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Altemus M, Pigott T, L'Heureux F, Davis CL, Rubinow DR, Murphy
DL, Gold PW.
CSF somatostatin in obsessive-compulsive disorder.
Am
J Psychiatry. 1993 Mar;150(3):460-4.
"OBJECTIVE: Because the central administration
of somatostatin to experimental animals produces behaviors with some similarities
to the compulsions of patients with obsessive-compulsive disorder and because
serotonin reuptake inhibitors have been reported to reduce brain content of somatostatin,
the authors examined central somatostatin activity in patients with obsessive-compulsive
disorder. METHOD: CSF for measurement of somatostatin was obtained from 15 drug-free
outpatients with obsessive-compulsive disorder and 27 normal volunteers. RESULTS:
The mean CSF somatostatin level was significantly higher in the patients with
obsessive-compulsive disorder than in the normal subjects. CONCLUSIONS: Although
the functional significance of this finding is unknown, these data are consistent
with a role for somatostatin in the clinical symptomatology of obsessive-compulsive
disorder and its response to neuropharmacological agents. The high levels of CSF
somatostatin reported here in a patient subgroup whose predominant symptoms consisted
of overly focused, perseverative thought processes are in contrast to the consistently
low levels of CSF somatostatin seen in patients with a spectrum of disorders characterized
by substantial cognitive deficits." [Abstract]
Schettini G.
Brain somatostatin: receptor-coupled
transducing mechanisms and role in cognitive functions.
Pharmacol
Res. 1991 Apr;23(3):203-15.
" Biological studies on the effects of increased
brain somatostatin showed a facilitation in learning behavioural tasks, while
brain somatostatin depletion by cysteamine caused memory loss. These observations,
along with the severe somatostatinergic neurotransmission impairment demonstrated
in Alzheimer's patients, strongly suggest a fundamental role for somatostatin
in the modulation of cognitive functions." [Abstract]
Roy BF, Benkelfat C, Hill JL, Pierce PF, Dauphin
MM, Kelly TM, Sunderland T, Weinberger DR, Breslin N.
Serum antibody
for somatostatin-14 and prodynorphin 209-240 in patients with obsessive-compulsive
disorder, schizophrenia, Alzheimer's disease, multiple sclerosis, and advanced
HIV infection.
Biol Psychiatry. 1994 Mar 1;35(5):335-44.
"Patients
with obsessive-compulsive disorder (OCD) demonstrated significant levels of antibody
for somatostatin-28, its C-terminal fragment somatostatin-14, and prodynorphin.
In contrast there were lower levels of reactivity for somatostatin-28(1-14) (the
N-terminal fragment of somatostatin-28) and negligible reactivity for several
other peptides including beta-endorphin and corticotropin. Healthy volunteers
and disease controls [schizophrenia, Alzheimer's disease, multiple sclerosis,
and subjects with advanced human immunodeficiency virus (HIV) infection] exhibited
negligible reactivity. These data raise the consideration of an autoimmune mechanism
for some OCD." [Abstract]
Allen JP, Hathway GJ, Clarke NJ, Jowett MI, Topps S, Kendrick
KM, Humphrey PP, Wilkinson LS, Emson PC.
Somatostatin receptor 2
knockout/lacZ knockin mice show impaired motor coordination and reveal sites of
somatostatin action within the striatum.
Eur J Neurosci.
2003 May;17(9):1881-95.
"The peptide somatostatin can modulate the functional
output of the basal ganglia. The exact sites and mechanisms of this action, however,
are poorly understood, and the physiological context in which somatostatin acts
is unknown. Somatostatin acts as a neuromodulator via a family of five 7-transmembrane
G protein-coupled receptors, SSTR1-5, one of which, SSTR2, is known to be functional
in the striatum. We have investigated the role of SSTR2 in basal ganglia function
using mice in which Sstr2 has been inactivated and replaced by the lacZ reporter
gene. Analysis of Sstr2lacZ expression in the brain by beta-galactosidase histochemistry
demonstrated a widespread pattern of expression. By comparison to previously published
in situ hybridization and immunohistochemical data, Sstr2lacZ expression was shown
to accurately recapitulate that of Sstr2 and thus provided a highly sensitive
model to investigate cell-type-specific expression of Sstr2. In the striatum,
Sstr2 expression was identified in medium spiny projection neurons restricted
to the matrix compartment and in cholinergic interneurons. Sstr2 expression was
not detected in any other nuclei of the basal ganglia except for a sparse number
of nondopaminergic neurons in the substantia nigra. Microdialysis in the striatum
showed Sstr2-null mice were selectively refractory to somatostatin-induced dopamine
and glutamate release. In behavioural tests, Sstr2-null mice showed normal levels
of locomotor activity and normal coordination in undemanding tasks. However, in
beam-walking, a test of fine motor control, Sstr2-null mice were severely impaired.
Together these data implicate an important neuromodulatory role for SSTR2 in the
striatum." [Abstract] Hathway
GJ, Humphrey PP, Kendrick KM.
