Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
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Neuropsychopharmacology · Mar 2006
Significant association of catechol-O-methyltransferase (COMT) haplotypes with nicotine dependence in male and female smokers of two ethnic populations.
The catechol-O-methyltransferase (COMT) gene plays a prominent role in dopaminergic circuits central to drug reward. Allelic variants within the COMT gene are therefore potential candidates for examining interindividual differences in vulnerability to nicotine dependence (ND). We analyzed five single nucleotide polymorphisms (SNPs), including the Val/Met variant (rs4680), which results in a three- to four-fold difference in enzyme activity within COMT, for association with the three ND measures, SQ, HSI, and FTND, in 602 nuclear families of African-American (AA) or European-American (EA) origin. ⋯ Moreover, we found a major high-risk T-A-T haplotype (frequency 56.7%) that showed significant association with the three ND measures in EA males. Further examination of two protective haplotypes, A-G-T in AAs and T-G-T in EAs, indicated that the low COMT enzyme activity Met allele is protective to become nicotine dependent. In summary, our results provide evidence for a role of COMT in the susceptibility to ND and further confirm that its effect is ethnic and gender specific.
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Neuropsychopharmacology · Mar 2006
A mouse model system for genetic analysis of sociability: C57BL/6J versus BALB/cJ inbred mouse strains.
Impairments in social behaviors are highly disabling symptoms of autism, schizophrenia, and other psychiatric disorders. Mouse model systems are useful for identifying the many genes and environmental factors likely to affect complex behaviors, such as sociability (the tendency to seek social interaction). To progress toward developing such a model system, we tested the hypothesis that C57BL/6J inbred mice show higher levels of sociability than BALB/cJ inbred mice. ⋯ We propose that C57BL/6J and BALB/cJ mice will be a useful mouse model system for future genetic and neurobiological studies of sociability.
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Neuropsychopharmacology · Feb 2006
Comparative StudyRegulation of amygdala-dependent learning by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol-3-kinase.
This study is designed to characterize the signal cascades by which brain-derived neurotrophic factor (BDNF) modulates long-term memory of fear conditioning. Enzyme-linked immunosorbent assay (ELISA) and Western blot analysis of tissue homogenates taken from fear-conditioned rats showed an increase in the amygdala of BDNF protein levels and its receptor TrkB phosphorylation. Bilateral administration of a TrkB ligand scavenger TrkB IgG and a Trk-specific tyrosine kinase inhibitor K252a to the amygdala impaired fear memory, as measured with fear-potentiated startle. ⋯ BDNF-induced MAPK phosphorylation in the amygdala is mediated via TrkB and the Shc-binding site. Shc binding to TrkB leads to activation of Ras, Raf, and MEK. In addition, BDNF could induce phosphorylation of MAPK via activation of PI-3 kinase.
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Neuropsychopharmacology · Nov 2005
Comparative StudyCOMT polymorphisms and anxiety-related personality traits.
High neuroticism and low extraversion are characteristic of anxiety-prone individuals. A functional variant in the catechol-O-methyltransferase (COMT) gene, the Val158Met ('val/met') polymorphism, has been associated in some prior studies with several phenotypes, including neuroticism. We tested the hypothesis that the val158met polymorphism would be associated with both high neuroticism and low extraversion, making it a plausible candidate locus for anxiety susceptibility. ⋯ These data suggest that involvement of the COMT locus in susceptibility to anxiety-related traits (ie low extraversion and high neuroticism) is unlikely to be wholly accounted for by the well-studied rs4680 ('val/met') polymorphism. Other functional variants may exist that contribute to this relationship. Possible sex-specific effects remain to be further studied and explained.
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Neuropsychopharmacology · Nov 2005
Comparative StudyThe GABAB receptor-positive modulator GS39783 and the GABAB receptor agonist baclofen attenuate the reward-facilitating effects of cocaine: intracranial self-stimulation studies in the rat.
There is an increasing interest in the development of nondopaminergic pharmacotherapies for cocaine abuse. Emerging preclinical and clinical data with the metabotropic GABAB receptor agonist baclofen support a role for the modulation of GABAB receptors in the treatment of drug addiction. Nevertheless, the muscle relaxant, hypothermic, and sedative properties of baclofen somewhat limit its widespread potential therapeutic utility. ⋯ Moreover, both GS39783 and baclofen attenuated the threshold lowering effect of cocaine administration (10 mg/kg intraperitoneally) in a dose-related manner. These data strongly suggest that activation of GABAB receptors attenuates the rewarding effects of acute cocaine. Therefore, GABAB-positive modulation may represent a novel therapeutic strategy for the treatment of cocaine dependence and possibly other drugs of abuse without the side effects of full GABAB receptor agonists.