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 Rats were withdrawn from continuous cocaine administration (40 mg/kg per day cocaine for 14 days) for 7 days, and then slices from the nucleus accumbens obtained.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 mu M 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.