Bipolar Disorder and Dopamine -- Neurotransmitter.net

(Updated 8/25/04)

Gerner RH, Fairbanks L, Anderson GM, Young JG, Scheinin M, Linnoila M, Hare TA, Shaywitz BA, Cohen DJ.
CSF neurochemistry in depressed, manic, and schizophrenic patients compared with that of normal controls.
Am J Psychiatry 1984 Dec;141(12):1533-40
"A total of 114 subjects (41 depressed, 20 schizophrenic, 15 manic, and 38 normal controls) underwent lumbar puncture and their CSF was analyzed for levels of tyrosine, tryptophan, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), choline, gamma-aminobutyric acid (GABA), and calcium. Results showed that depressed patients, particularly those over 40 years of age, had lower levels of GABA than did controls, and that their level of HVA increased with age, while controls' decreased. Schizophrenic subjects tended to have higher levels of 5-HIAA and manic subjects tended to have higher levels of HVA and MHPG. Age-associated changes were found in HVA, 5-HIAA, MHPG, GABA, and choline concentrations." [Abstract]

Tandon R, Channabasavanna SM, Greden JF.
CSF biochemical correlates of mixed affective states.
Acta Psychiatr Scand 1988 Sep;78(3):289-97
"To evaluate the question of whether "mixed" bipolar disorder is a distinct entity, we compared selected cerebrospinal fluid (CSF) biochemical parameters from patients with bipolar disorder, mixed, to those with mania and major depression. Fourteen patients in each category (DSM-III) were studied with regard to CSF HVA, 5HIAA, sodium, potassium, calcium, and magnesium levels under carefully controlled conditions. CSF HVA, 5HIAA, and sodium were found to be significantly higher in manics than in major depressives. Discriminant analysis of the biochemical variables of the mixed affective group identified two biochemically distinct and clinically different subgroups of seven patients each, one resembling the manic group and the other the major depressive group." [Abstract]

Joyce PR, Fergusson DM, Woollard G, Abbott RM, Horwood LJ, Upton J.
Urinary catecholamines and plasma hormones predict mood state in rapid cycling bipolar affective disorder.
J Affect Disord 1995 Apr 4;33(4):233-43
"Over the course of 1 year, a patient with a rapid cycling bipolar affective disorder was followed at weekly intervals to examine whether plasma hormones and urinary catecholamines could predict current or future mood. Higher cortisol levels were found to predict depressed mood 3 days after blood sampling, higher urinary dopamine predicted a manic mood 3 days after blood sampling, urinary norepinephrine was associated with severity of current mood and prolactin was lower with concurrent depressed mood. In multivariate analyses of mood against cortisol, prolactin and three urinary catecholamines, > 50% of the variance in mood state in 3 days was explained by combinations of these biologic measures, especially cortisol and urinary dopamine, while all five biologic variables contributed to explaining 50% of the variance in current mood state. Based on the interrelationships between urinary dopamine, norepinephrine and mood, we postulate the existence of an overcompensating mechanism which is reflected in opposing correlations between urinary dopamine and norepinephrine with mood, despite the two urinary catecholamines being positively correlated." [Abstract]

Chou JC, Czobor P, Tuma I, Charles O, Bebe R, Cooper TB, Chang WH, Lane HY, Stone DL.
Pretreatment plasma HVA and haloperidol response in acute mania.
J Affect Disord. 2000 Jul;59(1):55-9.
"INTRODUCTION: Pretreatment plasma homovanillic acid (HVA) levels have been reported to be a correlate of clinical response to typical antipsychotics for schizophrenic, bipolar manic, and mixed groups of psychotic patients. Biological markers of clinical response to antipsychotics could be useful for optimizing drug treatment. METHOD: Thirty-one consenting acute inpatient subjects between ages 19 and 66 years with a DSM-III-R clinical diagnosis of bipolar disorder, manic with psychotic features were entered into this double-blind study and were randomly assigned to receive either haloperidol 25 mg/day or haloperidol 5 mg for the 3-week study. Subjects also received one of the following concomitant medications: standard lithium, lorazepam 4 mg/day, or placebo. RESULTS: The primary multiple regression analysis, including all subjects on both haloperidol doses, yielded a significant main effect for pretreatment plasma HVA (n=31, F=5.7, P=0.025), indicating that higher pretreatment plasma HVA was predictive of better clinical response. In addition, the interaction between haloperidol dose and pretreatment plasma HVA was also significantly associated with clinical response (F=12.59, P=0.0015). When the two haloperidol doses were analyzed separately, we found that pretreatment plasma HVA was only correlated with clinical response in the low haloperidol 5 mg/day group (n=18, F=11.73, P=0.0038) and was unrelated to clinical response to the high haloperidol 25 mg/day group. LIMITATIONS: The sample size was small. Results may have been confounded by prior antipsychotic treatment and concomitant use of lithium or lorazepam. DISCUSSION: These results suggest that pretreatment plasma HVA could be useful for dosing antipsychotics. Patients with high plasma HVA levels would be good candidates for low-dose treatment because they are more likely to improve on such a dose, while patients with low plasma HVA levels might warrant more rapid dosage escalation." [Abstract]

Fortunati F, Mazure C, Preda A, Wahl R, Bowers M Jr.
Plasma catecholamine metabolites in antidepressant-exacerbated mania and psychosis.
J Affect Disord 2002 Apr;68(2-3):331-4
"We measured plasma free HVA and MHPG in 39 cases of psychosis or mania judged to be caused by antidepressant exacerbation of symptoms. A total of 24 of patients had been receiving selective serotonin reuptake inhibitors (SSRI's). The SSRI group showed a pattern of increased plasma HVA similar to a comparison group of patients with a psychotic/manic relapse secondary to medication non-compliance." [Abstract]

