Effects of cannabinoids on prefrontal neuronal responses to ventral tegmental area stimulation

Cannabinoids activate the firing of mesoprefrontocortical dopamine neurons and release dopamine in the prefrontal cortex. This study was undertaken wi th the aim of clarifying the interaction between cannabinoids and mesocorti cal system in the prefrontal cortex. The effect of Delta (9)-tetrahydrocann abinol (Delta (9)-THC) and the synthetic CB1 agonist WIN55,212-2 (WIN) was studied by extracellular single unit recordings, in chloral hydrate anaesth etised rats, on the spontaneous activity of pyramidal neurons and on the in hibition produced on these neurons by the electrical stimulation of the ven tral tegmental area (VTA). Intravenously administered Delta (9)-THC and WIN (1.0 and 0.5 mg/kg, respectively), increased the firing rate of pyramidal neurons projecting to the VTA. VTA stimulation produced a phasic inhibition (167 +/- 6 ms) in 79% of prefrontal cortex pyramidal neurons. Delta (9)-TH C and WIN reverted this inhibition in 73% and 100% of the neurons tested, r espectively. The subsequent administration of the selective CB1 antagonist SR141716A (1 mg/kg) readily suppressed the effects of both cannabinoids and restored the inhibitory response to VTA stimulation. Moreover, when admini stered alone, SR141716A prolonged the inhibition in 55.6% of the neurons te sted. The results indicate that stimulation of CB1 receptors by cannabinoid s results in an enhanced excitability of prefrontal cortex pyramidal neuron s as indexed by the suppression of the inhibitory effect of VTA stimulation and by the increase in firing rate of antidromically identified neurons pr ojecting to the VTA. Furthermore, our results support the view that endogen ous cannabinoids exert a negative control on dopamine activity in the prefr ontal cortex. This study may be relevant in helping to understand the influ ence of cannabinoids on cognitive processes mediated by the prefrontal cort ex.