident projection neurons, which were darkly labeled for subunit alpha1-, beta2-, and gamma2-immunoreactivities. The globus pallidus, ventral pallidum, entopeduncular nucleus, and substantia nigra pars reticulata, all areas receiving innervations from the striatum, displayed strong subunit gamma1-immunoreactivity compared to other brain areas. In the substantia nigra pars compacta and in the ventral tegmental area, numerous presumptive dopaminergic neurons were labeled for subunits alpha3, gamma3, and/or delta. This highly heterogeneous distribution of individual GABA(A) receptor subunits suggests the existence of differently assembled, and presumably also functionally different, GABA(A) receptors within individual nuclei of the basal ganglia and associated limbic brain areas." [Abstract]

Shi WX, Rayport S.
GABA synapses formed in vitro by local axon collaterals of nucleus accumbens neurons.
J Neurosci 1994 Jul;14(7):4548-60
"GABAergic medium-spiny neuron axons not only form the principal projections of the nucleus accumbens (nAcc) but also branch locally in a dense network overlapping their own dendrites, suggesting that their recurrent synapses mediate the major information processing functions of the nAcc. We used postnatal nAcc cultures to study these synapses individually. In culture, as in the intact nAcc, medium-spiny neurons account for over 95% of the cells and are GABAergic. Strikingly, these neurons showed a spike afterhyperpolarization (AHP) that was largely blocked by the GABAA antagonist bicuculline. The bicuculline-sensitive AHP occurred without or with latency, and met criteria for monosynapticity; consistent with this, dye fills showed the presence of recurrent axons and a low incidence of dye coupling. Blockade of Ca2+ influx eliminated this autaptic PSP, while TTX almost completely eliminated it, indicating that it is due to exocytic GABA release principally at axodendritic contacts. While blocking GABAB receptors had no direct effect on the autaptic PSP, activating these receptors with baclofen produced presynaptic inhibition, as well as directly mediated hyperpolarization; together, these actions increased the signal-to-noise ratio in the cellular response to synaptic inputs. Bicuculline also increased the signal-to-noise ratio; in addition, it induced burst firing and depolarization inactivation. In contrast, the indirect GABA agonist flurazepam and the GABA uptake blocker nipecotic acid each enhanced autaptic PSPs. Since autapses formed in vitro appear to be functionally equivalent to synapses between neighboring medium-spiny neurons that receive similar inputs, these results bear on the function of intrinsic GABA synapses in the intact nAcc. Thus, intrinsic GABA synapses are likely to regulate the signal-to-noise ratio in nAcc information processing and may be important targets for the modulatory actions of endogenous neurotransmitters and drugs." [Abstract]

Morikawa, Hitoshi, Manzoni, Olivier J., Crabbe, John C., Williams, John T.
Regulation of Central Synaptic Transmission by 5-HT1B Auto- and Heteroreceptors
Mol Pharmacol 2000 58: 1271-1278
"Although 5-HT(1B) receptors are believed to be expressed on nerve terminals, their precise mode of action is not fully understood because of the lack of selective antagonists. The 5-HT(1B) receptor knockout mouse was used in the present investigation to assess the function of 5-HT(1B) receptors in the modulation of synaptic transmission in three areas of the central nervous system: the dorsal raphe, the ventral midbrain, and the nucleus accumbens. N-(3-Trifluoromethylphenyl)piperazine, a 5-HT(1B) receptor agonist, potently inhibited 5-HT(1A) receptor-mediated slow inhibitory postsynaptic potentials (IPSPs) in the dorsal raphe of wild-type but not knockout mice. Both synaptically released 5-HT and exogenous 5-HT caused a presynaptic inhibition that outlasted the postsynaptic hyperpolarization only in wild-type mice. In the ventral midbrain, 5-HT(1B) receptor-dependent inhibition of gamma-aminobutyric acid(B) IPSPs in dopamine neurons was present in wild-type animals and absent in knockout animals. Similar results were obtained in the nucleus accumbens measuring glutamate-mediated excitatory postsynaptic currents in medium spiny neurons. Finally, cocaine, which blocks 5-HT uptake, inhibited IPSPs in the dorsal raphe and the ventral midbrain of wild-type but not knockout mice, whereas cocaine produced comparable inhibition of excitatory postsynaptic currents in the nucleus accumbens of both types of animals. These results indicate that 5-HT(1B) receptors function as autoreceptors and heteroreceptors to exert presynaptic inhibition of transmitter release in the central nervous system. Furthermore, this study underscores the role played by presynaptic 5-HT(1B) receptors in mediating the effects of cocaine on synaptic transmission." [Full Text]

