Striatopallidal cannabinoid type-1 receptors mediate amphetamine-induced sensitization

Abstract

Repeated exposure to psychostimulants, such as amphetamine, causes a long-lasting enhancement in the behavioral responses to the drug, called behavioral sensitization.¹ This phenomenon involves several neuronal systems and brain areas, among which the dorsal striatum plays a key role.² The endocannabinoid system (ECS) has been proposed to participate in this effect, but the neuronal basis of this interaction has not been investigated.³ In the CNS, the ECS exerts its functions mainly acting through the cannabinoid type-1 (CB₁) receptor, which is highly expressed at terminals of striatal medium spiny neurons (MSNs) belonging to both the direct and indirect pathways.⁴ In this study, we show that, although striatal CB₁ receptors are not involved in the acute response to amphetamine, the behavioral sensitization and related synaptic changes require the activation of CB₁ receptors specifically located at striatopallidal MSNs (indirect pathway). These results highlight a new mechanism of psychostimulant sensitization, a phenomenon that plays a key role in the health-threatening effects of these drugs.

Keywords: CB(1) receptor; psychostimulants; sensitization; striato-pallidal transmission.