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BEHAVIORAL PHARMACOLOGY

Effects of 4'-Chloro-3-(diphenylmethoxy)-tropane on Mesostriatal, Mesocortical, and Mesolimbic Dopamine Transmission: Comparison with Effects of Cocaine

Psychobiology (G.T., A.E., J.L.K.) and Medicinal Chemistry (A.H.N.) Sections, Medications Discovery Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland

Increase in dopamine (DA) neurotransmission resulting from blockade of the DA transporter (DAT) after administration of cocaine is believed to play a major role in mediating its behavioral and reinforcing effects. Since it was hypothesized that drugs that block the DAT have cocaine-like behavioral effects, it was of interest to study in the present article the stimulant effects of cocaine on locomotor activity and on pattern of activation of DA neurotransmission in different DAergic terminal areas in rats and compare these effects with those of 4'-chloro-3-(diphenylmethoxy)-tropane (4-Cl-BZT), a benztropine analog showing higher affinity for the DAT, but reduced behavioral effects compared with cocaine. Administration of cocaine resulted in a dose-dependent stimulation of locomotor activity and DA neurotransmission in the nucleus accumbens shell and core, dorsal caudate, and in the medial prefrontal cortex (PFCX) measured by microdialysis. At comparable doses, the effects of 4-Cl-BZT on DA levels in all brain areas except the PFCX were generally reduced compared with those of cocaine, as were the effects on locomotor activity. The differences in behavioral effects corresponded generally to differences between the drugs with regard to their stimulation of extracellular DA levels, although the mechanism(s) for the differences in extracellular DA may involve effects mediated by sites other than the DAT or differences in the efficiency of the two drugs in blocking DA uptake. Nonetheless, the present results suggest that the differences in behavioral effects between cocaine and 4-Cl-BZT are related to differences in their patterns of activation of DA transmission.

Address correspondence to: Dr. Gianluigi Tanda, National Institute on Drug Abuse, Intramural Research Program, NIH/DHHS, 5500 Nathan Shock Dr., Baltimore, MD 21224. E-mail: gtanda{at}intra.nida.nih.gov

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