Muramatsu M, Lapiz MD, Tanaka E, Grenhoff J.
Serotonin inhibits synaptic glutamate currents in rat nucleus accumbens neurons via presynaptic 5-HT1B receptors.
Eur J Neurosci 1998 Jul;10(7):2371-9
"Neurons in the nucleus accumbens septi in brain slices from adult male rats were studied with patch clamp recording in the whole-cell conformation. Cells filled with Lucifer Yellow were identified as medium spiny neurons. Electrical stimulation close to the recorded cell evoked excitatory and inhibitory synaptic currents. In the presence of picrotoxin or bicuculline, stimulation at a holding potential of -90 mV evoked an inward excitatory current that was blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), identifying it as an excitatory postsynaptic current (EPSC) mediated by glutamate acting at AMPA/kainate receptors. Serotonin (5-hydroxytryptamine, 5-HT; 3-100 microM in the bath) decreased the EPSC in about 90% of the cells. The action of 5-HT was mimicked by N-(3-trifluoromethylphenyl)-piperazine HCl (TFMPP), but not by (+/-)-8-hydroxydipropylaminotetralin (8-OH-DPAT) or (+/-)-2,5-dimethoxy-4-iodoamphetamine HCl (DOI). The 5-HT effect was antagonized by pindolol or cyanopindolol, but not by spiperone, ketanserin or tropisetron. Taken together, these results indicate that 5-HT acts at 5-HT1B receptors. The effect of 5-HT was potentiated by cocaine (0.3-3 microM) or the selective serotonin reuptake inhibitor citalopram. Miniature synaptic currents recorded in the presence of tetrodotoxin were inhibited by CNQX, identifying them as spontaneous miniature EPSCs. 5-HT reduced the frequency of these miniature EPSCs without affecting their amplitude, which indicates a presynaptic site of action. This presynaptic inhibition by 5-HT might be involved in the behavioural effects of cocaine.' [Abstract]

Rodriguez JJ, Garcia DR, Pickel VM.
Subcellular distribution of 5-hydroxytryptamine2A and N-methyl-D-aspartate receptors within single neurons in rat motor and limbic striatum.
J Comp Neurol 1999 Oct 18;413(2):219-31
"The dorsolateral caudate-putamen nucleus (CPN) and the nucleus accumbens (NAc) shell, respectively, are involved in many motor and limbic functions that are affected by activation of the 5-hydroxytryptamine2A receptor (5HT2AR) and the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR). We examined the functional sites for 5HT2AR activation and potential interactions involving the NMDAR subunit NR1 (NMDAR1) within these striatal regions. For this examination, sequence-specific antipeptide antisera against these receptors were localized by electron microscopic dual-labeling immunocytochemistry in the rat brain. In the dorsolateral CPN and the NAc shell, the 5HT2AR-labeled profiles were mainly dendrites, but somata and axons were also immunoreactive. The neuronal somata contained round unindented nuclei that are typical of spiny striatal neurons, although few dendritic spines were 5HT2AR immunolabeled. In all neuronal profiles, the 5HT2AR labeling was primarily associated with cytoplasmic organelles and more rarely was localized to synaptic or nonsynaptic plasma membranes. Colocalization of 5HT2AR and NMDAR1 was seen primarily in somata and dendrites. Significantly greter numbers of 5HT2AR- or 5HT2AR- and NMDAR1-containing dendrites were seen in the dorsolateral CPN than in the NAc shell. As compared with 5HT2AR, NMDAR1 labeling was more often observed in dendritic spines, and these were also more numerous in the CPN. These results indicate that 5HT2A and NMDA receptors are coexpressed but differentially targeted in single spiny striatal neurons and are likely to play a major role in control of motor functions involving the dorsolateral CPN." [Abstract]

