DOI:10.1038/nrn2163

Drugs of abuse target dopaminergic neurons in the ventral tegmental area (VTA), but it is unclear whether or how these drugs disrupt their normal functioning. Now, Nugent et al. show that dopaminergic activity in VTA neurons is modulated by long-term potentiation (LTP) of inhibitory synapses, and that LTP is blocked by a single dose of morphine, thus suggesting a mechanism by which opioids deregulate neuronal activity, which may lead to addiction.

LTP, the strengthening of syn-aptic connections in response to patterned stimulation, is thought to underlie learning. LTP is most commonly reported at excitatory synapses, but there is evidence that it can also occur at inhibitory, GABA (γ-aminobutyric acid)-releasing syn-apses. Using whole-cell recording in rat brain slices, the authors showed that electrical stimulation of GABA afferents triggered LTP of GABAA-mediated synaptic transmission

(LTPGABA) onto dopamine neurons of the VTA. This required NMDA (N-methyl-d-aspartate) receptor activa-tion, indicating that LTPGABA involves multiple synapses; it is triggered by activation of NMDAR at glutamater-gic synapses, which in turn affects neighbouring GABA-releasing synapses on the same neuron.

Nugent et al. next established that nitric oxide (NO) could be the retrograde signal that triggers presynaptic LTPGABA: They found that inhibiting NO production or adding NO scavengers blocked LTPGABA. Furthermore, increasing NO levels potentiated GABA synapses on dopamine neurons. NO can facilitate GABA release by activation of presynaptic guanylate cyclase, which catalyses the formation of cyclic GMP (cGMP). Indeed, a guanylate cyclase inhibitor blocked LTPGABA, whereas a cGMP analogue mimicked it, indicating that NO-stimulated cGMP production triggers GABA release.

Taken together, these findings identify some of the cellular and molecular processes underlying LTPGABA in dopaminergic VTA neurons. LTPGABA in turn may be a mechanism that increases the inhibitory input, and thus reduces the excitability, of VTA dopamine neurons.

Opioids are known to target the VTA; previous experiments had shown that μ-opioid agonists alter GABA-releasing synapses and reduce inhibitory synaptic transmission in VTA dopamine neurons. Now, the researchers tested whether opioid-

induced alterations in LTPGABA also occur. They added morphine or a different μ-opioid agonist to VTA slices and found that LTPGABA was blocked at a level upstream of NO production.

They next determined whether in vivo morphine administration also altered LTPGABA. VTA slices from rats that had received morphine 24 hours earlier did not show plasticity of GABA-releasing synapses, indicating that a single in vivo dose of morphine can prevent LTPGABA 24 hours later. But what is the mechanism by which morphine achieves this? Increasing NO levels had no effect on GABA synapses in morphine-treated ani-mals, whereas adding a cGMP ana-logue potentiated GABA synapses, indicating that in vivo, morphine affects LTPGABA downstream from NO but upstream from cGMP, perhaps at the level of guanylate cyclase.

This study shows that a single dose of morphine can prevent LTP of inhibitory synapses onto dopamin-ergic neurons in the VTA, effectively removing the brake on dopamine transmission in this area. The data further suggest that addiction may result from changes in synaptic plas-ticity and, importantly, that guanylate cyclase may provide a target for the development of drugs aimed to treat addiction.

Leonie Welberg

ORIGINAL RESEARCH PAPER Nugent, F. S.,

et al. Opioids block long-term potentiation of

inhibitory synapses. Nature 446, 1086–1090

(2007)

A D D I C T I O N

Learning to be addicted

R E S E A R C H H I G H L I G H T S

NATURE REVIEWS | NEUROSCIENCE VOLUME 8 | JUNE 2007

© 2007 Nature Publishing Group