The proposed experiments will test the hypothesis that both enhanced dopamine (DA) overflow and increased functionality of D-1DA receptors contribute to the behavioral sensitization observed following repeated cocaine administration. Specifically, we hypothesize that following withdrawal from repeated cocaine administration, evoked DA overflow from nerve terminals will be increased only when a cocaine challenge is given but that terminal release-modulating D-2DA autoreceptors and postsynaptic D-1DA receptors will be supersensitive whether or not a cocaine challenge is given. In vivo voltammetry in anesthetized rats and n vitro slice preparations will be used to study cocaine-induced changes in DA overflow in the nucleus accumbens (NAc) and striatum. Rats will be treated with saline or cocaine (10 mg/kg, i.p.; twice daily) for 14 days and withdrawn for 7 days. Using in vivo voltammetry, electrical-and K+-evoked DA overflow will be compared in the NAc and striatum following no cocaine challenge, local cocaine or DA challenge and systemic cocaine challenge. These experiments will indicate whether cocaine challenge is required to increase evoked DA overflow, whether the change in overflow is observed when the stimulus is restricted to the terminal or dependent on the cell body and/or impulse flow and whether changes in vesicular release and/or the DA transporter are involved. Slice preparations will be used to investigate changes in the ability of cocaine to enhance DA overflow and changes in the ability of terminal D-2DA autoreceptors to modulate this overflow. In vitro radioligand binding and adenylate cyclase assays will be used to investigate changes in agonist interactions with D-1 and D-2 DA receptor subtypes in these same regions. Increases in the proportion of high affinity receptors in the magnitude of the guanine nucleotide-induced shift in agonist affinity and/or receptor-coupled adenylate cyclase activity could contribute to enhanced postsynaptic DA responsiveness following repeated cocaine administration. To further test the relationship of the observed neurochemical and behavioral changes persist for the same duration. Also, pretreatment with either SCH-23390, a D-1 DA receptor antagonist, or with MK-801, an N-methyl-D-aspartate receptor antagonist, has been reported to block development of stimulant-induced behavioral sensitization. These two pharmacological pretreatments will used to block cocaine-induced behavioral sensitization and to determine the effect on the cocaine-induced neurochemical changes identified in the previous Specific Aims. The results of these studies will enhance our understanding of persistent changes in DA neurochemistry and regulation of the mesolimbic and nigrostriatal DA systems that occur as a result of repeated cocaine administration. It is our hope that understanding these changes will enhance our ability to predict the long-term consequences of low-level,intermittent use of cocaine on central DA systems.
Showing the most recent 10 out of 51 publications