Delle Donne KT, Sesack SR, Pickel VM.
Ultrastructural immunocytochemical localization of the dopamine D2 receptor within GABAergic neurons of the rat striatum.
Brain Res 1997 Jan 23;746(1-2):239-55
"Classical antipsychotics, which block dopamine (DA) D2 receptors, showing intrastriatal variation in their effectiveness in modulating GABAergic function. To determine the cellular basis for such differences, we examined the electron microscopic immunocytochemical labeling of D2 receptors and GABA in the dorsolateral caudate-putamen (CPn) and the nucleus accumbens (Acb) shell. In both regions, peroxidase reaction product and gold-silver deposits representing D2 receptor immunoreactivity (D2-IR) and GABA immunoreactivity (GABA-IR), respectively, were detected in dendrites and perikarya having characteristics of either spiny projection neurons or aspiny interneurons. Some perikarya in both regions are dually labeled with D2-IR and GABA-IR. Neurons axon terminals in each region also contained one or both markers. However, there were notable regional differences in the immunolabeling patterns. In the CPn, D2-IR was more commonly seen in dendrites/spines than in axon terminals, and proportionally more dendrites were dually labeled than in the Acb. In the Acb shell, D2-IR was detected with similar frequency in terminals and dendrites/spines, but more terminals co-localized D2-IR and GABA-IR in this region compared with the CPn. These results provide the first ultrastructural evidence for direct D2-mediated effects of DA on striatal GABAergic neurons. They further suggest that modulation of GABAergic neurons by DA acting at D2 receptors may be relatively more postsynaptic in the CPn, but more presynaptic in the Acb shell." [Abstract]

Khan ZU, Gutierrez A, Martin R, Penafiel A, Rivera A, de la Calle A.
Dopamine D5 receptors of rat and human brain.
Neuroscience 2000;100(4):689-99
"In contrast to dopamine D1 receptors, the anatomical distribution of D5 receptors in the CNS is poorly described. Therefore, we have studied the localization of dopamine D5 receptors in the brain of rat and human using our newly prepared subtype-specific antibody. Western blot analysis of brain tissues and membranes of cDNA transfected cells, and immunoprecipitation of brain dopamine receptors suggest that this antibody is highly selective for native dopamine D5 receptors. The D5 antibody labeled dopaminergic neurons of mesencephalon, and cortical and subcortical structures. In neostriatum, the D5 receptors were localized in the medium spiny neurons and large cholinergic interneurons. The D5 labeling in caudate nucleus was predominantly in spines of the projection neurons that were frequently making asymmetric synapses. Occasionally, the D5 receptors were also found at the symmetric synapses. Within the cerebral cortex and hippocampus, D5 antibody labeling was prominent in the pyramidal cells and their dendrites. Dopamine D5 receptors were also prominent in the cerebellum, where dopamine innervation is known to be very modest. Differences in the localization of D5 receptors between both species were generally indistinguishable except in hippocampus. In rat, the hippocampal D5 receptor was concentrated in the cell body, whereas in human it was also associated with dendrites.These results show that D5 receptors are localized in the substantia nigra-pars compacta, hypothalamus, striatum, cerebral cortex, nucleus accumbens and olfactory tubercle. Furthermore, the presence of D5 receptors in the areas of dopamine pathways suggests that this receptor may participate actively in dopaminergic neurotransmission." [Abstract]

Surmeier, D. James, Song, Wen-Jie, Yan, Zhen
Coordinated Expression of Dopamine Receptors in Neostriatal Medium Spiny Neurons
J. Neurosci. 1996 16: 6579-6591 [Full Text]