Somatostatin induces striatal dopamine
release and contralateral turning behaviour in the mouse.
Neurosci
Lett. 2004 Mar 25;358(2):127-31.
"Application of somatostatin to the striatum
of the anaesthetized rat has previously been shown to elicit large increases in
extracellular levels of dopamine and GABA via a glutamate-dependent mechanism.
These actions have been ascribed to the SSTR2 receptor. Here we describe experiments
designed to investigate whether these effects occur in C57Bl6 mice and if they
elicit rotational behaviours associated with increased dopamine in the striatum.
Application of somatostatin resulted in increased concentrations of dopamine in
striatum, hippocampus and amygdala of anaesthetized mice. Unilateral striatal
infusions of the peptide by retrodialysis increased locomotion. Application of
N-methyl-D-aspartate and AMPA to the freely-moving mouse striatum resulted in
increased dopamine release; however, only AMPA caused increased locomotion. These
results further confirm that somatostatin can play a role in the control of locomotor
function by modulating striatal dopamine release." [Abstract] Magalie
Rocheville, Daniela C. Lange, Ujendra Kumar, Shutish C. Patel, Ramesh C. Patel,
and Yogesh C. Patel
Receptors for Dopamine and Somatostatin: Formation
of Hetero-Oligomers with Enhanced Functional Activity
Science
2000; 288 (5463) : 154-157. (in Reports)
"Somatostatin and dopamine are
two major neurotransmitter systems that share a number of structural and functional
characteristics. Somatostatin receptors and dopamine receptors are colocalized
in neuronal subgroups, and somatostatin is involved in modulating dopamine-mediated
control of motor activity. However, the molecular basis for such interaction between
the two systems is unclear. Here, we show that dopamine receptor D2R and somatostatin
receptor SSTR5 interact physically through hetero-oligomerization to create a
novel receptor with enhanced functional activity. Our results provide evidence
that receptors from different G protein (heterotrimeric guanine nucleotide binding
protein)-coupled receptor families interact through oligomerization. Such direct
intramembrane association defines a new level of molecular crosstalk between related
G protein-coupled receptor subfamilies." [Full
Text] |
Bendotti C, Tarizzo G, Fumagalli F, Baldessari S, Samanin R.
Increased
expression of preproneuropeptide Y and preprosomatostatin mRNA in striatum after
selective serotoninergic lesions in rats.
Neurosci Lett.
1993 Oct 1;160(2):197-200.
"The levels of neuropeptide Y and somatostatin
may change when serotoninergic neurotransmission is altered in different brain
regions. To assess whether serotonin regulates the synthesis of these peptides,
we measured the levels of preproneuropeptide Y (ppNPY) and preprosomatostatin
(ppSOM) mRNA in different brain regions after intracerebroventricular injection
of 5,7-dihydroxytryptamine (5,7-DHT), a selective serotonin neurotoxin. The mRNA
of these peptides significantly increased in the striatum but not in hippocampus
and frontal cortex. It thus appears that serotonin has an inhibitory effect on
the biosynthesis of neuropeptide Y and somatostatin in striatum whereas it probably
acts by stimulating the release of these peptides in hippocampus and frontal cortex."
[Abstract]
Mota A, Bento A, Penalva A, Pombo M, Dieguez C.
Role
of the serotonin receptor subtype 5-HT1D on basal and stimulated growth hormone
secretion.
J Clin Endocrinol Metab. 1995 Jun;80(6):1973-7.
"Our
results indicate that 5-HT1D receptors have a stimulatory effect on GH secretion,
possibly by inhibiting hypothalamic somatostatin release." [Abstract] Mundo
E, Richter MA, Zai G, Sam F, McBride J, Macciardi F, Kennedy JL.
5HT1Dbeta
Receptor gene implicated in the pathogenesis of Obsessive-Compulsive Disorder:
further evidence from a family-based association study.
Mol
Psychiatry 2002;7(7):805-9
"Obsessive-Compulsive Disorder (OCD) is a psychiatric
condition with strong evidence for a genetic component and for the involvement
of genes of the serotonin system. In a recent family-based association study we
reported an association between the G allele of the G861C polymorphism of the
5HT1Dbeta receptor gene and OCD. The aim of the present study was to further investigate
for the presence of linkage disequilibrium between each of two polymorphisms of
the 5HT1Dbeta receptor gene and OCD in a larger sample of OCD families. In a total
of 121 families the G861C and the T371G polymorphisms of the 5HT1Dbeta receptor
gene were genotyped using standard protocols. The genotyping data were analyzed
with a new extension of the Transmission Disequilibrium Test (FBAT). The phenotypes
considered in the analyses were the diagnosis of OCD and two quantitative phenotypes
related to the diagnosis and clinically relevant, ie, the age at onset and the
severity of OCD symptoms. We confirmed the previously found preferential transmission
of the G861 allele to the affected subjects (z = 2.262, P = 0.02). No significant
association was found between the polymorphism and the quantitative phenotypes
considered. These results represent a confirmation of our previous published study
and thus, could have important implications for the role of the 5HT1Dbeta receptor
gene in the pathogenesis and treatment of OCD. Further genetic investigations
on this marker considering additional polymorphisms and other quantitative phenotypes
related to OCD are warranted." [Abstract]
Prosperini E, Rizzi M, Fumagalli F, Tarizzo G, Samanin
R, Bendotti C.
