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February, 2010 NIDA - Director's Report - February, 2010 NIDA Home > Publications > Director's Reports Director's Report to the National Advisory Council on Drug Abuse - February, 2010 Report Index Index Older Reports - go to the Archives Research Findings Basic Neurosciences Research Basic Behavioral Research Behavioral and Brain Development Research NACDA Clinical Neuroscience Research Legislation Epidemiology and Etiology Research Prevention Research Research on Behavioral and Combined Treatments for Drug Abuse Research on Pharmacotherapies for Drug Abuse Research on Medical Consequences of Drug Abuse and Co-Occurring Infections (HIV/AIDS, HCV) Services Research Clinical Trials Network Research International Research Intramural Research Program Activities Extramural Policy and Review Activities Congressional Affairs International Activities Meetings and Conferences Media and Education Activities Planned Meetings Publications Staff Highlights Grantee Honors https://archives.drugabuse.gov/DirReports/DirRep210/[11/17/16, 11:24:55 PM] NIDA - Director's Report - February, 2010 Archive Home | Accessibility | Privacy | FOIA (NIH) | Current NIDA Home Page The National Institute on Drug Abuse (NIDA) is part of the National Institutes of Health (NIH) , a component of the U.S. Department of Health and Human Services. Questions? _ See our Contact Information. https://archives.drugabuse.gov/DirReports/DirRep210/[11/17/16, 11:24:55 PM] NIDA - Director's Report - February, 2010 NIDA Home > Publications > Director's Reports > February, 2010 Index Director's Report to the National Advisory Council on Drug Abuse - February, 2010 Index Research Findings - Basic Neuroscience Research Research Findings Activation of the Kappa Opioid Receptor in the Dorsal Raphe Basic Neurosciences Nucleus, and Involving Serotonergic but not Dopaminergic Research Transmission, Mediates the Aversive Effects of Stress and Basic Behavioral Research Reinstates Drug Seeking Behavioral and Brain Development Research Although stress has profound effects on motivated behavior including drug seeking, the underlying mechanisms responsible are incompletely understood. Clinical Neuroscience Previous studies have supported a role for the dynorphin/kappa opioid receptor Research (KOR) system in mediating the pro-addictive effects of stress-induced relapse. Epidemiology and Etiology However, the brain region(s) and circuitry underlying KOR action are Research unresolved. This study elucidates a functional neural pathway in mouse brain Prevention Research that encodes the aversive effects of stress and mediates stress-induced reinstatement of cocaine conditioned place preference (CPP). Activation of the Research on Behavioral and dynorphin/kappa opioid receptor (KOR) system by either repeated stress or Combined Treatments for agonist produces conditioned place aversion (CPA). Because KOR inhibition of Drug Abuse dopamine release in the mesolimbic pathway has been proposed to mediate Research on the dysphoria underlying this response, Dr. Chavkin and his colleagues tested Pharmacotherapies for Drug dopamine-deficient mice in this study and found that KOR agonist in these mice Abuse still produced CPA. However, inactivation of serotonergic KORs by injection of Research on Medical the KOR antagonist norBNI into the dorsal raphe nucleus (DRN), blocked Consequences of Drug aversive responses to the KOR agonist U50,488 and blocked stress-induced Abuse and Co-Occurring reinstatement of CPP. Additionally, KOR knockout (KO) mice did not develop Infections (HIV/AIDS, HCV) CPA to U50,488; however, lentiviral re-expression of KOR in the DRN of KOR KO mice restored place aversion. DRN serotonergic neurons project broadly Services Research throughout the brain, but the inactivation of KOR in the nucleus accumbens Clinical Trials Network (NAc) coupled with viral re-expression of KOR in the DRN of KOR KO mice Research demonstrated that aversion was encoded by a DRN to NAc projection. These International Research results suggest that the adverse effects of stress may converge on the serotonergic system and offers an approach to controlling stress-induced Intramural Research dysphoria and relapse. Land BB, Bruchas MR, Schattauer S, et al. Activation of Program Activities the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking. Proc Natl Acad Sci U S A. 2009 Extramural Policy and Nov 10;106(45):19168-19173. Review Activities Dopamine Enables In Vivo Synaptic Plasticity Associated with the Congressional Affairs Addictive Drug Nicotine International Activities Addictive drugs induce a dopamine signal that contributes to the initiation of addiction, and the dopamine signal influences drug-associated memories that Meetings and