Antagonizing 5-HT2A receptors with M100907 and stimulating 5-HT2C receptors with Ro60-0175 blocks cocaine-induced locomotion and zif268 mRNA expression in Sprague-Dawley rats

Serotonin (5-HT) plays a role in several psychiatric disorders including drug addiction. The 5-HT system modulates the activity of midbrain dopamine (DA) systems, and the behavioural effects of psychostimulants mediated by these systems. The direction of this modulation depends upon the 5-HT receptor subtypes involved, with 5-HT2A and 5-HT2C receptors having opposing effects. For example the 5-HT2A receptor antagonist M100907 and the 5-HT2C receptor agonist Ro60-0175 both attenuate several cocaine-induced behavioural and neurochemical effects. To investigate the possible brain regions involved in the interactions between 5-HT2A or 5-HT2C receptor ligands and cocaine-induced behaviour, we examined the effects of M100907 or Ro60-0175 on cocaine-induced locomotion and mRNA expression of the immediate early gene zif268. Sprague-Dawley rats were pre-treated with M100907 (0.5 mg/kg), Ro60-0175 (1.0 mg/kg) or vehicle, and then injected with cocaine (15 mg/kg) or vehicle. Locomotor activity was monitored for 60 min before rats were sacrificed for zif268 mRNA in situ hybridization mapping. Cocaine increased locomotor activity and zif268 mRNA expression consistently in the nucleus accumbens core, the orbitofrontal cortex and the caudate. M100907 attenuated cocaine-induced locomotion and zif268 mRNA expression in these brain regions in a defined subset of rats but failed to alter any effects of cocaine in another defined subset of rats. Ro60-0175 blocked cocaine-induced locomotion and zif268 mRNA expression in similar brain regions. Our results suggest that despite the opposing actions of 5-HT at 5-HT2A and 5-HT2C receptors, ligands acting on these receptors likely modulate cocaine-induced locomotion via a common mechanism to influence DA-dependent circuitry.

► We examine the effects of M100907 and Ro60-0175 on cocaine-induced locomotion and neural activation.
► Cocaine increases locomotor activity and zif268 mRNA expression in the brain.
► M100907 blocks cocaine-induced locomotor activity and zif268 mRNA expression in a subset of rats.
► Ro60-0175 blocks cocaine-induced locomotor activity and zif268 mRNA expression.
► 5-HT2A and 5-HT2C receptors modulate cocaine-induced behaviour through similar dopamine-rich circuits.