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Of Mice and Men R01 DA 12849 (JG), R01 DA 13441 (AO), R01 DA 012979 (RSS), K24 DA 00445 (RSS), P50-DA12762 (TRK)

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Of Mice and Men R01 DA 12849 (JG), R01 DA 13441 (AO), R01 DA 012979 (RSS), K24 DA 00445 (RSS), P50-DA12762 (TRK) Neuropsychopharmacology (2005) 30, S1-S76 © 2005 Nature Publishing Group All rights reserved 0893-133X/05 www.neuropsychopharmacology.org S1 Monday, December 12, 2005 this hypothesis. (2) -1021C>T does not associate with cocaine-in- duced psychosis, as assessed by retrospective interviews of cocaine de- pendent individuals. (3) -1021 T allele carriers may be more respon- Panel Session sive to the cocaine-abstinence-promoting effects of disulfiram. Dopamine Beta Hydroxylase Genetics and Substance Abuse: Support: NIDA grants R01 DA12422 (JFC), K02 DA 15766 (JFC), Of Mice and Men R01 DA 12849 (JG), R01 DA 13441 (AO), R01 DA 012979 (RSS), K24 DA 00445 (RSS), P50-DA12762 (TRK). Human Genetics of Plasma DBH Activity in Cocaine Dependence Dopamine β-Hydroxylase Knockout Mice Have Alterations in Joseph F Cubells*, Richard S Schottenfeld, Alison Oliveto, Tony Dopamine Signaling and Are Hypersensitive to Cocaine George, Marek C Chawarski, James Poling, Henry R Kranzler, Joel Locomotion, Reward, and Aversion Gelernter and Thomas R Kosten Jesse R Schank, Rossella Ventura, Stefano Puglisi-Allegra, Antonio Human Genetics and Psychiatry & Beh. Sci, Emory Univ. Sch. Med., Alcara, L. C Liles, Philip Seeman and David Weinshenker* Atlanta, GA, USA Human Genetics, Emory University, Atlanta, GA, USA β Background: Dopamine -hydroxylase (DBH) catalyzes conversion Background: Multiple lines of evidence demonstrate that the nora- of dopamine (DA) to norepinephrine (NE). It is secreted into the cir- drenergic system provides both direct and indirect excitatory drive culation during synaptic exocytosis by sympathetic neurons, and can onto midbrain dopamine (DA) neurons, and alterations in noradren- be measured in the plasma. Studies dating to the 1970s have sug- ergic signaling can influence the degree and valence of psychostimu- gested that lower biochemical activity of plasma DBH associates with lant responses. psychotic symptoms in a number of disorders, including major de- Methods: We used dopamine β-hydroxylase knockout (Dbh -/-) mice pression, schizophrenia and disulfiram-induced psychosis. Disulfi- that lack norepinephrine (NE) to determine the consequences of ram and its metabolites potently inhibit DBH enzyme activity, chronic NE deficiency on midbrain DA neuron function in vivo. DA through their ability to chelate copper, a necessary co-factor. Disulfi- release was assessed by in vivo microdialysis, DA receptor signaling ram appears to be effective for promoting abstinence from cocaine in was assessed by in vitro radioligand binding, the psychomotor effects some, but not all cocaine-dependent individuals. Plasma DBH levels of cocaine were assessed by automated locomotor activity assays, and are highly heritable. Prior linkage results suggested that DBH, the cocaine reward and aversion were assessed by a place conditioning structural gene encoding DBH, accounts for much of that heritability. paradigm. Our lab studies the relationship between sequence variation at DBH Results: Basal extracellular DA levels were significantly attenuated in and variation in plasma DBH activity. the nucleus accumbens (NAc) and caudate putamen (CP), but not Methods: We performed a targeted re-sequencing study of DBH, tar- prefrontal cortex (PFC), of Dbh -/- mice, while amphetamine-in- geting exons, flanking intronic regions, and several kb of upstream duced DA release was absent in the NAc and attenuated in the CP and and downstream sequence, in subjects exhibiting very low, average, or PFC. The decrease in dopaminergic tone was associated with a pro- very high levels of plasma DBH. That study identified a single nu- found increase in the density of high-affinity state D1 and D2 DA re- cleotide polymorphism (SNP) that appears to account for 35-50% of ceptors in the NAc and CP, while DA receptors in the PFC were rela- the variance in plasma DBH levels. The SNP, -1021C>T, is located in tively unaffected. As a behavioral consequence of these the upstream region of the gene, 1021 bp 5’ of the translational start neurochemical changes, Dbh -/- mice were hypersensitive to the psy- codon. We tested two hypotheses: (1) the low-activity allele of - chomotor, rewarding, and aversive effects of cocaine. Antagonists of 1021C>T associates with cocaine-induced psychotic symptoms, as DA,but not 5-HT receptors attenuated the locomotor hypersensitiv- reported retrospectively by cocaine-depndent individuals. (2) that ity to cocaine in Dbh -/- mice. genotype at -1021C>T modulates response to disulfiram in cocaine- Discussion: Because DBH activity in humans is genetically con- dependent patients. trolled and the DBH inhibitor disulfiram