Cannabinoid addiction: behavioral models and neural correlates

Abstract

The use of cannabis sativa preparations as recreational drugs can be traced back to the earliest civilizations. However, animal models of cannabinoid addiction allowing the exploration of neural correlates of cannabinoid abuse have been developed only recently. We review these models and the role of the CB1 cannabinoid receptor, the main target of natural cannabinoids, and its interaction with opioid and dopamine transmission in reward circuits. Extensive reviews on the molecular basis of cannabinoid action are available elsewhere (Piomelli et al., 2000; Schlicker and Kathmann, 2001).

Fig. 1.

Molecular targets of major abused drugs. Cannabinoids, like opiates, activate a G-protein-coupled receptor, in this case the CB1R, which couples to transduction mechanisms, mainly adenylyl cyclase (AC), and voltage-gated potassium, and calcium channels through the small GTP-binding proteins G_s/olf and G_i/o. CB1 receptors thereby modulate the resting membrane potential and intracellular concentrations of cAMP. Subsequent modification of the activity of specific protein kinases, primarily PKA, but also mitogen-activated protein kinases, leads to both acute responses (modulation of neurotransmitter release or firing rates) and long-term adaptations associated with dependence and withdrawal.

Fig. 2.

Involvement of the endogenous opioid system in cannabinoid motivational properties, tolerance, and dependence. A, THC-induced CPP is abolished in MOR KO mice. Scores are calculated as the difference between test and preconditioning time spent in the drug-paired compartment (fromGhozland et al., 2002). B, Tolerance to THC-induced antinociception is reduced in KO mice deficient in the pre-proenkephalin gene (from Valverde et al., 2000). C, Severity of SR141716A-precipitated THC withdrawal syndrome is attenuated in KO mice deficient in the pre-proenkephalin gene. A global withdrawal score was calculated for each animal by giving each individual sign (tremor, wet dog shakes, ptosis, front paw tremor, ataxia, mastication, hunched posture, sniffing, piloerection, and penile lick) a proportional weight (from Valverde et al., 2000). Values are expressed as mean ± SEM; ▸▸ p < 0.05, ▸▸▸▸ p < 0.01, comparison between treatments; ◂◂ p < 0.05, ◂◂◂◂ p < 0.01, comparison between genotypes (one-way ANOVA).