Rationale: The serotonin 5-HT(2A) and 5-HT(2C) receptors, which are found in abundance in the mesolimbocortical dopaminergic system, appear to modulate the behavioral effects of cocaine.
Objectives: The present series of studies set out to investigate the role of 5-HT(2A) and 5-HT(2C) receptors on brain reward and on the reward-facilitating effect of cocaine and localize the neural substrates within the mesolimbocortical dopaminergic system that are responsible for these effects.
Methods: Male Sprague-Dawley rats were implanted with stimulating electrodes and bilateral cannulae for the experiments involving microinjections and were trained to respond to electrical stimulation. In the first study, we examined the effects of systemic administration of selective 5-HT(2A) and 5-HT(2C) receptor agonists (TCB-2 and WAY-161503) and antagonists (R-96544 and SB-242084) on intracranial self-stimulation (ICSS). In the second study, we examined the effectiveness of TCB-2, WAY-161503, R-96544, and SB-242084 in blocking the reward-facilitating effect of cocaine. In the third study, we examined the effects of intra-medial prefrontal cortex (mPFC), intra-nucleus accumbens (NAC), and intra-ventral tegmental area (VTA) injection of WAY-161503 on the reward-facilitating effect of cocaine.
Results: Acute systemic administration of TCB-2 and WAY-161503 increased ICSS threshold. Systemic WAY-161503 attenuated the reward-facilitating effect of cocaine. This effect was reversed by pretreatment with SB-242084. Intracranial microinjections of WAY-161503 into the mPFC and the NAC shell/core, but not the VTA, attenuated the reward-facilitating effect of cocaine.
Conclusion: These data indicate that 5-HT(2C) receptors within the mPFC and the NAC modulate the reinforcing effects of cocaine and provide evidence that 5-HT(2C) receptor agonists could be a possible drug discovery target for the treatment of psychostimulant addiction.