Conferences perpetuate drug use. The addiction process shares many commonalities with the synaptic plasticity mechanisms normally attributed to learning and Media and Education memory. Environmental stimuli repeatedly linked to addictive drugs motivate Activities continued drug use. This paper, employing in vivo recording techniques, shows https://archives.drugabuse.gov/DirReports/DirRep210/DirectorReport1.html[11/17/16, 11:24:59 PM] NIDA - Director's Report - February, 2010 for the first time that in freely moving and behaving mice, physiologically Planned Meetings relevant concentrations of the addictive drug, nicotine, directly cause in vivo hippocampal synaptic potentiation of the kind that underlies learning and Publications memory. This nicotine-induced long-term synaptic plasticity required a local hippocampal dopamine signal. Disrupting general dopamine signaling Staff Highlights prevented the nicotine-induced synaptic plasticity and conditioned place preference. These results suggest that dopaminergic signaling serves as a Grantee Honors functional label of salient events by enabling and scaling synaptic plasticity that underlies drug-induced associative memory. Tang J, Dani JA. Dopamine enables in vivo synaptic plasticity associated with the addictive drug nicotine. Neuron. 2009 Sep 10;63(5):673-682. Selective Blockade of the Hydrolysis of the Endocannabinoid, 2- AG, but not of Anandamide (AEA), Enhances Retrograde Endocannabinoid Signaling and the Duration of Endocannabinoid- mediated Synaptic Transmission Endocannabinoid (eCB) signaling mediates depolarization-induced suppression of excitation (DSE) and inhibition (DSI), two prominent forms of retrograde synaptic transmission (synaptic depression). N-Arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), two known eCBs, are degraded by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Selective blockade of FAAH and MAGL is critical for determining the roles of the eCBs in DSE/DSI and understanding how their action is regulated. 4-Nitrophenyl 4-(dibenzo[d][1,3]dioxol-5- yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) is a recently developed, highly selective, and potent MAGL inhibitor that increases 2-AG but not AEA concentrations in mouse brain. Here, NIDA supported investigators report that JZL184 prolongs DSE in Purkinje neurons in cerebellar slices and DSI in CA1 pyramidal neurons in hippocampal slices. In contrast, neither the selective FAAH inhibitor cyclohexylcarbamic acid 3'-carbomoylbiphenyl-3-yl ester (URB597) nor FAAH knockout has a significant effect on DSE/DSI. These results indicate that the degradation of 2-AG by MAGL is the rate-limiting step that determines the time course of DSE/DSI and that JZL184 is a useful tool for the study of 2-AG-mediated signaling. Pan B, Wang W, Long JZ, Sun D, Hillard CJ, Cravatt BF, Liu QS. Blockade of 2-arachidonoylglycerol hydrolysis by selective monoacylglycerol lipase inhibitor 4-nitrophenyl 4-(dibenzo[d] [1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) enhances retrograde endocannabinoid signaling. J Pharmacol Exp Ther. 2009 Nov;331(2):591-597. Persistent Changes in Brain Function after Repeated Ketamine The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is a pediatric and veterinary anesthetic that is also abused at lower doses (as "Special K," etc.). Ketamine elicits and exacerbates psychotic symptoms resembling schizophrenia, including auditory hallucinations, blunted affect, and withdrawal. In some cases, past ketamine abuse is associated with a persisting psychosis, and it is not possible to determine whether a pre-existing psychosis was made florid by the drug, or the drug caused a new psychotic illness. Steven Siegel and his colleagues assessed the effects of chronic administration of a sub- anesthetic dose of ketamine on contextual fear conditioning, detection of pitch deviants, and auditory gating, in mice; deficits in these tests serve as models of schizophrenia. After four weeks of daily ketamine injections, mice exhibited decreased freezing in the fear conditioning paradigm (48 hr after cessation of treatment, which was the final test). Gating of the P80 component of auditory evoked potentials was significantly altered, as the four weeks of daily ketamine caused a significant decrease in S1 amplitude (3 and 5 weeks (last test) after cessation of treatment). S1 P20 latency was significantly increased as a result of ketamine treatment (3 and 5 weeks after cessation of treatment). Although https://archives.drugabuse.gov/DirReports/DirRep210/DirectorReport1.html[11/17/16, 11:24:59 PM] NIDA - Director's Report - February, 2010 there was no effect of ketamine on detection of pitch deviants, these results indicate that repeated
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