U.S. Department of Defense


Date of this Version



Published in Neuropharmacology 61 (2011) 1166-1171; doi:10.1016/j.neuropharm.2010.11.012


Adaptive behaviors often require the learning of appropriate responses to rewarding stimuli, yet aberrant learning processes can lead to serious diseases such as addiction. Dopamine (DA) neurons of the ventral tegmental area (VTA) play an essential role in the treatment of rewarding stimuli, and they exhibit plasticity in response to such stimuli, but also to drugs of abuse. Previously we discovered a form of presynaptic nitric oxide (NO)-mediated long-term potentiation (LTPGABA) at GABAergic synapses onto VTA DA neurons that is prevented with morphine in vivo 24 h after exposure. Here we investigated whether the same GABAergic synapses are capable of exhibiting long-term depression (LTD in addition to LTPGABA) and its possible modulation by morphine in vivo. We found that indeed the efficacy of VTA GABAergic synapses can be down-regulated through induction of a novel form of LTD (i.e., LTDGABA) in response to synaptic stimulation. Paired pulse ratio (PPR) and coefficient of variance (CV) analyses of evoked IPSCs confirmed that this plasticity may be postsynaptic. Consistently, LTDGABA did not involve presynaptic cannabinoid CB1receptors (CB1Rs). Moreover, NMDAR activation was not necessary for LTDGABA. However, blockade of D2 dopamine receptors (D2R) significantly attenuated LTDGABA proposing a novel synaptic mechanism for the regulation of excitability of DA neurons by endogenous DA and D2R activation. Interestingly, 24 h after a single in vivo exposure to morphine, LTDGABA was absent in slices from morphine-treated rats but unaffected in slices from saline-treated rats, confirming a bidirectional impact of morphine on GABAergic synaptic plasticity in the VTA. The control of bidirectional GABAergic plasticity by morphine in the VTA may represent the neural correlates necessary for the addictive properties of opiates.