Among some of the more promising developments in addiction treatment involve the use of cannabinoid receptor (CB1) antagonists. Namely SR141716A, also known as Rimonabant, and AM251 have been shown to have promising effects in the treatment of opiates, ethanol, and psychostimulants. The shared pathways in these drugs of abuse act on brain reward pathways, especially the mesocorticolimbic system. Dopamine from the mesocorticolimbic system projects to the ventral tegmental area, nucleus accumbens, and amygdala with CB1 receptors being shown to modulate this pathway (Le foll & Goldberg, 2005). Lupica and Riegel (2005) reference endocannabinoids as being critical in the plasticity observed in the long-term depression of glutamate release, thus providing an underlying mechanism for this modulation.
Drugs of abuse have the common effect of increasing dopamine release in the ventral tegmental area. While different classes of substances act on different mechanisms, they all commonly show decreased “spontaneous DA neuron activity” following increased VTA DA firing associated with drug use (Lupica & Riegel, 2005). Lupica and Riegel (2005) cite Melis et al. (2004) who found that this depression of spontaneous DA firing could be reversed with the administration of Rimonabant. Interpreting these results and considering that endocannabinoids are found at the site of the dopamine neuron, it is possible that CB1 antagonists help to prevent the flooding of endocannabinoids during drug use and restore normal glutamate functioning. While drugs of abuse share this general route of synaptic plasticity, the routes there can look different.
Psychostimulants such as cocaine work by increasing the duration and quantity of dopamine in the synaptic cleft between neurons. Lupica and Riegel (2005) describe this as the inhibition of dopamine transporter (DAT) at the axon terminals. This DAT inhibition leads to an activation of EQUATION: Equation1-adrenergic receptors resulting in calcium depletion form intracellular locations. Without this “intracellular calcium” mGluR-1 are prohibited from activating SK channels which usually creates an inhibitory postsynaptic current that is responsible for limiting the excitability of DA neurons (Lupica & Riegel, 2005). In support of how this mechanism may also be involved in the process of relapse and reinstatement, Schindler et al. (2010) found that AM 251 diminished self-administration under a progressive ratio schedule and prevented priming induced reinstatement in studies with rhesus monkeys. Consequently it is possible that this CB1 antagonism allows the inhibitory postsynaptic current to manifest and reduce the “excitability” of dopamine release, thus the rewarding effect of the amphetamine is blocked.
One critical piece of information missing from the Lupica and Riegel (2005) study is the ability of CB1 antagonists to block environment-cued relapse. Indeed Le Foll and Goldberg (2005) cite that SR141716 was able to relapse to cocaine-seeking behavior in relation to cocaine-paired stimuli and cocaine priming but not to environmental stressors. Strangely, it appears that SR141716 can prevent conditioned place preference for heroine in CB1 knockout mice (Le Foll & Goldberg, 2005). Similar to the Schindler et al. (2010) experiment with psychostimulants, Le Foll and Goldberg (2005) reference multiple studies that found SR141716 to be effective in reducing the rate of responding in rats seeking heroin self-administration in progressive ratio schedules. Le Foll and Goldber (2005), Schindler et al. (2010), and Lupica and Riegel (2005) all state differences in the effectiveness of AM 251 and Rimonabant in rat versus primate models. What seems likely is that the antagonists work differently depending on the drug being abused and that drugs specific effects on dopaminergic and glutaminergic pathways.
Le Foll and Goldberg (2005) note that some effects of SR141716 are lessened in dopamine D3 receptor-deficient mice. The authors note that since D3 and CB1 receptors are both expressed in the mesolimbic dopamine brain reward circuit, that the two receptors may be responsible for the drug-related cues that trigger dopamine release. One promising sign is from Lupica and Riegel (2005) who demonstrated that AM 251 in combination with apamin (polypeptide bee venom toxin) can increase sensitivity of VTA DA neurons to glutamatergic inputs. This particular combination could potentially provide a mechanism through which calcium dependent inhibitory postsynaptic currents can regulate glutamate normally, and thus prevent the long-term depression of glutamate associated with cue-associated relapse.
Lupica, C., Riegel, A.C. (2005) Endocannabinoid release from midbrain dopamine neurons: A potential substrate for cannabinoid receptor antagonist treatment of addiction. Neuropharmacology 48, 1105-1116.
Schindler Panlilio, L.V. et al. (2010) Effects of cannabinoid receptor antagonists on maintenance and reinstatement of methamphetamine self-administration in rhesus monkeys. European Journal of Pharmacology 633, 44-49.
Le Foll, B., Goldberg, S.R. (2005). Cannabinoid CB1 receptor antagonists as promising new medications for drug dependence. Journal of Pharmacology and Experimental Therapeutics 312, 875-883.