Mazure CM, Bowers MB.
Pretreatment plasma HVA predicts neuroleptic response in manic psychosis.
J Affect Disord 1998 Feb;48(1):83-6
"Elevated pretreatment plasma free homovanillic acid (HVA) predicted acute response to neuroleptic treatment in patients with manic psychosis. These findings suggest that plasma HVA may be a useful predictor of a successful short-term response in manic as well as schizophrenic psychoses, and that elevated pre-synaptic dopaminergic release may play a role in more than one group of psychotic disorders." [Abstract]

Post RM, Jimerson DC, Bunney WE Jr, Goodwin FK.
Dopamine and mania: behavioral and biochemical effects of the dopamine receptor blocker pimozide.
Psychopharmacology (Berl) 1980;67(3):297-305
"Although recent data suggest that pimozide has effects at other neurotransmitter receptor sites, it is one of the more specific neuroleptics in its effects on dopamine receptors. We report that in manic patients pimozide produces substantial clinical improvement with a magnitude and time course similar to that observed with the more routinely used phenothiazines chlorpromazine and thioridazine. Pimozide did not significantly increase probenecid-induced accumulations of the dopamine metabolite homovanillic acid (HVA) compared to pretreatment values. Higher HVA values were observed in manic than in nonmanic patients, however. These clinical and biochemical data add to a growing body of indirect evidence that a dopaminergic alteration may be associated with some components of the manic syndrome." [Abstract]

Gerner RH, Post RM, Bunney WE Jr.
A dopaminergic mechanism in mania.
Am J Psychiatry 1976 Oct;133(10):1177-80
"The authors present a case study that explores the relationship of dopamine function and manic illness through the use of two drugs with relatively specific effects in stimulating and blocking dopamine receptors--piribedil (ET--495) and pimozide, respectively. Piribedil, as well as d-amphetamine, was associated with manic episodes, while pimozide had an antimanic effect. These observations suggest that dopaminergic mechanisms may be involved in the mediation of manic episodes in at least some patients." [Abstract]

Anand, Amit, Verhoeff, Paul, Seneca, Nicholas, Zoghbi, Sami S., Seibyl, John P., Charney, Dennis S., Innis, Robert B.
Brain SPECT Imaging of Amphetamine-Induced Dopamine Release in Euthymic Bipolar Disorder Patients
Am J Psychiatry 2000 157: 1108-1114
"In a group of euthymic patients with bipolar disorder, this study did not find evidence for increased striatal dopamine release. Instead, these data are consistent with enhanced postsynaptic dopamine responsivity in patients with bipolar disorder." [Abstract]

Wieck A, Davies RA, Hirst AD, Brown N, Papadopoulos A, Marks MN, Checkley SA, Kumar RC, Campbell IC.
Menstrual cycle effects on hypothalamic dopamine receptor function in women with a history of puerperal bipolar disorder.
J Psychopharmacol. 2003 Jun;17(2):204-9.
"Neuroendocrine challenge tests of hypothalamic dopamine receptor function in the early postpartum period suggest that the sensitivity of these receptors is increased in women with a history of bipolar disorder after childbirth. We tested the hypothesis that, in women predisposed to bipolar disorder in the puerperium, hypothalamic dopamine receptor function is more sensitive to changes in circulating ovarian hormone concentrations than in women without such histories. Eight fully recovered and drug-free women who had had at least one episode of bipolar illness following childbirth were compared with nine normal controls. Growth hormone (GH) responses to apomorphine (APO 0.005 mg s.c.) were measured in the early follicular phase, when plasma concentrations of ovarian hormones are low, and in the mid-luteal phase, when they are relatively high. The recovered bipolar subjects and the controls did not differ from each other in their follicular and midluteal oestrogen and progesterone concentrations. In the midluteal phase, both groups had increased oestrogen and progesterone levels. The recovered bipolar subjects did not differ from controls in baseline concentrations of GH in either of the menstrual phases. The APO-GH responses of the two groups did not differ in the follicular phase, but in the midluteal phase, when female sex steroids are relatively increased, the recovered group had significantly enhanced APO-GH responses [MANOVA for repeated measures: (i) area under the curve, group by phase effect: p < 0.04; (ii) GH peak rise after APO, group by phase effect: p < 0.056] and the responses were not related to concurrent measures of mood. The results of this small study of women predisposed to bipolar disorder in the puerperium shows an increased dopaminergic receptor sensitivity in the luteal phase of the menstrual cycle. It suggests that their dopaminergic systems have increased sensitivity to changes in circulating female sex steroids. This may be aetiologically relevant to the pathogenesis of puerperal bipolar disorder." [Abstract]

