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Persistent changes in excitatory and inhibitory synaptic strengths to the ventral tegmental area (VTA) dopamine (DA) neurons in response to addictive drugs may underlie the transition from casual to compulsive drug use. While an enormous amount of work has been done in the area of glutamatergic plasticity of the VTA, little is known regarding the learning rules governing GABAergic plasticity in the VTA. Spike timing-dependent plasticity, STDP, has attracted considerable attention primarily due to its potential roles in processing and storage of information in the brain and there is emerging evidence for the existence of STDP at inhibitory synapses. We therefore used whole-cell recordings in rat midbrain slices to investigate whether near-coincident pre- and postsynaptic firing induces a lasting change in synaptic efficacy of VTA GABAergic synapses. We found that a Hebbian form of STDP including long-term potentiation (LTP) and long-term depression (LTD) can be induced at GABAergic synapses onto VTA DA neurons and relies on the precise temporal order of pre- and postsynaptic spiking. Importantly, GABAergic STDP is heterosynaptic (NMDA receptor dependent): triggered by correlated activities of the presynaptic glutamatergic input and postsynaptic DA cells. GABAergic STDP is postsynaptic and has an associative component since pre- or postsynaptic spiking per se did not induce STDP. STDP of GABAergic synapses in the VTA provides physiologically relevant forms of inhibitory plasticity that may underlie natural reinforcement of reward-related behaviours. Moreover, this form of inhibitory plasticity may mediate some of the reinforcing, aversive and addictive properties of drugs of abuse.

The postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling complex regulates excitatory synaptic transmission and strength through tethering protein kinase A (PKA), PKC, and calcineurin (CaN) to the postsynaptic densities of neurons (Sanderson and Dell'Acqua, 2011), but its role in inhibitory synaptic transmission and plasticity is unknown. Using immunofluorescence and whole-cell patch-clamp recording in rat midbrain slices, we show that activation of postsynaptic D(2)-like family of dopamine (DA) receptor in the ventral tegmental area (VTA) induces long-term depression (LTD) of GABAergic synapses on DA neurons through an inositol triphosphate receptor-mediated local rise in postsynaptic Ca(2+) and CaN activation accompanied by PKA inhibition, which requires AKAP150 as a bridging signaling molecule. Our data also illuminate a requirement for a clathrin-mediated internalization of GABA(A) receptors in expression of LTD(GABA). Moreover, disruption of AKAP-PKA anchoring does not affect glutamatergic synapses onto DA neurons, suggesting that the PKA-AKAP-CaN complex is uniquely situated at GABA(A) receptor synapses in VTA DA neurons to regulate plasticity associated with GABA(A) receptors. Drug-induced modulation of GABAergic plasticity in the VTA through such novel signaling mechanisms has the potential to persistently alter the output of individual DA neurons and of the VTA, which may contribute to the reinforcing or addictive properties of drugs of abuse.

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 (LTP(GABA)) 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 LTP(GABA)) 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., LTD(GABA)) 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, LTD(GABA) did not involve presynaptic cannabinoid CB₁ receptors (CB₁Rs). Moreover, NMDAR activation was not necessary for LTD(GABA). However, blockade of D₂ dopamine receptors (D₂R) significantly attenuated LTD(GABA) 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, LTD(GABA) 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., (Published by Elsevier Ltd.)