Biomedical subjects

B Kolachana

Publications and source records attributed to B Kolachana.

4 recordsLinked to original sources

PubMed2006

Impact of complex genetic variation in COMT on human brain function.

Catechol-O-methyltransferase (COMT) has been shown to be critical for prefrontal dopamine flux, prefrontal cortex-dependent cognition and activation. Several potentially functional variants in the gene have been identified, but considerable controversy exists regarding the contribution of individual alleles and haplotypes to risk for schizophrenia, partly because clinical phenotypes are ill-defined and preclinical studies are limited by lack of adequate models. Here, we propose a neuroimaging approach to overcome these limitations by characterizing the functional impact of ambiguous haplotypes on a neural system-level intermediate phenotype in humans. Studying 126 healthy control subjects during a working-memory paradigm, we find that a previously described risk variant in a functional Val158Met (rs4680) polymorphism interacts with a P2 promoter region SNP (rs2097603) and an SNP in the 3' region (rs165599) in predicting inefficient prefrontal working memory response. We report evidence that the nonlinear response of prefrontal neurons to dopaminergic stimulation is a neural mechanism underlying these nonadditive genetic effects. This work provides an in vivo approach to functional validation in brain of the biological impact of complex genetic variations within a gene that may be critical for its clinical association.

Adult↗

PubMed2003

Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse.

CNS-focused cDNA microarrays were used to examine gene expression profiles in dorsolateral prefrontal cortex (dlPFC, Area 46) from seven individual sets of age- and post-mortem interval-matched male cocaine abusers and controls. The presence of cocaine and related metabolites was confirmed by gas chromatography-mass spectrometry. Sixty-five transcripts were differentially expressed, indicating alterations in energy metabolism, mitochondria and oligodendrocyte function, cytoskeleton and related signaling, and neuronal plasticity. There was evidence for two distinct states of transcriptional regulation, with increases in gene expression predominating in subjects testing positive for a metabolite indicative of recent 'crack' cocaine abuse and decreased expression profiles in the remaining cocaine subjects. This pattern was confirmed by quantitative polymerase chain reaction for select transcripts. These data suggest that cocaine abuse targets a distinct subset of genes in the dlPFC, resulting in either a state of acute activation in which increased gene expression predominates, or a relatively destimulated, refractory phase.

Adult↗

PubMed1999

The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia.

BACKGROUND: Pathology of dorsolateral prefrontal cortex and dysregulation of dopaminergic neurons have been associated with the pathophysiology of schizophrenia, but how these phenomena relate to each other in patients has not been known. It has been hypothesized that prefrontal cortical pathology might induce both diminished steady-state and exaggerated responses of dopaminergic neurons to certain stimuli (e.g., stress). We examined the relationship between a measure of prefrontal neuronal pathology and striatal dopamine activity in patients with schizophrenia and in a nonhuman primate model of abnormal prefrontal cortical development. METHODS: In the patients, we studied in vivo markers of cortical neuronal pathology with NMR spectroscopic imaging and of steady-state striatal dopamine activity with radioreceptor imaging. In the monkeys, we used the same NMR technique and in vivo microdialysis. RESULTS: Measures of N-acetyl-aspartate concentrations (NAA) in dorsolateral prefrontal cortex strongly and selectively predicted D2 receptor availability in the striatum (n = 14, rho = -.64, p < .01), suggesting that the greater the apparent dorsolateral prefrontal cortex pathology, the less the steady-state dopamine activity in these patients. A similar relationship between NAA measures in dorsolateral prefrontal cortex and steady-state dopamine concentrations in the striatum was found in the monkeys (n = 5, rho = .70, p < .05). We then tested in the same monkeys the relationship of prefrontal NAA and striatal dopamine overflow following amphetamine infusion into dorsolateral prefrontal cortex. Under these conditions, the relationship was inverted, i.e., the greater the apparent dorsolateral prefrontal cortex pathology, the greater the dopamine release. CONCLUSIONS: These data demonstrate direct relationships between putative neuronal pathology in dorsolateral prefrontal cortex and striatal dopamine activity in human and nonhuman primates and implicate a mechanism for dopamine dysregulation in schizophrenia.

Adult↗

PubMed1992

D1 and D2 receptor modulation in rat striatum and nucleus accumbens after subchronic and chronic haloperidol treatment.

The antipsychotic effects of neuroleptic drugs are believed to be achieved by chronic blockade of dopaminergic transmission in the limbic system. Nevertheless, the effects of chronic (3-12 months) haloperidol administration on the dopaminergic transmission in the nucleus accumbens of rodents remains poorly understood. Studies of spontaneous locomotor activity (SLA), a behavioral measure related to limbic dopamine transmission, and of dopamine D2 receptor density in the nucleus accumbens after chronic oral haloperidol treatment have yielded conflicting results. We evaluated these indices after 8 months of parenteral administration of haloperidol decanoate. We report here that, after 8 months of parenteral treatment, SLA stays significantly decreased and D2 receptors in the nucleus accumbens exhibit the same up-regulation as in the striatum (about 50%). These results fail to support the notion of a different pattern of D2 receptor adaptation to neuroleptic treatment between the nucleus accumbens and the striatum. In contrast, dopamine D1 receptors were found to be unaffected in the nucleus accumbens but decreased in the striatum by 22% after 8 months of treatment. This observation could be relevant to the pathogenesis of tardive dyskinesia.

Animals↗