Behavioral consequences of human methamphetamine (METH) abuse have been extensively documented. However, underlying neurobiological mechanisms for those behaviors remain unspecified. A more precise and thorough examination of those processes still requires the use of appropriate animal models that address the broad range of abuse patterns in humans. For the proposed studies, we will model aspects of human chronic METH exposure in nonhuman primates with an integrated evaluation of biological, psychological, and environmental determinants. A 6 month escalating METH dose protocol that reflects human METH abuse patterns will be administered to vervet monkeys (Cercopithecus aethiops sabaeus) housed in naturally composed social groups. Presynaptic striatal dopamine (DA) transporter binding decreases will be determined in vivo throughout the study with PET to establish its sensitivity as an in vivo index of behavioral reactivity to METH. Behavioral alterations of impulsivity, aggression, and social relationships will be evaluated throughout the METH exposure and then continued for 6 months post-METH abstinence period to assess potential recovery. Cognitive alterations will be assessed by a battery of neuropsychological tasks. Individual differences in behavioral reactivity to METH, which are often seen in humans, will be evaluated in our METH subjects by measurement of pre-METH CSF monoamine metabolite levels (HVA, 5-HIAA, MHPG) and the extent of their changes, post-METH. Neurotoxicity of METH as expressed in dopamine and serotonin pathways within cortical, nigrostriatal and limbic regions will be evaluated by post-mortem measures of substantia nigra cell loss, pre-synaptic transporter and post-synaptic receptor densities (DA 1, DA2, 5-HT 1 A, 5-HT2A). The results will show in socially-housed adult nonhuman primates, the vulnerability of regional brain systems to METH exposure in conjunction with specific behavioral and cognitive assessments. This paradigm will represent a validated primate model to evaluate the efficacy of pharmacotherapies designed for treatment of neurological and behavioral deficits associated with human METH abuse.
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