Svingos, Adena L., Moriwaki, Akiyoshi, Wang, Jia Bei, Uhl, George R., Pickel, Virginia M.
µ-Opioid Receptors Are Localized to Extrasynaptic Plasma Membranes of GABAergic Neurons and Their Targets in the Rat Nucleus Accumbens
J. Neurosci. 1997 17: 2585-2594
"The activation of µ-opioid receptors in the nucleus accumbens (Acb) produces changes in locomotor and rewarding responses that are believed to involve neurons, including local -aminobutyric acid (GABA)ergic neurons. We combined immunogold-silver detection of an antipeptide antiserum against the cloned µ-opioid receptor (MOR) and immunoperoxidase labeling of an antibody against GABA to determine the cellular basis for the proposed opioid modulation of GABAergic neurons in the rat Acb. MOR-like immunoreactivity (MOR-LI) was localized prominently to plasma membranes of neurons having morphological features of both spiny and aspiny cells, many of which contained GABA. Of 351 examples of profiles that contained MOR-LI and GABA labeling, 65% were dendrites. In these dendrites, MOR-LI was seen mainly along extrasynaptic portions of the plasma membrane apposed to unlabeled terminals and/or glial processes. Dually labeled dendrites often received convergent input from GABAergic terminals and/or from unlabeled terminals forming asymmetric excitatory-type synapses. Of all profiles that contained both MOR and GABA immunoreactivity, 28% were axon terminals. MOR-containing GABAergic terminals and terminals separately labeled for MOR or GABA formed synapses with unlabeled dendrites and also with dendrites containing MOR or GABA. Our results indicate that MOR agonists could modulate the activity of GABA neurons in the Acb via receptors located mainly at extrasynaptic sites on dendritic plasma membranes. MOR ligands also could alter the release of GABA onto target dendrites that contain GABA and/or respond to opiate stimulation." [Full Text]

Martin LJ, Blackstone CD, Huganir RL, Price DL.
The striatal mosaic in primates: striosomes and matrix are differentially enriched in ionotropic glutamate receptor subunits.
J Neurosci 1993 Feb;13(2):782-92
"The cellular and subcellular distributions of the ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-preferring glutamate receptor (GluR) in monkey striatum were demonstrated immunocytochemically using anti-peptide antibodies to individual subunits of the AMPA receptor. These antibodies specifically recognize GluR1, GluR4, and an epitope common to GluR2 and GluR3 (designated as GluR2/3). On immunoblots, the antibodies detect proteins ranging from 102 to 108 kDa in total homogenates of monkey striatum, hippocampus, and cerebellum. By immunoblotting, GluR1 and GluR2/3 are considerably more abundant than GluR4 in the caudate nucleus. Within the caudate nucleus, putamen, and nucleus accumbens, numerous neuronal perikarya, dendrites, and spines show GluR1 and GluR2/3 immunoreactivities. GluR1- and GluR2/3-enriched striatal neurons have the morphology, transmitter specificity, and distribution of medium-sized (10-20 microns) spiny neurons; large (20-60 microns) round neurons exhibit GluR4 immunoreactivity. GluR1 immunoreactivity, but not GluR2/3 or GluR4 immunoreactivity, is more intense in the ventral striatum (i.e., nucleus accumbens) than in the dorsal striatum, and GluR1 is enriched within dendritic spines in the neuropil of the nucleus accumbens and striosomes in the dorsal striatum. In the caudate nucleus, these patches of dense GluR1 immunoreactivity align with regions low in calcium binding protein immunoreactivity and high in substance P immunoreactivity. Within striosomes, GluR1 immunoreactivity is more abundant than GluR2/3 immunoreactivity; GluR4 immunoreactivity is sparse in striosomes, but the matrix contains large, GluR4-positive cholinergic neurons. This study demonstrates that, within monkey striatum, subunits of ionotropic AMPA GluR have differential distributions within striosomes and matrix. Furthermore, the results suggest that neurons within striatal striosomes and matrix may express different combinations of GluR subunits, thus forming receptors with different channel properties and having consequences that may be relevant physiologically and pathophysiologically. Neurons within these two striatal compartments may have different roles in the synaptic plasticity of motor systems." [Abstract]