Graf WD, Unis AS, Yates CM, Sulzbacher S, Dinulos MB, Jack RM, Dugaw KA, Paddock MN, Parson WW.
Catecholamines in patients with 22q11.2 deletion syndrome and the low-activity COMT polymorphism.
Neurology 2001 Aug 14;57(3):410-6
"OBJECTIVE: To investigate catecholamine phenotypes and the effects of a tyrosine hydroxylase inhibitor in individuals with the 22q11.2 deletion syndrome and low-activity catechol-O-methyltransferase (COMT). BACKGROUND: Many persons with the 22q11.2 deletion syndrome suffer severe disability from a characteristic ultrarapid-cycling bipolar disorder and associated "affective storms." One etiologic hypothesis for this condition is that deletion of the COMT gene from one chromosome 22 results in increased catecholamine neurotransmission, particularly if the undeleted chromosome 22 encodes a variant of COMT with low activity. METHODS: In a preliminary study, plasma, urine, and CSF catecholamines and catecholamine metabolites were measured in four teenage patients with a neuropsychiatric condition associated with 22q11.2 deletion and the low-activity COMT polymorphism on the nondeleted chromosome. In these four patients, and an additional institutionalized adult with the condition, an uncontrolled, open-label trial of metyrosine was administered in an attempt to lower catecholamine production and to alleviate symptoms. RESULTS: Mild elevations of baseline CSF homovanillic acid (HVA) were found in three of four patients and a moderate reduction in CSF HVA after metyrosine treatment in the patient with the highest pretreatment concentration. The course of the five patients during the clinical trial is described. CONCLUSIONS: In patients with the 22q11.2 deletion syndrome and low-activity COMT, controlled studies of pharmacologic agents that decrease catecholamine production, block presynaptic catecholamine storage, or enhance S-adenosylmethionine, the cosubstrate of COMT, are warranted." [Abstract]
Linnoila M, Karoum F, Potter WZ.
Effects of antidepressant treatments on dopamine turnover in depressed patients.
Arch Gen Psychiatry 1983 Sep;40(9):1015-7
"Effects of five antidepressant treatments--clorgyline, desipramine hydrochloride, electroconvulsive treatment, lithium carbonate, and zimelidine hydrochloride--on urinary outputs of dopamine, dihydroxyphenylacetic acid, and homovanillic acid (HVA) were investigated in unipolar and bipolar depressed patients. Clorgyline and lithium carbonate, which stabilized mood in bipolar patients, reduced the urinary output of HVA and whole-body dopamine turnover. Electroconvulsive treatment and zimelidine were without major effects, whereas desipramine had variable effects on these indexes of dopamine metabolism. Three patients, two receiving desipramine and one receiving clorgyline, who had increased HVA output during the drug treatments, became severely agitated and delusional." [Abstract]
Swann AC, Koslow SH, Katz MM, Maas JW, Javaid J, Secunda SK, Robins E.
Lithium carbonate treatment of mania. Cerebrospinal fluid and urinary monoamine metabolites and treatment outcome.
Arch Gen Psychiatry 1987 Apr;44(4):345-54
"Treatment of manic patients with lithium carbonate was associated with significant decreases in cerebrospinal fluid (CSF) 3-methoxy-4-hydroxyphenylglycol (MHPG) and urinary norepinephrine excretion. These measures, before treatment, were higher in manic patients than in either depressed or normal subjects and correlated significantly with severity of mania. Levels in CSF of homovanillic acid and 5-hydroxyindoleacetic acid did not correlate with severity or with change during lithium carbonate treatment. Responders (about 70% of the patients) did not differ from nonresponders in pretreatment mania ratings or neurotransmitter measures. The CSF MHPG and urinary norepinephrine excretion were reduced during lithium carbonate treatment in both responders and nonresponders. Unlike the case before treatment, urinary MHPG excretion was higher during treatment in nonresponders than in responders and correlated with several indexes of symptom severity. These results support a relationship between mania and increased noradrenergic function. Treatment outcome, however, was not related exclusively to the reduction of noradrenergic indexes by lithium carbonate since reductions were similar in both responders and nonresponders. Reduced noradrenergic activity may therefore be necessary but not sufficient for successful outcome during lithium carbonate treatment." [Abstract]
Post RM.
Time course of clinical effects of carbamazepine: implications for mechanisms of action.
J Clin Psychiatry 1988 Apr;49 Suppl:35-48
"The relatively acute time course of antimanic efficacy may be related to the above-mentioned mechanisms or to other effects related to systems postulated to be altered in the manic syndrome. These effects might include carbamazepine's ability to increase acetylcholine in the striatum, decrease probenecid-induced levels of CSF homovanillic acid (HVA) in man and dopamine turnover in animals, decrease CSF norepinephrine in manic patients, inhibit adenylate cyclase activity (in response to norepinephrine, dopamine, adenosine, or ouabain), decrease GABA turnover, or act as a vasopressin agonist." [Abstract]
Swann AC, Secunda S, Davis JM, Robins E, Hanin I, Koslow SH, Maas JW.
CSF monoamine metabolites in mania.
Am J Psychiatry 1983 Apr;140(4):396-400
"As part of the National Institute of Mental Health Clinical Research Branch Collaborative Program on the Psychobiology of Depression, the authors compared concentrations of CSF monoamine metabolites (the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol [MHPG], the dopamine metabolite homovanillic acid [HVA], and the serotonin metabolite 5-hydroxyindoleacetic acid [5-HIAA]) from 14 hospitalized manic patients with concentrations from 62 healthy comparison subjects. The manic patients had significantly higher levels of MHPG. Levels of 5-HIAA and HVA did not differ between the manic patients and the comparison male subjects, but they were elevated in the female manic patients. MHPG was the only metabolite that correlated significantly with mania symptom ratings. These data are consistent with findings that have shown abnormal, perhaps excessive, central noradrenergic activity in patients with mania, but not with those suggesting deficits in serotoninergic function." [Abstract]
Koh PO, Undie AS, Kabbani N, Levenson R, Goldman-Rakic PS, Lidow MS.
Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic and bipolar patients.
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):313-7. Epub 2002 Dec 20.
"The delineation of dopamine dysfunction in the mentally ill has been a long-standing quest of biological psychiatry. The present study focuses on a recently recognized group of dopamine receptor-interacting proteins as possible novel sites of dysfunction in schizophrenic and bipolar patients. We demonstrate that the dorsolateral prefrontal cortex in schizophrenia and bipolar cases from the Stanley Foundation Neuropathology Consortium display significantly elevated levels of the D2 dopamine receptor desensitization regulatory protein, neuronal calcium sensor-1. These levels of neuronal calcium sensor-1 were not influenced by age, gender, hemisphere, cause of death, postmortem period, alcohol consumption, or antipsychotic and mood stabilizing medications. The present study supports the hypothesis that schizophrenia and bipolar disorder may be associated with abnormalities in dopamine receptor-interacting proteins." [Abstract]