Acute and chronic treatments with citalopram lower
somatostatin levels in rat brain striatum through different mechanisms.
J
Neurochem. 1997 Jul;69(1):206-13.
"The suggestion that somatostatin is
involved in the pathophysiology of obsessive-compulsive disorder and the evidence
that selective serotonin reuptake inhibitors show significant antiobsessional
effect prompted us to examine the effect of citalopram, a selective and potent
serotonin reuptake inhibitor, on the somatostatinergic system in different brain
regions of the rat. A single intraperitoneal injection of 10 mg/kg citalopram
significantly reduced somatostatin levels in the striatum and nucleus accumbens
after 4 but not 1, 8, or 24 h. No changes were found in hippocampus. In addition,
we found that the K+-evoked overflow of somatostatin-like immunoreactivity from
striatal slices was significantly increased 1 h after a single injection of citalopram
and was still higher, although not significantly, 4 h after the drug injection.
Levels of preprosomatostatin mRNA were unchanged in striatum and accumbens 1 and
4 h after a single drug administration. In rats treated with citalopram (10 mg/kg
i.p.) twice daily for 14 days, the levels of somatostatin and its mRNA were significantly
decreased in the striatum but not in other brain regions 24 h after the last dose.
No change was found in the basal or K+-evoked overflow of somatostatin-like immunoreactivity
at 1, 4, and 24 h after the last drug injection. These results suggest that acute
and chronic treatment with citalopram reduces somatostatin levels in striatum
by different mechanisms. Whereas a single dose of the drug reduces somatostatin
levels by increasing the release of the peptide, repeated drug treatment reduces
the biosynthesis of somatostatin." [Abstract]
Altemus M, Swedo SE, Leonard HL, Richter D, Rubinow
DR, Potter WZ, Rapoport JL.
Changes in cerebrospinal fluid neurochemistry
during treatment of obsessive-compulsive disorder with clomipramine.
Arch
Gen Psychiatry. 1994 Oct;51(10):794-803.
"BACKGROUND: This study examined
the effect of long-term (mean, 19 months) treatment with clomipramine hydrochloride
on cerebrospinal fluid (CSF) levels of several neuropeptides and monoamine metabolites
in children and adolescents with obsessive-compulsive disorder. METHODS: The CSF
levels of corticotropin-releasing hormone, vasopressin, somatostatin, and oxytocin
and of the monoamine metabolites 5-hydroxyindoleacetic acid, homovanillic acid,
and 3-methoxy-4-hydroxyphenylglycol were measured in 17 children and adolescents
with obsessive-compulsive disorder before and after long-term treatment with clomipramine.
RESULTS: Treatment resulted in significant decreases in CSF levels of corticotropin-releasing
hormone (mean +/- SD, 175 +/- 32 vs 152 +/- 25 pmol/L, P < .03) and vasopressin
(mean +/- SD, 1.30 +/- 0.57 vs 0.86 +/- 0.54 pmol/L, P < .02) and a trend toward
a decrease in somatostatin levels (mean +/- SD, 21.3 +/- 8.5 vs 15.3 +/- 9.8 pmol/L,
P < .06). Treatment also significantly increased CSF oxytocin levels (mean
+/- SD, 6.05 +/- 1.60 vs 6.70 +/- 1.44 pmol/L, P < .01). Significant changes
in CSF monoamine metabolite levels with treatment included significant decreases
in CSF levels of 5-hydroxyindoleacetic acid (mean +/- SD, 109 +/- 31 vs 77 +/-
23 pmol/mL, P < .001), CSF homovanillic acid (mean +/- SD, 273 +/- 111 vs 237
+/- 101 pmol/mL, P < .04), and 3-methoxy-4-hydroxyphenylglycol (mean +/- SD,
42.4 +/- 10.2 vs 36.1 +/- 4.8 pmol/L, P < .02) and a significant increase in
the homovanillic acid-5-hydroxyindoleacetic acid ratio (mean +/- SD, 2.44 +/-
0.46 vs 3.42 +/- 0.84, P < .0001). CONCLUSIONS: These neuropeptide results
coupled with evidence that central administration of corticotropin-releasing hormone,
vasopressin, and somatostatin to laboratory animals increases arousal and acquisition
of conditioned behaviors whereas central administration of oxytocin has opposite
behavioral effects are consistent with a role for these neuropeptides in the pathophysiologic
processes and pharmacologic treatment of obsessive-compulsive disorder."
[Abstract] |