Martin, Gilles, Siggins, George Robert
Electrophysiological Evidence for Expression of Glycine Receptors in Freshly Isolated Neurons from Nucleus Accumbens
J Pharmacol Exp Ther 2002 302: 1135-1145
"In the course of studying N-methyl-D-aspartate (NMDA) receptors of the nucleus accumbens (NAcc), we found that 20% of freshly isolated medium spiny neurons, as well as all interneurons, responded in an unexpected way to long (5-s) coapplication of NMDA and glycine, the coagonist of NMDA receptors. Whereas the reversal potential of the peak NMDA current of this subset of neurons was still around 0 mV, the desensitizing current became outward at hyperpolarized potentials around 30 mV. A Cl-free solution shifted the equilibrium potentials of the desensitized currents to around 0 mV. This outward current was not blocked by a Ca2+-free, Ba2+-containing solution, suggesting that the anionic conductance was not activated by Ca2+ influx through NMDA receptor channels. Interestingly, glycine alone also evoked a current with a similar hyperpolarized reversal potential in this subset of neurons. The glycine current reversed around 50 mV, rectified outwardly, and inactivated strongly. Its desensitization was best fitted with a double exponential. Only the slow desensitization showed clear voltage dependence. The glycine current was not blocked by 200 µM picrotoxin and 10 µM zinc, was weakly antagonized by 1 µM strychnine, and was not enhanced by 1 µM zinc. In addition, 1 mM taurine, but not GABA, inactivated glycine currents, and 1 mM glycine occluded 10 mM taurine-mediated currents. These data indicate that a subset of nucleus accumbens neurons expresses glycine receptors and that either glycine or taurine could be an endogenous agonist for these receptors." [Abstract]

Svenningsson P, Le Moine C, Aubert I, Burbaud P, Fredholm BB, Bloch B.
Cellular distribution of adenosine A2A receptor mRNA in the primate striatum.
J Comp Neurol 1998 Sep 21;399(2):229-40
"The cellular expression of adenosine A2A receptor mRNA in the adult monkey and human striatum was examined by using single and double in situ hybridization with ribonucleotide probes. Analysis on adjacent sections demonstrated a homogeneous overlapping expression of adenosine A2A receptor and preproenkephalin A mRNAs throughout nucleus caudatus, putamen, and nucleus accumbens. By contrast, high expression of preproenkephalin A mRNA but no expression of adenosine A2A receptor mRNA was found in the nucleus basalis of Meynert. Double in situ hybridization demonstrated an extensive colocalization of adenosine A2A receptor and preproenkephalin A mRNAs in approximately 50% of the medium-sized spiny neurons of the monkey nucleus caudatus, putamen, and nucleus accumbens. A small number of neurons (4-12%) that contained adenosine A2A receptor mRNA but not preproenkephalin A mRNA was found along the ventral borders of the striatum. Virtually all adenosine A2A receptor mRNA-containing neurons co-expressed dopamine D2 receptor mRNA, whereas only very few adenosine A2A receptor mRNA containing neurons co-expressed dopamine D1 receptor or substance P mRNAs. In addition, a sub-population of adenosine A2A receptor mRNA-expressing neurons that also contained preproenkephalin A mRNA was found in the septum in monkeys. These results demonstrate that there is a high expression of adenosine A2A receptor mRNA in the primate striatum that is extensively co-localized with dopamine D2 receptor and preproenkephalin A mRNAs. It is concluded that adenosine A2A receptors are likely to be important for the parallel organization of primate striatal neurotransmission and that these receptors could be a target for drug therapy in Parkinson's disease." [Abstract]