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Recent Bipolar Disorder & Dopamine Research
1) Samalin L, Garnier M, Llorca PM
Clinical potential of lurasidone in the management of schizophrenia.
Ther Clin Risk Manag. 2011;7:239-50.
Lurasidone is a new second-generation antipsychotic approved in October 2010 by the Food and Drug Administration for the treatment of schizophrenia. Like other second-generation antipsychotics, lurasidone is a powerful antagonist of D(2) dopamine and 5HT(2A) serotonin receptors, but differs from the other second-generation antipsychotics in its action profile for certain receptors. Lurasidone is the second-generation antipsychotic with the greatest affinity for 5HT(7) receptors and has a high affinity for 5HT(1A) serotonin receptors, compatible with favorable effects on cognitive function and an antidepressant action. By contrast, lurasidone has a low affinity for and ?(1) ?(2C)-adrenergic and 5HT(2C) serotonin receptors, and no affinity for histaminergic H(1) or muscarinic M(1) receptors, suggesting a better tolerability profile than the other second-generation antipsychotics. Lurasidone has demonstrated its efficacy in several short-term trials in acute schizophrenia, promptly and significantly reducing total Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale scores compared with placebo. Several long-term studies are in progress to assess its efficacy in the maintenance treatment of schizophrenic patients. The efficacy of lurasidone with regard to cognitive functions and depressive symptoms seems good, but requires further work. Lurasidone differs from the other second-generation antipsychotics by having a good tolerability profile, in particular for cardiometabolic tolerability. However, it seems to have a significant although moderate link with the occurrence of akathisia, extrapyramidal symptoms, and hyperprolactinemia at the start of treatment. This tolerance profile greatly broadens the scope of second-generation antipsychotics and so supports the view of some authors that the term "second-generation antipsychotic" is now outdated. Other therapeutic perspectives of lurasidone are assessed here, in particular bipolar depression. [PubMed Citation] [Order full text from Infotrieve]

2) Beaulieu JM
A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health.
J Psychiatry Neurosci. 2011 Jul 1;36(4):110011.
Mental illnesses, such as bipolar disorder, attention-deficit/hyperactivity disorder, depression and schizophrenia are a major public health concern worldwide. Several pharmacologic agents acting on monoamine neurotransmission are used for the management of these disorders. However, there is still little understanding of the ultimate molecular mechanisms responsible for the therapeutic effects of these drugs or their relations with disease etiology. Here I provide an overview of recent advances on the involvement of the signalling molec ules Akt and glycogen synthase kinase-3 (GSK3) in the regulation of behaviour by the monoamine neurotransmitters dopamine (DA) and serotonin (5-HT). I examine the possible participation of these signalling molecules to the effects of antidepressants, lithium and antipsychotics, as well as their possible contribution to mental disorders. Regulation of Akt and GSK3 may constitute an important signalling hub in the subcellular integration of 5-HT and DA neurotransmission. It may also provide a link between the action of these neurotransmitters and gene products, like disrupted in schizophrenia 1 (DISC1) and neuregulin (NRG), that are associated with increased risk for mental disorders. However, changes in Akt and GSK3 signalling are not restricted to a single disorder, and their contribution to specific behavioural symptoms or therapeutic effects may be modulated by broader changes in biologic contexts or signalling landscapes. Under standing these interactions may provide a better understanding of mental illnesses, leading to better efficacy of new therapeutic approaches. [PubMed Citation] [Order full text from Infotrieve]

3) Levin R, Calzavara MB, Santos CM, Medrano WA, Niigaki ST, Ab�lio VC
Spontaneously Hypertensive Rats (SHR) present deficits in prepulse inhibition of startle specifically reverted by clozapine.
Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jun 13;
Deficits in an operational measure of sensorimotor gating - the prepulse inhibition of startle (PPI) - are presented in psychiatric disorders such as schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD). Some previous studies showed that the spontaneously hypertensive rats (SHR) present PPI deficit. Although SHR is suggested as an animal model to study ADHD, we have suggested that the behavioral phenotype of this strain mimics some aspects of schizophrenia. The aim of this study was to characterize the PPI response in SHR. Pharmacological characterization consisted in the evaluation of the effects of the following drugs administered to adult Wistar rats (WR) and SHR previously to the PPI test: amphetamine (used for ADHD and also a psychotomimetic drug), haloperidol and clozapine (antipsychotic drugs), metoclopramide (dopamine antagonist without antipsychotic properties) and carbamazepine (mood stabilizer). Our results showed that SHR presented reduced PPI. This deficit was similar to that induced by amphetamine in WR. Only the atypical antipsychotic clozapine improved the PPI deficit observed in SHR. These findings reinforce the SHR strain as an animal model to study several aspects of schizophrenia, including the abnormalities in sensorimotor gating associated with this disease. [PubMed Citation] [Order full text from Infotrieve]

