Cannabinoid-dopamine interactions: Modulation of midbrain DA neurons by endocannabinoids

A key feature of human and animal behavior is to learn from environmental stimuli to adapt efficiently. Under physiological conditions, dopaminergic (DA) neurons are used to evaluate and learn new sensory information and adjust behavior to maximize reward and minimize aversive consequences. The two main DA pathways in the mesencephalon originate from the substantia nigra pars compacta (SNpc) and the ventral tegmental area (VTA). Both in vivo and in vitro studies have established that DA neurons exhibit spontaneous spike firing that is driven by intrinsic electrophysiological properties, with their activity modulated by afferent inputs and a number of neuromodulators, including endocannabinoids. In the VTA and SNpc, cannabinoid type 1-CB (CB1 ) and ionotropic transient receptor potential vanilloid type 1 (TRPV1) receptors are abundantly expressed as well as their endogenous ligands, mainly anandamide and 2-arachidonoylglycerol. This chapter attempts to summarize some of the major research findings demonstrating that SNpc and VTA DA neurons vary significantly in their molecular and physiological properties according to target location, and that endocannabinoids act on GABAergic, glutamatergic and cholinergic terminals to participate in discrete mechanisms aimed at DA cell homeostatic regulation. As a result, given the role of the endocannabinoid system in modulating DA neuronal function of the SNpc and the VTA, they might take part in associative learning, reward signaling, goal directed behavior, motor skill learning and action-habit transformation. These considerations help explaining the correlation between an unbalanced endocannabinoid signal and altered DA-dependent processes underpinning diverse pathological conditions of both nigrostriatal and mesocorticolimbic systems.