DeMet EM, Chicz-DeMet A.
Localization of adenosine A(2A)-receptors in rat brain with [(3)H]ZM-241385.
Naunyn Schmiedebergs Arch Pharmacol 2002 Nov;366(5):478-81
"Adenosine plays a key role in the regulation of tissue oxygenation, neuronal firing, and neurotransmitter release. Four receptor subtypes have been identified and cloned: A(1), A(2A), A(2B), and A(3), although only A(1) and A(2A) receptors are prominent in rat brain. Much evidence now indicates that A(2A) receptors (A(2A)R) are highly enriched within striatal medium-sized spiny GABAergic neurons where they are closely associated with, and modulate, D(2)-dopaminergic receptors involved in motor control and reward behaviors. There is also consensus that A(2A)R are present in the nucleus accumbens and olfactory tubercle where they have been postulated to interact with prostaglandins in the regulation of sleep. There is less agreement as to whether or not A(2A)R are present in other brain regions. The present study describes an autoradiographic procedure that utilizes [(3)H]ZM-241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-alpha][1,3,5]triazin-5-ylamino]ethyl)phenol), a highly selective A(2A)-receptor ligand. Saturable specific binding was found in the rat caudate putamen with a K(d)=1.1 nM and B(max)=1150 fmol/mg. Binding was also found in the nucleus accumbens and the olfactory tubercle, but was not detected in extra-striatal brain regions." [Abstract]

James M. Brundege, and John T. Williams
Increase in Adenosine Sensitivity in the Nucleus Accumbens Following Chronic Morphine Treatment
J Neurophysiol 87: 1369-1375, 2002.
"There is a growing body of evidence suggesting that the neuromodulator adenosine is involved in drug addiction and withdrawal and that adenosine signaling pathways may offer new targets for therapeutic treatments of addiction. Recent studies have suggested that chronic exposure to drugs of abuse may alter adenosine metabolism in the nucleus accumbens, a brain region critically involved in drug addiction and withdrawal. The present study examined the effects of chronic morphine treatment on the ability of adenosine to inhibit excitatory postsynaptic currents in nucleus accumbens medium spiny neurons. It was found that chronic morphine treatment via subcutaneous implantation of morphine pellets in rats for 1 wk did not alter the level of adenosine-mediated tonic inhibition of nucleus accumbens excitatory synapses. However, chronic morphine treatment did induce a leftward shift in the adenosine dose-response curve, indicating an increase in the sensitivity of synaptic currents to exogenously applied adenosine. This shift was not due to a change in adenosine receptors or their effectors, because chronic morphine treatment had no effect on the dose-response relationship of a nonmetabolized adenosine receptor agonist. When adenosine transport was blocked, the ability of chronic morphine to shift the adenosine dose-response curve was eliminated. These experiments suggest that the increase in the sensitivity of nucleus accumbens synapses to the inhibitory effects of adenosine may be due to a decrease in adenosine transport. The identification of these changes in the adenosine system after chronic drug exposure may help identify new therapeutic strategies aimed at easing withdrawal from opioids." [Abstract]

Manzoni, Olivier, Pujalte, Didier, Williams, John, Bockaert, Joel
Decreased Presynaptic Sensitivity to Adenosine after Cocaine Withdrawal
J. Neurosci. 1998 18: 7996-8002
"The nucleus accumbens (NAc) is a site mediating the rewarding properties of drugs of abuse, such as cocaine, amphetamine, opiates, nicotine, and alcohol (Wise and Bozarth, 1987; Koob, 1992; Samson andHarris, 1992; Woolverton and Johnson, 1992; Self and Nestler, 1995; Pontieri et al., 1996). Acute cocaine has been shown to decrease excitatory synaptic transmission mediated by the cortical afferents to the NAc (Nicola et al., 1996), but the effects of long-term cocaine treatment and withdrawal have not been explored. Here, we report that long-term (1 week) withdrawal from chronic cocaine reduced the potency of adenosine to presynaptically inhibit glutamate (Glu) release by activating adenosine A1 receptors. Adenosine A1 receptors were not desensitized, because the potency of the metabolically stable adenosine analog N6-cyclopentyl-adenosine was unchanged after chronic cocaine withdrawal. When adenosine transporters were blocked, the potency of adenosine to inhibit Glu release from naive and cocaine-withdrawn NAc slices was similar. These results suggest that one of the long-term consequences of cocaine withdrawal is an augmented uptake of adenosine. This long-lasting change expressed at the presynaptic excitatory inputs to the medium spiny output neurons in the NAc may help identify new therapeutic targets for the treatment of drug abuse." [Full Text]