4) Chevreuil C, Polard E, Lemonnier E, Guillemot P, Bentu�-Ferrer D
[Aripiprazole Use in Children and Adolescent Psychiatric Patients.]
Therapie. 2011 3-4;66(2):123-130.
Aripiprazole inaugurates a new generation of antipsychotics called dopamine-serotonin system stabilizers. Its mechanism of action is different as aripiprazole is a partial dopamine D(2) and serotonin 5-HT(1A) receptor agonist and 5-HT(2A) receptor antagonist. Therefore, aripiprazole is thought to have an antagonistic action in the mesolimbic pathway but an agonistic action in the mesocortical pathway, tending to normalize the dopaminergic transmission regardless of the type of imbalance. Clinical trials involving children and adolescents have demonstrated the efficacy of aripiprazole in bipolar disorders, schizophrenia, mood disorders associated with pervasive developmental disorders, in tics and Tourette's. The most frequent side effects are extrapyramidal symptoms and sleepiness and are dose-dependant. Nevertheless, contrary to other second-generation antipsychotics available in France, it induces little weight gain, does not modify lipid and glucidic profiles, does not increase prolactin levels, or induce QTc lengthening. The main advantage of aripiprazole is its good safety profile, with different toxicity targets to other second-generation antipsychotics available in France. Aripiprazole appears to be an alternative for children and adolescents who are vulnerable to these side effects and are having trouble coping with them. [PubMed Citation] [Order full text from Infotrieve]

5) Dean OM, van den Buuse M, Berk M, Copolov DL, Mavros C, Bush AI
N-acetyl cysteine restores brain glutathione loss in combined 2-cyclohexene-1-one and d-amphetamine-treated rats: Relevance to schizophrenia and bipolar disorder.
Neurosci Lett. 2011 Jul 25;499(3):149-53.
Oxidative stress and reduced brain levels of glutathione have been implicated in schizophrenia and bipolar disorder. N-acetyl cysteine (NAC) is a precursor of glutathione and has additional effects on glutamate neurotransmission, neurogenesis and inflammation. While NAC treatment has shown benefits in both schizophrenia and bipolar disorder, the mechanisms of action are largely unknown. Similarly, the interaction between oxidative stress and altered dopaminergic activities in psychiatric illness is not yet characterized. This study investigated the capacity of NAC in restoring brain glutathione depletion in rats that received 2-cyclohexene-1-one (CHX, 75mg/kg), d-amphetamine (2.5mg/kg) or both. CHX, but not amphetamine, induced significant depletion of glutathione levels in the striatum and frontal cortex. Glutathione depletion was reversed by NAC (1000mg/kg) in saline-treated and amphetamine-treated (frontal cortex only) rats. While NAC was shown to be beneficial in this model, the lack of additional glutathione depletion by amphetamine in combination with CHX does not support a summative interaction between oxidative stress and altered dopamine transmission. [PubMed Citation] [Order full text from Infotrieve]

6) Fountoulakis KN, Kelsoe JR, Akiskal H
Receptor targets for antidepressant therapy in bipolar disorder: An overview.
J Affect Disord. 2011 May 19;
The treatment of bipolar depression is one of the most challenging issues in contemporary psychiatry. Currently only quetiapine and the olanzapine-fluoxetine combination are officially approved by the FDA against this condition. The neurobiology of bipolar depression and the possible targets of bipolar antidepressant therapy remain relatively elusive. We performed a complete and systematic review to identify agents with definite positive or negative results concerning efficacy followed by a second systematic review to identify the pharmacodynamic properties of these agents. The comparison of properties suggests that the stronger predictors for antidepressant efficacy in bipolar depression were norepinephrine alpha-1, dopamine D1 and histamine antagonism, followed by 5-HT2A, muscarinic and dopamine D2 and D3 antagonism and eventually by norepinephrine reuptake inhibition and 5HT-1A agonism. Serotonin reuptake which constitutes the cornerstone in unipolar depression treatment does not seem to play a significant role for bipolar depression. Our exhaustive review is compatible with a complex model with multiple levels of interaction between the major neurotransmitter systems without a single target being either necessary or sufficient to elicit the antidepressant effect in bipolar depression. [PubMed Citation] [Order full text from Infotrieve]

7) Anc�n I, Cabranes JA, V�zquez-�lvarez B, Santos JL, S�nchez-Morla E, Garc�a-Jim�nez M�, Fern�ndez C, Barabash A
Sensory gating deficit is associated with catechol-O-methyltransferase polymorphisms in bipolar disorder.
World J Biol Psychiatry. 2011 Aug;12(5):376-84.
Abstract Objectives. Recent studies have evidenced that bipolar patients show a sensory gating deficit (P50). Among the neural systems that could be influencing this electrophysiological phenotype, dopamine seems to play an important role. We hypothesize that catechol-O-methyltransferase (COMT), the main metabolizer of dopamine in prefrontal cortex, is related to this deficit. Methods. We selected three polymorphisms in COMT gene: rs2075507 (Promoter 2 region), Val158Met (rs4680) and rs165599 (3' region). A case-control study was performed in 784 controls and 238 bipolar patients. Besides, 122 euthymic bipolar subjects and 95 healthy subjects carried out a sensory gating task (P50). Results. Polymorphism rs165599 in the COMT gene was associated with susceptibility to bipolar disorder (BD), mainly in women (AG: OR = 1.46; GG: OR = 1.84; P = 0.03). In the female group, haplotype AAG was associated with an OR = 7.6. Subjects who carried Val158 allele evidenced a deficit in suppression (P = 0.046) and rs165599 allele G carriers (mainly in homozygosis) had a bigger S2 amplitude and a higher S2/S1 ratio (1.6(e-5) < P < 0.01). Not a single association was proven in the control group. Conclusions. Our results support the association of the COMT gene with BD and with one of its potential endophenotypes, auditory sensory gating deficit, measured by the P50 paradigm. [PubMed Citation] [Order full text from Infotrieve]

