Scientific Report 2007

Committee on the Neurobiology of Addictive Disorders

Neurobiology of Addiction

G.F. Koob, B.J. Mason, L.H. Parsons, M.A. Taffe, E.P. Zorrilla, M. Roberto, C. Mandyam, H.N. Richardson, R.H. Purdy,* K.R. Buffkins, M. Le Moal,** S.H. Ahmed, L. Stinus,** L. Pulvirenti,*** K. Inoue,**** A. Tabarin,***** Y. Zhao, V. Sabino, C.K. Funk, R. Crean, B.M. Walker, T.N. Greenwell, S. Wee, N. Gilpin, O. George, L. Alvarez, P. Cottone, L. Orio, K. Misra, M. Cruz, R. Lintz, I. Polis, E. Crawford, R. Schroeder, T. Kimber, M. Cole, M.A. Arends, M. Brennan, S. Davis, D. Stouffer, Y. Grant, S. Quello, K. Morikawa

* VA Medical Center, San Diego, California
** Université Victor Ségalen Bordeaux 2, Bordeaux, France
*** Claude Bernard Neuroscience Institute, Pozzilli, Italy
**** Osaka City University Medical School, Osaka, Japan
***** Université Victor Ségalen Bordeaux 2, Hopital du Haut-Lévêque, Pessac, France

In the Laboratory of Psychopharmacology, we continue to focus on the neuropharmacologic mechanisms involved in motivated and emotional behavior and how these mechanisms are altered in addiction, stress, and genetic variability.

In studies on the neurobiology of addiction, we continue to explore the role of neurochemical systems in the extended amygdala in the neuroadaptations associated with the transition from drug taking to drug dependence that is an integral part of the development of addiction. We are developing animal models for excessive drug intake and charting the changes in neurocircuitry associated with such intake.

Animal Models of Escalated Drug Intake with Prolonged Access

Previous research established that prolonged access to cocaine and alcohol can produce progressive increases in drug intake that are paralleled by decreases in reward function. This escalation in drug intake is paralleled also by decreased reward, as indicated by elevations in thresholds for intracranial self-stimulation. More recent studies suggest that a similar escalation in drug intake with prolonged access also can occur with intake of methamphetamine, opioids, and nicotine.

Animals with prolonged 6-hour access to methamphetamine intake showed pronounced escalation, whereas animals with 1-hour access to the drug showed no escalation. Chronic exposure to methamphetamine produced a withdrawal syndrome, as indicated by decreases in appetitive responding for a sweetened solution. Similarly, 23 hours of access to heroin produced strong escalation in heroin intake and resulted in dependence, as indicated by both motivational and physical signs of withdrawal. More importantly, in rats with 23 hours of access to heroin, sensitive measures of diurnal activity and meal patterns revealed early signs of the onset of dependence. Access to nicotine for 23 hours also produced motivational and physical dependence, as indicated by physical signs, anxiety-like behavior, measures of meal patterns, and measures of diurnal activity. A marked increase in nicotine intake occurred during 23 hours of access after deprivation from access to the drug. This nicotine deprivation effect is long-lasting and increases with repeated deprivations.

These results suggest that a common component of extended access to drugs is the development of compulsive use concomitant with the development of dependence. This compulsive use not only has face validity for the human condition but also heuristic value for exploring the neurobiological mechanisms associated with the development of dependence.

Dependence-induced Intake of Alcohol

The animal models of excessive drug intake have been extended to alcohol; animals are made dependent on alcohol and then allowed access to it during acute withdrawal. Withdrawal-induced drinking in these animals is 3–4 times greater than drinking in nondependent animals. Dependence-induced drinking is selectively blocked by systemic administration of antagonists selective for receptor 1 of corticotropin-releasing factor (CRF₁).

The neurobiological substrate for CRF antagonism appears to be the central nucleus of the amygdala. Administration of a combined CRF₁/CFR₂ peptide antagonist into the central nucleus of the amygdala dose dependently reversed the excessive drinking associated with alcohol dependence. No effect was observed in nondependent animals. Microinjections of the antagonist into the bed nucleus of the stria terminalis and shell of the nucleus accumbens had no effect. The alcohol-dependent animals also had decreases in CRF immunoreactivity in the central nucleus of the amygdala at the same time point during withdrawal, suggesting increased release of CRF. Taken together, these results suggest a powerful contribution of increased CRF activity in the central nucleus of the amygdala to the motivation for excessive drinking in alcohol dependence.

Neurocircuits in Addiction

The conceptual framework for the neurobiological changes that drive addiction continue to evolve. Three major neurocircuits have been identified in the brain that drive different components of the addiction process: the reward circuit in the nucleus accumbens involving dopamine and opioid peptides as prominent neurochemical components, the antireward circuit in the extended amygdala involving CRF and other neuromodulatory agents as prominent neurochemical components, and the craving circuit in the prefrontal cortex involving glutamatergic connections. Studies in humans and animals have revealed at least 3 common components of addiction: decreases in reward, increases in brain stress systems, and hypofunctioning of the prefrontal cortex associated with impulsivity and impaired decision making. The identification of explicit neurocircuitry and neurochemical elements in the different stages of the addiction cycle provides a conceptual framework for identifying molecular targets for individual differences that underlie vulnerability to pathologic changes that affect the emotional systems of the brain.

Medications for Treatment of Addiction

An additional thrust of the Laboratory of Psychopharmacology and the Pearson Center for Alcoholism and Addiction Research has been to develop novel medications for the treatment of addiction. The combination of information from animal models and data from studies in humans has provided a conceptual framework not only for developing new medications for the clinic but also for validating the animal models. Animal models that have indicated targets for medications that may be selective for treatment of addiction include extended-access intravenous self-administration, dependence-induced drinking, and binge drinking. Drugs such as naltrexone and acamprosate (which are on the market for treatment of alcoholism) have shown efficacy in these models. Novel targets such as nalmefene and a GABAergic modulator have also been explored.

