2004 Scientific Report

Neuropharmacology

Primate Neurobehavioral Laboratory

M.A. Taffe, S.N. Katner, S.A. Davis, A.J. Kirsten, C.C. Lay, S.N. Von Huben

We study the neuropharmacologic mechanisms involved in cognitive disruption associated with developmental disorders, aging, and repeated exposure to drugs of abuse. We developed procedures analogous to neuropsychologic evaluation in humans. Macaque monkeys are trained to perform a series of behavioral tests, thereby allowing the simultaneous evaluation of multiple cognitive domains such as learning, memory, attention, and motor function.

Attention-Deficit/Hyperactivity Disorder

We developed a nonhuman primate model of attentional focusing to investigate cognitive impairments associated with attention-deficit/hyperactivity disorder (ADHD). Using this model and methylphenidate (Ritalin), the stimulant used to treat ADHD in humans, we found that adolescent monkeys treated with methylphenidate can shift their attentional focus more efficiently than can monkeys not given the stimulant and that the dopamine D₂ receptor antagonist raclopride inhibits such shifts. We are also investigating the effects of nonstimulant ADHD medications and the role played by nondopaminergic neuronal systems in attentional focusing. This research in adolescent monkeys creates a nonhuman primate model of ADHD that can be used to examine the impact of chronic ADHD pharmacotherapy on cognition, physiology, and growth.

Age-Related Cognitive Decline

We adapted our neuropsychologic testing battery to aged monkeys and found significant age-related deficits in number of cognitive and behavioral domains. These studies are being done in collaboration with M. Tuszynski, University of California, San Diego. We are using gene transfer via viral vectors to restore the function of atrophic neurons in the prefrontal cortex and temporal cortex of aged monkeys. In these studies, we will determine the regional selectivity of improvement in cognitive function associated with gene therapy in aged macaques. The results will be critical for individually determining the type or location of gene transfer in human patients with divergent dementias.

Alcohol abuse

Using our model of chronic oral alcohol consumption, we can produce blood alcohol levels in excess of the legal limit in both periadolescent and young adult monkeys, producing obvious intoxication and impaired motor performance. In ongoing studies, we are examining the effects of repeated intoxication during adolescence on the learning of complex cognitive tasks, circadian patterns, and CNS neurochemistry. The results will help elucidate the risks posed by alcohol consumption during a period critical for brain development and formal schooling in humans. We are also using this model, in collaboration with H.S. Fox, Department of Neuropharmacology, to determine if alcohol use alters the pathogenicity of simian immunodeficiency virus infection in the rhesus model of neuroAIDS.

Publications

Katner, S.N., Davis, S.A., Kirsten, A.J., Taffe M.A. Effects of nicotine and mecamylamine on cognition in rhesus monkeys. Psychopharmacology (Berl.), in press.

Katner, S.N., Flynn, C.T., Von Huben, S.N., Kirsten, A.J., Davis, S.A., Lay, C.C., Cole, M., Roberts, A.J., Fox, H.S., Taffe M.A. Controlled and behaviorally relevant levels of oral ethanol intake in rhesus macaques using a flavorant-fade procedure. Alcohol. Clin. Exp. Res. 28:873, 2004.

Madden, L.J., Zandonatti, M.A., Flynn, C.T., Taffe, M.A., Marcondes, M.C.G., Schmitz, J.E., Reimann, K.A., Henriksen, S.J., Fox, H.F. CD8⁺ cell depletion amplifies the acute retroviral syndrome. J. Neurovirol. 10(Suppl. 1):58, 2004.

Roberts, E.S., Zandonatti, M.A., Watry, D.D., Madden, L.J., Henriksen, S.J., Taffe, M.A., Fox, H.S. Induction of pathogenic sets of genes in macrophages and neurons in neuroAIDS. Am. J. Pathol. 162:2041, 2003.

Taffe, M.A. Effects of parametric feeding manipulations on behavioral performance in macaques. Physiol. Behav. 81:59, 2004.

Taffe, M.A., Huitrón-Reséndiz, S., Schroeder, R., Parsons, L.H., Henriksen, S.J., Gold, L.H. MDMA exposure alters cognitive and electrophysiological sensitivity to rapid tryptophan depletion in rhesus monkeys. Pharmacol. Biochem. Behav. 76:141, 2003.

Taffe, M.A., Weed, M.R., Gutierrez, T., Davis, S.A., Gold, L.H. Modeling a task that is sensitive to dementia of the Alzheimer’s type: individual differences in acquisition of a visuo-spatial paired-associate learning task in rhesus monkeys. Behav. Brain Res, 149:123, 2004.

Weed, M.R., Gold, L.H., Polis, I., Koob, G.F., Fox, H.S., Taffe M.A. Impaired performance on a rhesus monkey neuropsychological testing battery following simian immunodeficiency virus infection. AIDS Res. Hum. Retroviruses 20:77, 2004.