Constitutive cannabinoid 1 and mu opioid receptor activity in the ventral tegmental area: occurrence, function and therapeutic relevance

Abstract

Cannabinoid 1 receptors (CB1Rs) play a crucial role in regulating systems dedicated to processing rewards and emotions. It was known that in artificial systems, CB1Rs can exhibit activity that is independent of the typical agonist-driven form. However, it remained largely unclear whether this constitutive activity also occurred in native tissue (e.g. the brain), and if so, what role it plays in neurotransmission and behavior. In this thesis we have taken a multi-disciplinary approach to show that CB1R inverse agonism (which interferes with both constitutive and agonist-driven activation) and neutral antagonism (which only interferes with agonist-driven activation) has markedly different effects on neurotransmission in the dopamine reward system in brain slices, dopamine neuron activity in freely moving rats, and processing of rewards and emotions. The inverse agonist interfered with reward processing and induced anxiety, whereas the neutral antagonist did neither. Strikingly, the neutral antagonist and inverse agonist were equally able to reduce weight gain and food intake. This is particularly of interest since the inverse agonist (rimonabant) had been previously marketed as a weight loss compound, but was discontinued due to side effects in the realms of anxiety and depression. Our findings therefore suggest that CB1R neutral antagonists may provide a safer and efficacious alternative to the discontinued CB1R inverse agonists. In a similar vein, we show that the mu opioid receptor (MOR), which is closely akin to the CB1R, is also constitutively active in the dopamine reward system. We provide evidence that, during a state of morphine withdrawal, this MOR constitutive activity is enhanced and likely serves a protective function that limits withdrawal symptoms. MOR antagonists with inverse agonistic profiles are currently in use to treat narcotic overdose and drug addiction. Problematically, this can lead to severe side effects. Our findings provide evidence that MOR neutral antagonists may also prove to be better therapeutic alternatives with fewer side effects, as they leave the potentially protective MOR constitutive activity during opioid withdrawal intact.