Endocrine Abstracts

Drug addiction is a brain psychiatric disorder, whose etiology involves interaction of inherited predispositions and environmental factors. Addictive drugs share the properties of being self-administered by laboratory animals, and of activating the brain reward circuitry, which stems from the ventral tegmental area (VTA) where dopamine (DA) cells are located. These neurons are involved in neural processing contributing to drug addiction and DA plays a crucial role as learning signal by changing the synaptic strength of neural circuits involved in action selection to optimize goal-directed behavior. Endocannabinoids serve as retrograde signaling molecules at many synapses in the brain, and regulate reward seeking by modulating DA signaling. In fact, endocannabinoids regulate different forms of synaptic plasticity in the VTA, exert a critical modulation of DA release and, ultimately, of the circuits within the limbic systems driving motivated behaviors. In this framework, evidence for the modulation of DA neuronal activity by endocannabinoids, which shape afferent neuronal activity in a short- and long-lasting fashion, in the context of vulnerability to drug addiction will be presented. Indeed, significant sex differences in cannabinoid self-administration displayed by Lister Hooded (LH) female and male rats, and of one of the few pairs of lines of rats selectively bred for their voluntary alcohol preference, that is Sardinian alcohol-preferring (sP) rat line represent two vulnerable phenotypes for Cannabis and alcohol dependence, respectively. Both vulnerable phenotypes share a dysfunctional form of endocannabinoid-mediated short-term synaptic plasticity at inhibitory afferents onto VTA DA neurons. This phenomenon does not depend upon differences in cannabinoid receptor number and/or function, but rather on the rate of endocannabinoid degradation. Thus, it appears that differences in equipment of the endocannabinoid system machinery might control specific sources of vulnerability for both cannabis and alcohol dependence.