Dopamine neurons of the midbrain are involved in psychopathologies such as addiction and psychosis. Research conducted at the cellular level demonstrates that these neurons are indirectly modulated by “cannabis (marijuana)-like” endocannabinoid neurotransmitters binding at cannabinoid type 1 (CB1) receptor binding sites. This research suggests involvement of CB1 receptors in dopamine-mediated pathologies. Drug addiction is a chronic relapsing disorder that currently has no effective pharmacological treatment. Recent trials utilizing cannabinoid antagonists have shown promising results in reducing relapse for most drugs of abuse. It has been suggested that the reduction of relapse produced by CB1 antagonists is due to the action at CB1 receptors to reduce midbrain dopamine neuron activity (for review see Gardner, 2005). However, studies to date have not selectively investigated if modulation of cannabinoid CB1 receptors in the midbrain alter dopamine release in vivo. Previous electrophysiological techniques have demonstrated that the activation of presynaptic CB1 receptors on GABAergic neurons disinhibits dopamine cells to increase dopamine cell firing (Gardner 2005). However recent electrophysiological studies also demonstrate that CB1 receptors are located presynaptically on glutamate terminals and act to inhibit glutamate release in the midbrain ventral tegmental area (VTA, Melis et al. 2004). This implies that during burst firing of dopamine cells, endocannabinoids may be released by dopamine cells to inhibit incoming input from both stimulatory (glutamate) and inhibitory (GABA) projections. The purpose of this study was to elucidate the effect on in vivo dopamine release in the forebrain nucleus accumbens (NAc) of directly stimulating or inhibiting the cannabinoid CB1 receptor in the midbrain VTA. This study is an in vivo examination of cannabinoid type one (CB1) receptor modulation of the midbrain dopamine reward system. The effects of CB1 receptor agonists and antagonists infused directly into the midbrain VTA were measured on dopamine release in the forebrain NAc following electrical stimulation of the Prefrontal Cortex (PFC) in rats. Methods: Urethane-anaesthetised male Lewis rats were instrumented with an electrode into the PFC, a drug infusion cannula into the VTA and a carbon fibre electrode into the NAc for the measurement of dopamine levels using fixed potential amperommetry. PFC stimulated changes in dopamine levels in the NAc were measured following the VTA infusion of vehicle, a CB1 agonist (WIN55212−2, 1 nmol, 3 nmol and 10 nmol) and a CB1 antagonist (AM251, 1 nmol, 3 nmol and 10 nmol). The results show that application of a CB1 agonist into the VTA produced a dose-dependent increase in PFC stimulated NAc dopamine release, indicating cannabinoid activity on GABA cells within the VTA. Conversely, application of a CB1 antagonist into the VTA only produced a predicted decrease in PFC stimulation-evoked dopamine release at the 10 nmol dose. At 3 nmol an increase in dopamine signal occurred, suggesting cannabinoid activity on glutamate afferents at the lower dose. In conclusion, these results may indicate that the midbrain dopamine reward system is modulated primarily by CB1 receptors on GABA cells within the VTA, and to a lesser extent glutamate cells. References  Gardner EL, 2005, Endocannabinoid signaling system and brain reward: emphasis on dopamine. Pharmacol Biochem Behav 81, 263–284.  Melis M, Pistis M, Perra S, Muntoni AL, Pillolla G, Gessa GL, 2004, Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J Neurosci 24, 53−62.