8) Vangveravong S, Zhang Z, Taylor M, Bearden M, Xu J, Cui J, Wang W, Luedtke RR, Mach RH
Synthesis and characterization of selective dopamine D₂ receptor ligands using aripiprazole as the lead compound.
Bioorg Med Chem. 2011 Jun 1;19(11):3502-11.
A series of compounds structurally related to aripiprazole (1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D(?-like) dopamine receptors. These compounds also share structural elements with the classical D(?-like) dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (7) were found to (a) bind to the D? receptor subtype with high affinity (K(i) values < 0.3 nM), (b) exhibit >50-fold D? versus D? receptor binding selectivity and (c) be partial agonists at both the D? and D? receptor subtype. [PubMed Citation] [Order full text from Infotrieve]

9) Cagnin A, Pompanin S, Manfioli V, Briani C, Zambon A, Saladini M, Dam M
γ-Hydroxybutyric acid-induced psychosis and seizures.
Epilepsy Behav. 2011 Jun;21(2):203-5.
Disulfiram and ?-hydroxybutyric acid (GHB) are used to treat alcohol dependence and may both increase dopamine brain levels and modulate GABAergic transmission. We describe a patient affected by bipolar disorder (on valproate as mood-stabilizing treatment) and alcohol dependence who developed a disulfiram-induced hypomanic episode and in whom the switch from disulfiram to GHB induced recurrent convulsive seizures, not responsive to treatment with diazepam, and psychosis. Seizures and psychiatric symptoms ceased after GHB discontinuation. We outline the deregulation of the neurotransmitter systems (GABAergic and dopaminergic networks) that are involved in these drug-drug interactions and that might be responsible for both psychosis and generalized tonic-clonic seizures resistant to standard treatments. [PubMed Citation] [Order full text from Infotrieve]

10) Pinsonneault JK, Han DD, Burdick KE, Kataki M, Bertolino A, Malhotra AK, Gu HH, Sadee W
Dopamine Transporter Gene Variant Affecting Expression in Human Brain is Associated with Bipolar Disorder.
Neuropsychopharmacology. 2011 Jul;36(8):1644-55.
The gene encoding the dopamine transporter (DAT) has been implicated in CNS disorders, but the responsible polymorphisms remain uncertain. To search for regulatory polymorphisms, we measured allelic DAT mRNA expression in substantia nigra of human autopsy brain tissues, using two marker SNPs (rs6347 in exon 9 and rs27072 in the 3'-UTR). Allelic mRNA expression imbalance (AEI), an indicator of cis-acting regulatory polymorphisms, was observed in all tissues heterozygous for either of the two marker SNPs. SNP scanning of the DAT locus with AEI ratios as the phenotype, followed by in vitro molecular genetics studies, demonstrated that rs27072 C>T affects mRNA expression and translation. Expression of the minor T allele was dynamically regulated in transfected cell cultures, possibly involving microRNA interactions. Both rs6347 and rs3836790 (intron8 5/6 VNTR) also seemed to affect DAT expression, but not the commonly tested 9/10 VNTR in the 3'UTR (rs28363170). All four polymorphisms (rs6347, intron8 5/6 VNTR, rs27072 and 3'UTR 9/10 VNTR) were genotyped in clinical cohorts, representing schizophrenia, bipolar disorder, depression, and controls. Only rs27072 was significantly associated with bipolar disorder (OR=2.1, p=0.03). This result was replicated in a second bipolar/control population (OR=1.65, p=0.01), supporting a critical role for DAT regulation in bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

11) Gamo NJ, Arnsten AF
Molecular modulation of prefrontal cortex: rational development of treatments for psychiatric disorders.
Behav Neurosci. 2011 Jun;125(3):282-96.
Dysfunction of the prefrontal cortex (PFC) is a central feature of many psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), schizophrenia, and bipolar disorder. Thus, understanding molecular influences on PFC function through basic research in animals is essential to rational drug development. In this review, we discuss the molecular signaling events initiated by norepinephrine and dopamine that strengthen working memory function mediated by the dorsolateral PFC under optimal conditions, and weaken working memory function during uncontrollable stress. We also discuss how these intracellular mechanisms can be compromised in psychiatric disorders, and how novel treatments based on these findings may restore a molecular environment conducive to PFC regulation of behavior, thought and emotion. Examples of successful translation from animals to humans include guanfacine for the treatment of ADHD and related PFC disorders, and prazosin for the treatment of PTSD. [PubMed Citation] [Order full text from Infotrieve]

