Alcoholism is a psychiatric disorder, whose aetiology involves inherited predispositions and environmental factors. Alcohol activates the brain reward circuitry, which stems from the ventral tegmental area (VTA) where dopamine (DA) cells are located. Among synaptic inputs that regulate DA neuron impulse activity, those arising from the newly identified rostromedial tegmental nucleus (RMTg) play a major role. DA neurons can escape their afferent control by releasing endocannabinoids, which serve as retrograde signaling molecules at many synapses in the brain. In this study we took advantage of significant differences between pairs of lines of rats selectively bred for their voluntary alcohol preference or aversion, that is the Sardinian alcohol-preferring (sP) or nonpreferring (sNP) rat line and investigated their electrophysiological properties and synaptic plasticity both in vivo and in vitro. Extracellular single unit recordings in anesthetized rats revealed a difference in baseline firing activity of DA neurons between sP and sNP rats consistent with our previous study (Melis et al., 2009). More particularly, sP rats showed an increased spontaneous neuronal activity that was paralleled by a reduced strength of RMTg inputs. This enhanced firing activity of DA cells in sP rats negatively correlated with the duration of inhibition elicited by electrical stimulation of the RMTg. We next examined one form of short-term synaptic plasticity mediated by endocannabinoids that is depolarization-induced suppression of inhibition (DSI), at inhibitory synapses of DA cells. We have found that DSI 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 upon 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 phenotype, and that they possess this endocannabinoid-mediated DSI, our results suggest that differences in the 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 VOLUNTARY ALCOHOL PREFERENCE

SAGHEDDU, CLAUDIA;
2013-01-01

Abstract

Alcoholism is a psychiatric disorder, whose aetiology involves inherited predispositions and environmental factors. Alcohol activates the brain reward circuitry, which stems from the ventral tegmental area (VTA) where dopamine (DA) cells are located. Among synaptic inputs that regulate DA neuron impulse activity, those arising from the newly identified rostromedial tegmental nucleus (RMTg) play a major role. DA neurons can escape their afferent control by releasing endocannabinoids, which serve as retrograde signaling molecules at many synapses in the brain. In this study we took advantage of significant differences between pairs of lines of rats selectively bred for their voluntary alcohol preference or aversion, that is the Sardinian alcohol-preferring (sP) or nonpreferring (sNP) rat line and investigated their electrophysiological properties and synaptic plasticity both in vivo and in vitro. Extracellular single unit recordings in anesthetized rats revealed a difference in baseline firing activity of DA neurons between sP and sNP rats consistent with our previous study (Melis et al., 2009). More particularly, sP rats showed an increased spontaneous neuronal activity that was paralleled by a reduced strength of RMTg inputs. This enhanced firing activity of DA cells in sP rats negatively correlated with the duration of inhibition elicited by electrical stimulation of the RMTg. We next examined one form of short-term synaptic plasticity mediated by endocannabinoids that is depolarization-induced suppression of inhibition (DSI), at inhibitory synapses of DA cells. We have found that DSI 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 upon 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 phenotype, and that they possess this endocannabinoid-mediated DSI, our results suggest that differences in the equipment of the endocannabinoid system machinery might control specific sources of vulnerability.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/87963
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