Addiction is a psychiatric disorder, whose aetiology involves interaction of inherited predispositions and environmental factors. Both clinical and preclinical findings indicate that there are important genetic variations in vulnerability to drug addiction, and that such differences may be mediated by the same biological mechanisms. 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. Endocannabinoids serve as retrograde signaling molecules at many synapses in the brain, including the VTA, and regulate reward seeking by modulating DA signaling. We took advantage of significant differences between pairs of lines of rats selectively bred for their voluntary alcohol preference or aversion, that is Sardinian alcohol-preferring (sP) or nonpreferring (sNP) rat line. We have found that depolarization-induced suppression of inhibition (DSI), a form of endocannabinoid-mediated short term synaptic plasticity, is differently expressed by two discrete sets of inhibitory synapses arising from rostral and caudal afferents onto VTA DA neurons. This phenomenon is selectively mediated by the endocannabinoid 2-arachidonoylglycerol (2-AG), which activates presynaptic type 1-cannabinoid (CB1) receptors. However, the two discrete DSI do not seem to depend upon differences in CB1 number and/or function, but rather on the rate 2-AG is degraded. Thus, 2-AG by differently depressing inhibitory synapses arising from either rostral or caudal afferents might indirectly alter DA neuron functional state, and enhance the responsiveness of the reward pathway to phasic DA. Given that sP rats are vulnerable phenotypes, and that they possess this endocannabinoid-mediated form of short term plasticity, our results suggest that differences in equipment of the endocannabinoid system machinery might control specific sources of vulnerability.
ENDOCANNABINOID-MEDIATED PLASTICITY AT INHIBITORY SYNAPSES ONTO MIDBRAIN DOPAMINE NEURONS AS A POSSIBLE MARKER OF VULNERABILITY TO ADDICTION
SAGHEDDU, CLAUDIA;
2013-01-01
Abstract
Addiction is a psychiatric disorder, whose aetiology involves interaction of inherited predispositions and environmental factors. Both clinical and preclinical findings indicate that there are important genetic variations in vulnerability to drug addiction, and that such differences may be mediated by the same biological mechanisms. 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. Endocannabinoids serve as retrograde signaling molecules at many synapses in the brain, including the VTA, and regulate reward seeking by modulating DA signaling. We took advantage of significant differences between pairs of lines of rats selectively bred for their voluntary alcohol preference or aversion, that is Sardinian alcohol-preferring (sP) or nonpreferring (sNP) rat line. We have found that depolarization-induced suppression of inhibition (DSI), a form of endocannabinoid-mediated short term synaptic plasticity, is differently expressed by two discrete sets of inhibitory synapses arising from rostral and caudal afferents onto VTA DA neurons. This phenomenon is selectively mediated by the endocannabinoid 2-arachidonoylglycerol (2-AG), which activates presynaptic type 1-cannabinoid (CB1) receptors. However, the two discrete DSI do not seem to depend upon differences in CB1 number and/or function, but rather on the rate 2-AG is degraded. Thus, 2-AG by differently depressing inhibitory synapses arising from either rostral or caudal afferents might indirectly alter DA neuron functional state, and enhance the responsiveness of the reward pathway to phasic DA. Given that sP rats are vulnerable phenotypes, and that they possess this endocannabinoid-mediated form of short term plasticity, our results suggest that differences in equipment of the endocannabinoid system machinery might control specific sources of vulnerability.
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