12) Nord M, Nyberg S, Brogren J, Jucaite A, Halldin C, Farde L
Comparison of D2 dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects.
Int J Neuropsychopharmacol. 2011 Apr 11;:1-10.
Quetiapine is an established drug for treatment of schizophrenia, bipolar disorder, and major depressive disorder. While initially manufactured as an immediate-release (IR) formulation, an extended-release (XR) formulation has recently been introduced. Pharmacokinetic studies show that quetiapine XR provides a lower peak and more stable plasma concentration than the IR formulation. This study investigated if the pharmacokinetic differences translate into different time curves for central D2 dopamine receptor occupancy. Eleven control subjects were examined with positron emission tomography (PET) and the radioligand [11C]raclopride. Eight subjects underwent all of the scheduled PET measurements. After baseline examination, quetiapine XR was administered once-daily for 8 d titrated to 300 mg/d on days 5-8, followed by 300 mg/d quetiapine IR on days 9-12. PET measurements were repeated after the last doses of quetiapine XR and IR at predicted times of peak and trough plasma concentrations. Striatal D2 receptor occupancy was calculated using the simplified reference tissue model. Peak D2 receptor occupancy was significantly higher with quetiapine IR than XR in all subjects (50�4% and 32�11%, respectively), consistent with lower peak plasma concentrations for the XR formulation. Trough D2 receptor occupancy was similarly low for both formulations (IR 7�7%, XR 8�6%). The lower peak receptor occupancy associated with quetiapine XR may explain observed pharmacodynamic differences between the formulations. Assuming that our findings in control subjects are valid for patients with schizophrenia, the study supports the view that quetiapine, like the prototype atypical antipsychotic clozapine, may show antipsychotic effect at lower D2 receptor occupancy than typical antipsychotics. [PubMed Citation] [Order full text from Infotrieve]

13) Isomura R, Kitajima K, Sato C
Structural and functional impairments of polysialic Acid by a mutated polysialyltransferase found in schizophrenia.
J Biol Chem. 2011 Jun 17;286(24):21535-45.
Polysialic acid (polySia), a unique acidic glycan modifying neural cell adhesion molecule (NCAM), is known to regulate embryonic neural development and adult brain functions. Polysialyltransferase STX is responsible for the synthesis of polySia, and two single nucleotide polymorphisms (SNPs) of the coding region of STX are reported from schizophrenic patients: SNP7 and SNP9, respectively, giving STX(G421A) with E141K and STX(C621G) with silent mutations. In this study, we focused on these mutations and a binding activity of polySia to neural materials, such as brain-derived neurotrophic factor (BDNF). Here we describe three new findings. First, STX(G421A) shows a dramatic decrease in polySia synthetic activity on NCAM, whereas STX(C621G) does not. The STX(G421A)-derived polySia-NCAM contains a lower amount of polySia with a shorter chain length. Second, polySia shows a dopamine (DA) binding activity, which is a new function of polySia as revealed by frontal affinity chromatography for measuring the polySia-neurotransmitter interactions. Interestingly, the STX(G421A)-derived polySia-NCAM completely loses the DA binding activity, whereas it greatly diminishes but does not lose the BDNF binding activity. Third, an impairment of the polySia structure with an endosialidase modulates the DA-mediated Akt signaling. Taken together, impairment of the amount and quality of polySia may be involved in psychiatric disorders through impaired binding to BDNF and DA, which are deeply involved in schizophrenia and other psychiatric disorders, such as depression and bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

14) Flaherty AW
Brain illness and creativity: mechanisms and treatment risks.
Can J Psychiatry. 2011 Mar;56(3):132-43.
Brain diseases and their treatment may help or hurt creativity in ways that shape quality of life. Increased creative drive is associated with bipolar disorder, depression, psychosis, temporal lobe epilepsy, frontotemporal dementia, Parkinson disease treatments, and autism. Creativity depends on goal-driven approach motivation from midbrain dopaminergic systems. Fear-driven avoidance motivation is of less aid to creativity. When serotonin and norepinephrine lower motivation and flexible behaviour, they can inhibit creativity. Hemispheric lateralization and frontotemporal connections must interact to create new ideas and conceptual schemes. The right brain and temporal lobe contribute skill in novelty detection, while the left brain and frontal lobe foster approach motivation and more easily generate new patterns of action from the novel perceptions. Genes and phenotypes that increase plasticity and creativity in tolerant environments with relaxed selection pressure may confer risk in rigorous environments. Few papers substantively address this important but fraught topic. Antidepressants (ADs) that inhibit fear-driven motivation, such as selective serotonin reuptake inhibitors, sometimes inhibit goal-oriented motivation as well. ADs that boost goal-directed motivation, such as bupropion, may remediate this effect. Benzodiazepines and alcohol may be counterproductive. Although dopaminergic agonists sometimes stimulate creativity, their doing so may inappropriately disinhibit behaviour. Dopamine antagonists may suppress creative motivation; lithium and anticonvulsant mood stabilizers may do so less. Physical exercise and REM sleep may help creativity. Art therapy and psychotherapy are not well studied. Preserving creative motivation can help creativity and other aspects of well-being in all patients, not just artists or researchers. [PubMed Citation] [Order full text from Infotrieve]