has shown promise as a Results: In contrast to our early findings, suggesting an association pharmacotherapy for cocaine dependence, these results have implica- between a low-activity associated haplotype at DBH and cocaine- tions for the influence of genetic and pharmacological DBH inhibi- induced paranoia, more extensive analysis in a larger independent tion on DA system function and psychostimulant addiction. sample does not support an association between genotype at - 1021C>T and cocaine-induced paranoia or other psychotic symp- toms assessed by retrospective interview. However, preliminary re- DBH Genotype and Human Self-Administration of Cocaine sults from a double-blind placebo-controlled trial of disulfiram in Robert Malison* cocaine-dependent opiate users maintained on buprenorphine sug- Psychiatry, Yale University, New Haven, CT, USA gest that carriers of the low-activity-associated T allele at -1021C>T may be more responsive to the abstinence-promoting effects of Background: Previous studies suggest an association between disulfiram (250 mg/day) than CC homozygotes. A separate study, ‘low–activity’ haplotypes at the gene for dopamine beta–hydroxylase examining the relationship between plasma DBH activity and disul- (DBH) and retrospective self–reports of cocaine–induced paranoia firam response in cocaine-dependent opiate users maintained on (CIP) in clinically dependent populations. These data are supported methadone suggests that individuals with lower plasma DBH activ- by preclinical observations of increased conditioned place aversion to ity may also be more responsive to doses of 250 mg of disulfiram cocaine in dbh –/– knockout mice. The current study used human (but not to 125 mg). Those results are consistent with the hypothe- laboratory methods to more directly evaluate potential pharmacoge- sis that the T allele at -1021C>T associates with better response to netic interactions between cocaine and a recently identified, func- disulfiram. tional, single nucleotide polymorphism (C—1021T) in DBH. Conclusions: (1) DBH is a major genetic determinant of plasma Methods: Thirty–one, non–treatment seeking, medically healthy, ex- DBH activity. -1021C>T may be a functional variant that accounts perienced cocaine users participated in a double blind, fully random- for much of that association, but further research is necessary to test ized laboratory study of intravenous cocaine (8, 16, and 32 mg/70 kg) ACNP 2005 Annual Meeting S2 self–administration on three test days, during which time partici- differential activation of noradrenergic nuclei. Restoration of DBH in pants had 2 hours of ‘ad lib’ access to cocaine under a fixed ratio 1: the LC of DBH-KO mice normalized OWD signs and restored CPA to timeout 5 minute schedule. Visual analog scale (VAS) self–ratings of OWD. Restoration of DBH into the NTS did not restore OWD signs paranoia were obtained at 5–min intervals throughout. Sessions were but did rescue CPA to OWD. conducted blind to DBH C—1021T genotype. Discussion: These data suggest a novel role for NE in opiate reward Results: Procedures were well tolerated by participants, and no sig- and confirm a role for NE in opiate locomotion. Further, these data nificant adverse events were noted. VAS self–ratings showed a signifi- identify the NTS as a critical component in opiate reward neural cant main effect of cocaine dose (F=19.3, p<0.001), no effect of DBH circuitry. The LC and the NTS both seem to contribute to opiate lo- genotype (F=0.7, p=0.50), but a significant dose x genotype interac- comotion. Previous findings support the idea that an increase in tion (F=2.8, p<0.05; rmANOVA, Huynh–Feldt), with ‘very low–aci- central NE neurotransmission underlies the somatic signs and pos- tivity’ TT homozygotes (N=5) reporting more paranoia than CT sibly the aversive properties of OWD. Our data suggest a more (N=11) or CC (N=15) individuals. Main effects of time (F=11.4, complex role for NE in OWD, with NE attenuating some signs p<0.001), but not genotype (F=1.64, p=0.20), and a significant geno- while intensifying others. Both the LC and NTS have been pro- type x time interaction (F=2.59, p<0.005) were also observed at the posed to play a role in OWD, though their relative contributions highest (32 mg) dose. Cocaine consumption did not differ between remain in dispute. These findings support a role for the LC in genotypic subgroups. OWD induced aversion and somatic signs and a role for the NTS in Discussion: Human laboratory data suggest that homozygous carri- OWD induced CPA. ers of ‘very low–activity’ (i.e., TT) DBH genotypes are more vulnera- ble to CIP. Panel Session Norepinephrine in Opiate Reward, Locomotion, and Withdrawal: Specificity of Cortical GABAergic Systems: Development Evidence for Distinct Contributions by the Locus Coeruleus and and Disturbances in Schizophrenia the Nucleus Tractus Solitarius Valerie Olson* Fate Determination
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