Pickel VM, Beck-Sickinger AG, Chan J, Weiland HA.
Y1 receptors in the nucleus accumbens: ultrastructural localization and association with neuropeptide Y.
J Neurosci Res 1998 Apr 1;52(1):54-68
"Neuropeptide Y (NPY) is present in aspiny neurons in the nucleus accumbens (NAc), which also contains moderate levels of ligand binding and mRNA for the Y1 receptor. To determine the potential functional sites for receptor activation, we examined the electron microscopic immunocytochemical localization of antipeptide antisera against the Y1 receptor in the rat NAc. We also combined immunogold and immunoperoxidase labeling to show that, in this region, Y1 receptors are present in certain somatodendritic and axonal profiles that contain NPY or that appose NPY containing neurons. The Y1-like immunoreactivity (Y1-LI) was seen occasionally along plasma membranes but was associated more commonly with smooth endoplasmic reticulum (SER) and tubulovesicular organelles in somata and dendrites of spiny and aspiny neurons. The mean density of immunoreactive dendrites and spines per unit volume was greater in the "motor-associated" core than in the shell of the NAc. Y1-LI was also seen in morphologically heterogenous axon terminals, including those forming asymmetric excitatory-type synapses, and in selective astrocytic processes near this type of junction. We conclude that Y1 receptors play a role in autoregulation of NPY-containing neurons but are also likely to be internalized along with endogenous NPY in NAc. Our results also implicate Y1 receptors in the NAc in post- and presynaptic effects of NPY and in glial functions involving excitatory neurotransmission. In addition, they suggest involvement of Y1 receptors in determining the output of a select population of neurons associated with motor control in the NAc core." [Abstract]

Pillot C, Heron A, Cochois V, Tardivel-Lacombe J, Ligneau X, Schwartz J, Arrang J.
A detailed mapping of the histamine H(3) receptor and its gene transcripts in rat brain.
Neuroscience 2002;114(1):173
"The presence of mRNAs in the substantia nigra pars compacta suggests that H(3) receptors are located upon nigrostriatal afferents. However, the absence of any signal in the ventral tegmental area indicates that some but not all dopaminergic neurons express H(3) receptors. In addition, the homogeneous mRNA expression within the caudate putamen and nucleus accumbens suggests that many striatal H(3) receptors are present on medium-sized, spiny projection neurons of both the direct and indirect movement pathways. In agreement, a dense binding, but low mRNA expression, is observed in external and internal pallidum and in substantia nigra pars reticulata." [Abstract]