15) Coque L, Mukherjee S, Cao JL, Spencer S, Marvin M, Falcon E, Sidor MM, Birnbaum SG, Graham A, Neve RL, Gordon E, Ozburn AR, Goldberg MS, Han MH, Cooper DC, McClung CA
Specific role of VTA dopamine neuronal firing rates and morphology in the reversal of anxiety-related, but not depression-related behavior in the ClockΔ19 mouse model of mania.
Neuropsychopharmacology. 2011 Jun;36(7):1478-88.
Lithium has been used extensively for mood stabilization, and it is particularly efficacious in the treatment of bipolar mania. Like other drugs used in the treatment of psychiatric diseases, it has little effect on the mood of healthy individuals. Our previous studies found that mice with a mutation in the Clock gene (Clock?19) have a complete behavioral profile that is very similar to human mania, which can be reversed with chronic lithium treatment. However, the cellular and physiological effects that underlie its targeted therapeutic efficacy remain unknown. Here we find that Clock?19 mice have an increase in dopaminergic activity in the ventral tegmental area (VTA), and that lithium treatment selectively reduces the firing rate in the mutant mice with no effect on activity in wild-type mice. Furthermore, lithium treatment reduces nucleus accumbens (NAc) dopamine levels selectively in the mutant mice. The increased dopaminergic activity in the Clock mutants is associated with cell volume changes in dopamine neurons, which are also rescued by lithium treatment. To determine the role of dopaminergic activity and morphological changes in dopamine neurons in manic-like behavior, we manipulated the excitability of these neurons by overexpressing an inwardly rectifying potassium channel subunit (Kir2.1) selectively in the VTA of Clock?19 mice and wild-type mice using viral-mediated gene transfer. Introduction of this channel mimics the effects of lithium treatment on the firing rate of dopamine neurons in Clock?19 mice and leads to a similar change in dopamine cell volume. Furthermore, reduction of dopaminergic firing rates in Clock?19 animals results in a normalization of locomotor- and anxiety-related behavior that is very similar to lithium treatment; however, it is not sufficient to reverse depression-related behavior. These results suggest that abnormalities in dopamine cell firing and associated morphology underlie alterations in anxiety-related behavior in bipolar mania, and that the therapeutic effects of lithium come from a reversal of these abnormal phenotypes. [PubMed Citation] [Order full text from Infotrieve]

16) Young JW, van Enkhuizen J, Winstanley CA, Geyer MA
Increased risk-taking behavior in dopamine transporter knockdown mice: further support for a mouse model of mania.
J Psychopharmacol. 2011 Jul;25(7):934-43.
Reduced functioning of the dopamine transporter (DAT) has been linked to bipolar disorder (BD). Mice with reduced DAT functioning (knockdown, KD) exhibit a behavioral profile in the mouse Behavioral Pattern Monitor (BPM) consistent with patients with BD mania in the human BPM. Patients with BD also exhibit increased risk taking, which can be quantified using the Iowa Gambling Task (IGT). We hypothesized that DAT KD mice would exhibit increased risk-taking behavior in a novel mouse version of the IGT. DAT KD and wildtype (WT) littermates were trained in the mouse IGT. In session 1, KD mice initially made riskier choices, but later performed comparably to WT mice. Once trained to stable choice performance, DAT KD mice continued to exhibit a trend to choose the riskier options more than WT mice. Finally, we confirmed that these DAT KD mice also exhibited an exploratory profile in the BPM consistent with patients with BD mania, where risky choice behavior modestly correlated with specific exploration. These data demonstrate that DAT KD mice chose the riskier options more than WT mice, providing further support for the use of DAT KD mice as a model of BD mania. [PubMed Citation] [Order full text from Infotrieve]

17) Schwartz TL, Stahl SM
Treatment strategies for dosing the second generation antipsychotics.
CNS Neurosci Ther. 2011 Apr;17(2):110-7.
[PubMed Citation] [Order full text from Infotrieve]

18) Benedetti F, Dallaspezia S, Locatelli C, Radaelli D, Poletti S, Lorenzi C, Pirovano A, Colombo C, Smeraldi E
Recurrence of bipolar mania is associated with catechol-O-methyltransferase Val(108/158)Met polymorphism.
J Affect Disord. 2011 Jul;132(1-2):293-6.
[PubMed Citation] [Order full text from Infotrieve]

19) Rosenfeld M, Brenner-Lavie H, Ari SG, Kavushansky A, Ben-Shachar D
Perturbation in mitochondrial network dynamics and in complex I dependent cellular respiration in schizophrenia.
Biol Psychiatry. 2011 May 15;69(10):980-8.
[PubMed Citation] [Order full text from Infotrieve]

20) Beaulieu JM, Gainetdinov RR
The physiology, signaling, and pharmacology of dopamine receptors.
Pharmacol Rev. 2011 Mar;63(1):182-217.
G protein-coupled dopamine receptors (D1, D2, D3, D4, and D5) mediate all of the physiological functions of the catecholaminergic neurotransmitter dopamine, ranging from voluntary movement and reward to hormonal regulation and hypertension. Pharmacological agents targeting dopaminergic neurotransmission have been clinically used in the management of several neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, bipolar disorder, Huntington's disease, attention deficit hyperactivity disorder (ADHD(1)), and Tourette's syndrome. Numerous advances have occurred in understanding the general structural, biochemical, and functional properties of dopamine receptors that have led to the development of multiple pharmacologically active compounds that directly target dopamine receptors, such as antiparkinson drugs and antipsychotics. Recent progress in understanding the complex biology of dopamine receptor-related signal transduction mechanisms has revealed that, in addition to their primary action on cAMP-mediated signaling, dopamine receptors can act through diverse signaling mechanisms that involve alternative G protein coupling or through G protein-independent mechanisms via interactions with ion channels or proteins that are characteristically implicated in receptor desensitization, such as ?-arrestins. One of the future directions in managing dopamine-related pathologic conditions may involve a transition from the approaches that directly affect receptor function to a precise targeting of postreceptor intracellular signaling modalities either directly or through ligand-biased signaling pharmacology. In this comprehensive review, we discuss dopamine receptor classification, their basic structural and genetic organization, their distribution and functions in the brain and the periphery, and their regulation and signal transduction mechanisms. In addition, we discuss the abnormalities of dopamine receptor expression, function, and signaling that are documented in human disorders and the current pharmacology and emerging trends in the development of novel therapeutic agents that act at dopamine receptors and/or on related signaling events. [PubMed Citation] [Order full text from Infotrieve]