5-HT3 receptor mediated dopamine release in the nucleus accumbens during withdrawal from continuous cocaine

The present experiment examined changes in the ability of the selective 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (mCPBG), to facilitate K(+)-induced dopamine (DA) release during withdrawal from continuous cocaine administration. Rats were withdrawn from continuous cocaine administration (40 mg/kg per day cocaine for 14 days) for 7 days, and then slices from the nucleus accumbens obtained. Following an equilibration period, the slices were perfused with 0, 12.5, 25, or 50 microM mCPBG in the absence and presence of 25 mM K+. The samples were assayed for DA content by HPLC with electrochemical detection. Continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K(+)-induced DA overflow compared to saline control rats. These results suggest that continuous cocaine administration functionally down-regulates 5-HT3 receptors in the nucleus accumbens. These results further suggest that 5-HT3 receptor subsensitivity may represent a partial mechanism for the tolerance induced by continuous cocaine administration.