Cannabinoid-dopamine interaction in the pathophysiology and treatment of CNS disorders

Abstract

Endocannabinoids and their receptors, mainly the CB(1) receptor type, function as a retrograde signaling system in many synapses within the CNS, particularly in GABAergic and glutamatergic synapses. They also play a modulatory function on dopamine (DA) transmission, although CB(1) receptors do not appear to be located in dopaminergic terminals, at least in the major brain regions receiving dopaminergic innervation, e.g., the caudate-putamen and the nucleus accumbens/prefrontal cortex. Therefore, the effects of cannabinoids on DA transmission and DA-related behaviors are generally indirect and exerted through the modulation of GABA and glutamate inputs received by dopaminergic neurons. Recent evidence suggest, however, that certain eicosanoid-derived cannabinoids may directly activate TRPV(1) receptors, which have been found in some dopaminergic pathways, thus allowing a direct regulation of DA function. Through this direct mechanism or through indirect mechanisms involving GABA or glutamate neurons, cannabinoids may interact with DA transmission in the CNS and this has an important influence in various DA-related neurobiological processes (e.g., control of movement, motivation/reward) and, particularly, on different pathologies affecting these processes like basal ganglia disorders, schizophrenia, and drug addiction. The present review will address the current literature supporting these cannabinoid-DA interactions, with emphasis in aspects dealing with the neurochemical, physiological, and pharmacological/therapeutic bases of these interactions.

Figure 1

Processes involved in the function of endocannabinoids and CB₁ receptors as a retrograde signaling mechanism in glutamatergic neurons.

Figure 2

Distribution of CB₁ and TRPV₁ receptors in different neuronal subpopulations in the basal ganglia circuitry (DA, dopamine; GABA, γ‐aminobutiric acid; GLU, glutamate).

Figure 3

Summary of potential therapeutic applications proposed for CB₁ receptor antagonists in pathologies related to dopamine transmission in the CNS.