The best characterized cellular mechanisms proposed to underlie information storage in the CNS are long-term potentiation and long-term depression (LTP and LTD). It is well established that excitatory glutamatergic synapses are strengthened or weakened in response to specific patterns of synaptic activation, and considerable evidence has accumulated suggesting that such changes in synaptic strength occur during learning and other adaptive responses to environmental stimuli. A single exposure to a variety of addictive drugs similarly potentiates excitatory synapses on dopaminergic cells in the ventral tegmental area (VTA). We have discovered a novel form of LTP (at GABAergic synapses onto VTA dopamine cells) that is prevented by exposure to opiate drugs.
GABAergic neurons represent up to 35 percent of VTA neurons. They act as local interneurons to inhibit VTA dopaminergic neurons and also provide important projections to the nucleus accumbens and prefrontal cortex. The normal functioning of GABAergic synapses in the ventral tegmental area is also altered as a result of in vivo exposure to drugs of abuse; at least two major classes of addictive drugs—opioids and ethanol—exert potent, direct effects on GABAergic synaptic transmission. We therefore investigated long-term potentiation of GABAA mediated inhibitory synaptic currents (IPSCs), using whole-cell recordings from VTA slices. High-frequency stimulation (100 Hz, 1 second, repeated twice; HFS) induced LTPGABA of IPSCs onto DA cells. This form of LTP is heterosynaptic, requiring an NMDA receptor-dependent increase in postsynaptic intracellular Ca2+ but resulting from increased presynaptic GABA release. Nitric oxide acts as a retrograde messenger linking postsynaptic NMDAR activation in dopamine neurons with increased synaptic release of GABA.
LTPGABA is absent after in vivo exposure to morphine, providing a novel mechanism by which µ-opioids trigger a long-lasting modulation of inhibitory circuits in the VTA. Our work suggests that twenty-four hours after a single treatment with morphine, GABAergic synapses in the VTA cannot potentiate in response to nitric oxide, but can potentiate in response to cyclic GMP, a downstream signal. These data suggest that the nitric oxide–sensitive cyclic GMP-producing enzyme, guanylate cyclase, either is downregulated or becomes insensitive to nitric oxide after morphine. This neuroadaptation to opioid drugs may contribute to early stages of addiction and may also be exploited therapeutically by drugs targeting GABAA receptors or guanylate cyclase.
Supported by DA11289, NS050570, NARSAD and F32 DA 018023.
