News and Publications

Behavioral Neuroscience

L.H. Gold, G.F. Koob, M.R. Weed, M.A. Taffe, A. Contarino, V. David, I. Polis, J.S. McDonald, S. Davis, T. Gutierrez

FUNCTIONAL ASSESSMENT OF DRUG AND VIRAL TOXIC EFFECTS IN PRIMATES

Rhesus monkeys trained in a battery of behavioral tests were treated with a regimen of high doses of 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy). Performance in tests used to measure memory, motivation, reaction time, and bimanual motor coordination were monitored. Performance in all behavioral tasks was disrupted during treatment with MDMA. Performance in the motivation test was impaired the week after treatment but then returned to baseline levels. Performance in the memory and reaction time tests was equivalent to baseline levels in the first week after treatment. Studies done in collaboration with S. Henriksen, Department of Neuropharmacology, indicated that MDMA treatment also produced alterations in sensory evoked potentials measured at 2 and 4 weeks after treatment. This MDMA dose regimen resulted in alterations of serotonergic neurochemistry, behavior, and electrophysiologic characteristics. A long-term follow-up study is under way.

Simian immunodeficiency virus (SIV) infection in rhesus monkeys is similar in many ways to HIV infection in humans. In collaboration with S. Henriksen and H. Fox, Department of Neuropharmacology, we are using behavioral and corresponding electrophysiologic and clinical methods to develop a profile of the progression of SIV disease. Initially, monkeys have high plasma levels of virus and show reductions in performance of the test of motivation. Generally, plasma levels of virus then decrease. Occasionally, viral titers return to high levels while antibody levels remain low, a situation that leads to a rapid onset of disease. In one monkey with these characteristics, behavioral and brain changes included reduced performance in the motivation test 4 weeks after infection, slowed response in the reaction time test at 5 weeks, slowed brain-stem auditory evoked potentials at 8 weeks, and impaired fine motor performance at 9 weeks. Performance of a spatial working memory task declined dramatically. In contrast, a monkey with a longer disease progression had slowed brain-stem auditory evoked potentials 7 months after infection, declines in performance in the tests for motivation and reaction time at 9 months, and impairments in the performance of fine motor tasks at 13 months. As with AIDS in humans, individual differences influence the clinical nature of SIV disease.

ASSESSMENT OF DRUG ABUSE AND VIRAL PATHOGENESIS IN MOUSE MODELS

Possible mediators of pathogenesis associated with neuroAIDS include virus-derived (gp120) and host-derived (IL-6) factors. Transgenic mice that express gp120 or IL-6 have unique neuropathologic changes that replicate specific aspects of the neuropathologic changes that occur in patients with AIDS. To examine the relationship between drugs of abuse and disease, we are examining the effects of cocaine on motor activation, suppression of food-reinforced operant responding, and intravenous drug self-administration in these transgenic mice. The dose-effect function for cocaine self-administration and the effects of cocaine on food-reinforced operant responding were similar in IL-6 transgenic mice and control mice; gp120 transgenic mice had reduced locomotor stimulation after cocaine administration. These results suggest that sensitivity to the reinforcing effects of cocaine may not be altered by long-term expression of cytokine (IL-6) and that the stimulant actions of cocaine may be affected by gp120.

The use of intravenous drug self-administration protocols in newly developed transgenic and knockout mouse models is valuable for studying the neuropharmacologic aspects of drug abuse. We evaluated the interaction between drugs and operant responses by using either nose-poke or lever-press responding to measure the acquisition of heroin self-administration. When nose-poke responses were used, most of the mice had a stable pattern of heroin intake by day 10. However, a few learned to discriminate the "active" from the "inactive" hole. Indeed, many responded predominantly in the inactive hole. In comparison, response efficiency (i.e., discrimination between active and inactive) for heroin during acquisition seemed to improve when lever-press responding was evaluated. These parametric studies are important for the development of an optimal protocol to compare the reinforcing effects of drugs among inbred and genetically modified mice.

PUBLICATIONS

Brot, M.D., Rall, G.F., Koob, G.F., Oldstone, M.B.A., Gold, L.H. Cognitive deficit remains despite clearance of long-term persistent viral infection in mice. J. Neurovirol. 3:265, 1997.

Deroche, V., Caine, S.B., Heyser, C.J., Polis, I., Koob, G.F., Gold, L.H. Differences in the liability to self-administer intravenous cocaine between C57BL/6 x SJL and Balb/cByJ mice. Pharmacol. Biochem. Behav. 57:429, 1997.

Fox, H.S., Gold, L.H., Henriksen, S.J., Bloom, F.E. Simian immunodeficiency virus: A model for neuroAIDS. Neurobiol. Dis. 4:265, 1997.

Gold, L.H., Fox, H.S., Henriksen, S.J., Buchmeier, M.J., Weed, M.R., Taffe, M.A., Huitron-Resendiz, S., Horn, T.F.W., Bloom T.E. Longitudinal analysis of behavioral neurophysiological, viral and immunological effects of SIV infection in rhesus monkeys. J. Med. Primatol., in press.

Heyser, C.J., McDonald, J.S., Beauchamp, V., Koob, G.F., Gold, L.H. The effects of cocaine on operant responding for food in several strains of mice. Psychopharmacology 132:202, 1997.

Roberts, A.J., Polis, I., Gold, L.H. Intravenous self-administration of heroin, cocaine and the combination in Balb/c mice. Eur. J. Pharmacol. 326:119, 1997.

Schulteis, G., Gold, L.H., Koob, G.F. Preclinical behavioral models for addressing unmet needs in opiate addiction. Semin. Neurosci. 9:94, 1997.

Smith, G.W., Aubry, J.-M., Dellu, F., Contarino, A., Bilezikjian, B., Gold, L., Chen, R., Marchuk, Y., Hauser, C., Bentley, C., Sawchenko, P.E., Koob, G., Vale, W., Lee, K.-F. Corticotropin releasing factor receptor 1 deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron, in press.

Weed, M.R., Gold, L.H. The effects of dopaminergic agents on reaction time in rhesus monkeys. Psychopharmacology, 137:32, 1998.