Wang JQ, McGinty JF.
Scopolamine augments c-fos and zip/268 messenger RNA expression induced by the full D(1) dopamine receptor agonist SKF-82958 in the intact rat striatum.
Neuroscience 1996 Jun;72(3):601-16
"It is generally accepted that the widely used, partial dopamine D(1) receptor agonist, SKF-38393, does not induce immediate early gene expression in striatal projection neurons unless D(1) receptors are sensitized and uncoupled from D(2) receptors by 6-hydroxydopamine lesions or reserpine treatment. In contrast, this study demonstrates, using quantitative in situ hybridization, that the full D(1) receptor agonist, SKF-82958, induced robust expression of c-fos and zif/268 messenger RNAs in the intact rat striatum, especially in the entire shell and medial and ventral core areas of the nucleus accumbens and olfactory tubercle, and in the cerebral cortex, 45 min after one injection. The induction of the striatal immediate early genes is characterized by (i) induction in only medium-sized spiny neurons, (ii) dose-dependent induction, which correlates well with dose-dependent increases in motor activity, and (iii) blockade by the D(1) receptor antagonist, SCH-23390. The muscarinic cholinergic receptor antagonist, scopolamine, which itself did not alter striatal gene expression, profoundly augmented the behaviors and expression of the two immediate early genes in the ventral and dorsal striatum induced by 0.1, 0.5 and 2.0 mg/kg SKF-82958. However, scopolamine attenuated basal, and SKF-82958-stimulated, expression of c-fos and zif/268 messenger RNAs in the cortex. Scopolamine also enabled SKF-38393 to induce locomotor stimulation and c-fos and zif/268 messenger RNA expression in the normosensitive striatum of the rat when SKF-38393 alone caused no such changes. These data demonstrate an ability of SKF-82958 to induce immediate early gene messenger RNA expression in normosensitive dorsal and ventral striatum. Furthermore, intrinsic muscarinic receptor-mediated cholinergic transmission in the striatum may provide an activity-dependent inhibitory control on striatal D(1) receptor stimulation." [Abstract]

Wang JQ, Smith AJ, McGinty JF.
A single injection of amphetamine or methamphetamine induces dynamic alterations in c-fos, zif/268 and preprodynorphin messenger RNA expression in rat forebrain.
Neuroscience 1995 Sep;68(1):83-95
"In this study, the effects of a single dose of the indirect dopamine agonists amphetamine and methamphetamine on behavior and messenger RNA expression were evaluated. Expression of c-fos, a member of the leucine zipper family, zif/268 (NGFI-A, egr1 and Krox-24), a member of the zinc finger family, and the opioid peptide, preprodynorphin, was investigated in various regions of rat forebrain with quantitative in situ hybridization histochemistry 1, 2, 3, 6 or 30 h after injection. Behavioral observations indicated that a qualitatively different behavioral syndrome was induced following methamphetamine (15 mg/kg, i.p.) as compared with that observed after amphetamine (5 mg/kg, i.p.). Similarly, methamphetamine induced a different pattern of c-fos and zif/268 messenger RNA induction in sensory/motor cortex, dorsal striatum (caudatoputamen) and ventral striatum (nucleus accumbens) than did amphetamine. The increase in c-fos messenger RNA expression peaked at 1 h and returned to basal levels in all regions by 3 h. In contrast, the increase in zif/268 messenger RNA expression in the cortical regions was equally strong at 1 and 2 h, gradually returning to basal levels by 6 h after either drug. However, in the striatal regions, zif/268 messenger RNA levels peaked at 1 h and declined gradually to basal levels by 6 h. Interestingly, methamphetamine caused an actual suppression of zif/268 gene expression (> 50%) in both caudatoputamen and nucleus accumbens at 3 h. Preprodynorphin messenger RNA expression was increased in a patchy motif in the caudatoputamen and nucleus accumbens beginning at 2 h and returning to basal levels by 30 h after injection of either drug. This study, together with our recently published observation that preprodynorphin messenger RNA is induced in the caudate 3, 6 and 18 h after amphetamine or methamphetamine injection, provides a detailed dynamic description of the differential modulation of c-fos, zif/268 and preprodynorphin messenger RNA expression in the cerebral cortex and striatum by amphetamines over time. These data implicate immediate early gene and preprodynorphin gene expression in the differential response of medium spiny striatal neurons to methamphetamine and amphetamine." [Abstract]

Hidaka S, Totterdell S.
Ultrastructural features of the nitric oxide synthase-containing interneurons in the nucleus accumbens and their relationship with tyrosine hydroxylase-containing terminals.
J Comp Neurol 2001 Mar 5;431(2):139-54
"The ultrastructural features of neuronal nitric oxide synthase (NOS) -immunoreactive interneurons of rat nucleus accumbens shell and core were studied and compared. The NOS-containing subpopulation displayed characteristics similar to those previously