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Friedbert Weiss, PhD



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Work in our laboratory is concerned with the neurobiological basis of motivation and reinforcement. Currently this research focuses predominantly on the understanding of neurochemical and neuroendocrine mechanisms in vulnerability to drug abuse and the development of dependence. To this end our laboratory combines behavioral analyses of drug and alcohol-seeking behavior with in vivo neurochemical, pharmacological, and molecular approaches.

Neurobiological Mechanisms of Drug Dependence. One of the research objectives in our laboratory is to identify neurochemical mechanisms that underlie the development of drug and alcohol dependence. Our observations indicate that dependence involves counteradaptive changes within the same neural systems that mediate the acute reinforcing actions of a drug (e.g., deficiencies in the release of forebrain neurotransmitters such as dopamine and serotonin)! as well as changes within systems that are not involved in the acute reinforcing actions of the drug but, when engaged, oppose the drug's reinforcing effecis (e.g., activation of brain stress systems such as corticotropin-releasing factor in the central nucleus of the amygdala). These neuroadaptive perturbations may lead to the emergence of withdrawal states that could motivate continued abuse of the drug. Our current interest is to further characterize the role of neuroadaptive changes in drug dependence and to examine their long-term behavioral consequences and role in vulnerability to relapse.

Development of Animal Models of Craving and Relapse. An important aspect of our work is the development of behavioral methods that can effectively model specific aspects of human drug-seeking behavior in animals. For example, high rates of relapse are a substantial problem in the treatment of drug abuse and dependence but the preclinical investigation of the neurobiologic basis of relapse and identification of potential therapeutic agents has been hampered by a lack of effective animal analogs. Drug craving and relapse in humans occurs most often in conjunction with exposure to drug-related environmental stimuli and the experience of stress. We have developed methods that permit investigation of drug-seeking behavior associated with these conditions experimentally by examining the motivational effects of drug-related environmental stimuli and stressors in rats. In this model, incentive-motivational stimuli associated with drugs of abuse can elicit and maintain robust drug-seeking behavior after extended periods of abstinence, an effect that is enhanced by concomitant exposure to stress. These motivational effects of drug-related stimuli seem to involve activation of central dopamine and opoid systems. Future efforts will more precisely establish the neurochemical basis of drug "craving" and relapse processes.

Detection of Large Molecular Weight Neuropeptides by Intracranial. In spite of the growing range of applications of microdialysis for the monitoring of analytes in the brain extracellular space, this technique has not been extensively applied to the measurement of neuropeptides, particularly those with molecular weights exceeding 2500 daltons. Neuropeptides are present only in low concentration in the extraneuronal compartment and tend to bind to dialysis membrane and tubing materials resulting in poor recovery and the requirement for extremely sensitive analytical methods. We have recently devised effective strategies to improve the recovery and detection of large molecular weight peptides by reducing nonspecific binding, inclusion of specific antibodies in the dialysis perfusion medium to maximize the inward diffusion gradient, and developing a highly sensitive "in vivo" radioimmunoassay. These modifications now permit reliable detection of basal extracellular levels of peptides such as corticotropin releasing factor (m.w.: 4,758) under physiologically relevant conditions. The nature of our research requires continuous technical advancement and validation of microdialysis methodologies as well as refinement of analytical techniques. We are currently developing procedures to adapt the microdialysis technique for the measurement of neuroactive steroids in the brain using ultra-sensitive mass-spectrometric techniques.

Weiss, F., Lorang, M.T., Bloom, F.E., and Koob, G.F. (1993). Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: Genetic and motivational determinants. Journal

Merlo Pich, E.M., Koob, G.F., Heilig, M., Menzaghi, F., Vale, W., and Weiss, F. (1993). Corticotropin releasing factor release from the mediobasal hypothalamus of the rat as measured by microdialysis.

Weiss, F., Parsons, L.H., Schulteis, G., Lorang, M.T., Hyyti;~, P., Bloom, F.E., and Koob, G.F. (1996). Ethanol self-administration restores withdrawal-associated deficiencies in accumbal dopamine and

Parsons, L.H., Koob, G.F., and Weiss, F. (1995). Serotonin dysfunction in the nucleus accumbens of rats during withdrawal after unlimited access to intravenous cocaine. Journal of Pharmacology and Exp

Weissenborn, R., Deroche, V., Koob, G.F., and Weiss, F. (1966). Effects of dopamine agonists and antagonists on cocaine-induced operant responding maintained by a cocaine-associated stimulus. Psychoph

De Fonseca, F.R., Carrera, M.R.A., Navarro, M., Koob, G.F., Weiss, F. (1997). Activation of Corticotropin-Releasing Factor in the Limbic System During Cannabinoid Withdrawal. Science 276: 2050-2054.

Weiss, F., Imperato, A., Casu, M.A., Mascia, M.S., and Gessa, G.L. (1997). Opposite effects of stress on dopamine release in the limbic system of drug-naive and chronically amphetamine-treated rats. E

Ciccocioppo, R., Sanna, P.P., Weiss, F. Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions following multiple months of abstinence: Reversal by D1 antagonists. Proc. Natl. Acad. Sci. USA 98:1976-1981, 2001.

Weiss, F. and Porrino, L. Minireview -- Behavioral neurobiology of alcohol addiction: Recent advances and challenges. The Journal of Neuroscience 22:3332-3337, 2002.

Liu, X. and Weiss, F. Additive effect of stress and drug cues on reinstatement of ethanol seeking: Exacerbation by history of dependence and role of concurrent activation of CRF and opioid mechanisms. The Journal of Neuroscience 22:7856-7861, 2002.

Izzo, E., Martin-Fardon, R., Koob, G.F., Weiss, F., Sanna, P.P. Neural plasticity and addiction: PI3-kinase and cocaine behavioral sensitization. Nature Neuroscience 5:1263-1264, 2002.

Ciccocioppo, R., Fedeli, A., Economidou, D., Policani, F., Weiss, F., Massi,. M. The bed nucleus of the stria terminalis is a neuroanatomical substrate for the anorectic effects of CRF and its reversal by nociceptin/orphanin FQ. The Journal of Neuroscience 23:9445-9451, 2003.

Ciccocioppo, R., Martin-Fardon, R., and Weiss, F. Stimuli associated with a single cocaine experience elicit long-lasting cocaine-seeking. Nature Neuroscience 7:495-496, 2004.

Baptista, M.A.S., Martin-Fardon, R., and Weiss, F. Preferential effects of the mGlu2/3 receptor agonist, LY379268, on conditioned reinstatement vs. primary reinforcement: Comparison between cocaine and a potent non-drug reinforcer. The Journal of Neuroscience RC 24:4723-4727, 2004.

Weiss, F. Neurobiology of craving, conditioned reward, and relapse. Current Opinion in Pharmacology 5:9-19, 2005.

Zhao, Y., Dayas, C.V., Aujla, H., Baptista, M.A.S., Martin-Fardon, R. Weiss, F. Activation of Group II metabotropic glutamate receptors attenuates both stress and cue-induced ethanol seeking and modulates c-fos expression in the hippocampus and amygdala. The Journal of Neuroscience 26:9967-9974, 2006.

Dayas, C.V., Liu,X., Simms, J.A., Weiss, F. Distinct patterns of neural activation associated with ethanol-seeking: Effects of naltrexone. Biological Psychiatry (PMID: 17098214).

Dayas, C.V., Martin-Fardon, R., Weiss, F. Stimuli linked to ethanol availability activate hypothalamic CART and orexin neurons in a reinstatement model of relapse. Biological Psychiatry (in press).