Additional studies in the development of medication include collaborations with K.D. Janda, Department of Chemistry, in which novel immunologic and chemical-immunologic approaches are used in the pharmacologic characterization of novel approaches to drug elimination. Immunoconjugates that induce an effective immune response to Δ⁹-tetrahydrocannabinol, the active ingredient in marijuana, and catalytic antibodies capable of degrading Δ⁹-tetrahydrocannabinol developed by Dr. Janda and coworkers may be useful for future immunopharmacologic approaches to treatment of addiction.

Publications

Chen, S.A., O'Dell, L., Hoefer, M., Greenwell, T.N., Zorrilla, E.P., Koob, G.F. Unlimited access to heroin self-administration: independent motivational markers of opiate dependence [published correction appears in Neuropsychopharmacology 31:2802, 2006]. Neuropsychopharmacology 31:2692, 2006.

Crabbe, J.C., Phillips, T.J., Harris, R.A., Arends, M.A., Koob, G.F. Alcohol-related genes: contributions from studies with genetically engineered mice. Addict. Biol. 11:195, 2006.

Eubanks, L.M., Rogers, C.J., Beuscher, A.E. IV, Koob, G.F., Alson, A.J., Dickerson, T.J., Janda, K.D. A molecular link between the active component of marijuana and Alzheimer's disease pathology. Mol. Pharm. 3:773, 2006.

Funk, C.K., O'Dell, L.E., Crawford, E.F., Koob, G.F. Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats. J. Neurosci. 26:11324, 2006.

Guillem, K., Vouillac, C., Azar, M.R., Parsons, L.H., Koob, G.F., Cador, M., Stinus, L. Monoamine oxidase A rather than monoamine oxidase B inhibition increases nicotine reinforcement in rats. Eur. J. Neurosci. 24:3532, 2006.

Hoefer, M.E., Voskanian, S.J., Koob, G.F., Pulvirenti, L. Effects of terguride, ropinirole, and acetyl-L-carnitine on methamphetamine withdrawal in the rat. Pharmacol. Biochem. Behav. 83:403, 2006.

Kenny, P.J., Chen, S.A., Kitamura, O., Markou, A., Koob, G.F. Conditioned withdrawal drives heroin consumption and decreases reward sensitivity. J. Neurosci. 26:5894, 2006.

Kitamura, O., Wee, S., Specio, S.E., Koob, G.F., Pulvirenti, L. Escalation of methamphetamine self-administration in rats: a dose-effect function. Psychopharmacology (Berl.) 186:48, 2006.

Koob, G.F. Alcohol dependence: the importance of neurobiology to treatment. Medscape Psychiatry Ment. Health November 2006. http://www.medscape.com/viewarticle/547893. Published October 11, 2006. Accessed October 19, 2007.

Koob, G.F. The neurobiology of addiction: a hedonic Calvinist view. In: Rethinking Substance Abuse: What the Science Shows, and What We Should Do About It. Miller, W.R., Carroll, K.M. (Eds.). Guilford Press, New York, 2006, p. 25.

Koob, G.F. The neurobiology of addiction: a neuroadaptational view relevant for diagnosis. Addiction 101(Suppl. 1):23, 2006.

Koob, G.F. A role for GABA in alcohol dependence. Adv. Pharmacol. 54:205, 2006.

Koob, G.F., Le Moal, M. Neurobiology of Addiction, Academic Press, San Diego, 2006.

Kranzler, H.R., Koob, G., Gastfriend, D.R., Swift, R.M., Willenbring, M.L. Advances in the pharmacotherapy of alcoholism: challenging misconceptions. Alcohol. Clin. Exp. Res. 30:272, 2006.

Mulligan, M.K., Ponomarev, I., Hitzemann, R.J., Belknap, J.K., Tabakoff, B., Harris, R.A., Crabbe, J.C., Blednov, Y.A., Grahame, N.J., Phillips, T.J., Finn, D.A., Hoffman, P.L., Iyer, V.R., Koob, G.F., Bergeson, S.E. Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis. Proc. Natl. Acad. Sci. U. S. A. 103:6368, 2006.

O'Brien, C.P., Koob, G.F., Mee-Lee, D., Rosenthal, R.N. New developments in addiction treatment: neurobiology of addiction and its impact on the development of future treatments. J. Clin. Psychiatry 67:1801, 2006.

O'Dell, L.E., Bruijnzeel, A.W., Smith, R.T., Parsons, L.H., Merves, M.L., Goldberger, B.A., Richardson, H.N., Koob, G.F., Markou, A. Diminished nicotine withdrawal in adolescent rats: implications for vulnerability to addiction. Psychopharmacology (Berl.) 186:612, 2006.

Sabino, V., Cottone, P., Koob, G.F., Steardo, L., Lee, M.J., Rice, K.C., Zorrilla, E.P. Dissociation between opioid and CRF₁ antagonist sensitive drinking in Sardinian alcohol-preferring rats. Psychopharmacology (Berl.) 189:175, 2006.

Solbrig, M.V., Adrian, R., Baratta, J., Lauterborn, J.C., Koob, G.F. Kappa opioid control of seizures produced by a virus in an animal model. Brain 129(Pt. 3):642, 2006.

Steffensen, S.C., Stobbs, S.H., Colago, E.E.O., Lee, R.S., Koob, G.F., Gallegos, R.A., Henriksen, S.J. Contingent and non-contingent effects of heroin on mu-opioid receptor-containing ventral tegmental area GABA neurons. Exp. Neurol. 202:139, 2006.