Conditioned place preference for cocaine is attenuated in mice over-expressing the 5-HT₃ receptor

The serotonin 5-HT₃ receptor is thought to play a role in the reward pathway and drug abuse by modulating dopamine release within the mesolimbic pathway. Dopamine release stimulated by cocaine and methamphetamine is blocked by administration of 5-HT₃ receptor antagonists. Animal studies demonstrate that 5-HT₃ receptor antagonists decrease cocaine and methamphetamine preference. We have developed a 5-HT₃ receptor over-expressing mouse to study the role of this receptor in substance abuse. No changes in either the dopamine receptors (D1, D2, D3, and D4) or in the dopamine transporter (DAT) were found over a wide range of brain regions. 5-HT₃ receptor over-expressing mice failed to develop conditioned place preference to 10 mg/kg or 6 mg/kg cocaine but showed a modest preference for 4 mg/kg cocaine. 5HT₃ receptor over-expressing mice were more sensitive to the locomotor activating effects of low dose cocaine and methamphetamine. Further, brain slices from the transgenic mice release more dopamine in response to low concentrations of cocaine. These data suggest that 5HT₃ receptor over-expression in the forebrain decreases cocaine preference and increases acute sensitivity with a corresponding increase in the amount of dopamine released in response to cocaine.