Figure 1. Two endocannabinoid-dependent mechanisms have been identified that are involved in mediating natural-reward and drug-seeking responses. A) One mechanism relates to disinhibition of ventral tegmental area (VTA) A10 dopamine neurons by cannabinoid type 1 (CB₁) receptor activation.¹⁶ Under baseline conditions, dopamine neurons within the VTA are inhibited by GABA through activation of GABA_B receptors. Following the presentation of drug-conditioned cues, dopamine neurons switch into phasic firing mode. Through this electrical event, intracellular calcium levels increase, which results in the activation of diacylglycerol lipase (DAGL) and the subsequent synthesis of 2-arachidonylglycerol (2-AG). 2-AG is then postsynaptically released and acts retrogradely at CB₁ receptors on GABAergic interneurons. CB₁-receptor activation leads to an inhibition of GABA release. This GABA suppression results in disinhibition of dopamine neurons, which further promotes burst firing. Blockade of either GABA_B receptors^38,39 or CB₁ receptors can also inhibit reward-seeking responses through this mechanism. B) The other mechanism relates to endocannabinoid/glutamate interactions within the nucleus accumbens (NAc) glutamatergic afferents from prefrontal regions impinging on D1-medium spiny neurons (D1-MSN). Glutamate-induced activation of metabotropic glutamate receptor 5 (mGluR5) leads to the induction of DAGL and 2-AG synthesis. 2-AG is then released and retrogradely activates Gi/o-coupled CB₁ receptors to inhibit further glutamate release. Blockade of either mGluR5^40,42 or CB₁ or CB₁ receptors^43,44 or CB₁ abolishes natural-reward– and drug-reward–seeking responses.³⁶ 2-AG, 2-arachidonylglycerol; Ca²⁺, calcium; CB₁, cannabinoid type 1 receptor; DA, dopamine; DAGL, diacylglycerol lipase; mGluR5, metabotropic glutamate receptor 5; MSN, medium spiny neurons; NAc, nucleus accumbens; VTA, ventral tegmental area.