Opioids block long-term potentiation of inhibitory synapses
Abstract
Excitatory brain synapses are strengthened or weakened in response to specific patterns of synaptic activation, and these changes in synaptic strength are thought to underlie persistent pathologies such as drug addiction, as well as learning. In contrast, there are few examples of synaptic plasticity of inhibitory GABA (gamma-aminobutyric acid)-releasing synapses. Here we report long-term potentiation of GABA(A)-mediated synaptic transmission (LTP(GABA)) onto dopamine neurons of the rat brain ventral tegmental area, a region required for the development of drug addiction. This novel form of LTP is heterosynaptic, requiring postsynaptic NMDA (N-methyl-d-aspartate) receptor activation at glutamate synapses, but resulting from increased GABA release at neighbouring inhibitory nerve terminals. NMDA receptor activation produces nitric oxide, a retrograde signal released from the postsynaptic dopamine neuron. Nitric oxide initiates LTP(GABA) by activating guanylate cyclase in GABA-releasing nerve terminals. Exposure to morphine both in vitro and in vivo prevents LTP(GABA). Whereas brief treatment with morphine in vitro blocks LTP(GABA) by inhibiting presynaptic glutamate release, in vivo exposure to morphine persistently interrupts signalling from nitric oxide to guanylate cyclase. These neuroadaptations to opioid drugs might contribute to early stages of addiction, and may potentially be exploited therapeutically using drugs targeting GABA(A) receptors.
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Nitric oxide causes activation of guanylate cyclase and synthesis of cGMP in the synaptic terminals of inhibitory afferents onto dopamine neurons.
“Nitric oxide in turn causes activation of guanylate cyclase and synthesis of cGMP in the synaptic terminals of inhibitory afferents onto dopamine neurons.”
From NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). (2012) · cites this paper as Nugent et al. 2007
In the ventral tegmental area, a form of plasticity called LTP GABA is induced by strong activation of NMDARs on dopamine neurons.
“In the ventral tegmental area, a similar form of plasticity called LTP GABA is induced by strong activation of NMDARs on dopamine neurons (Nugent et al. 2007).”
From NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). (2012) · cites this paper as Nugent et al. 2007
LTP GABA induction leads to activation of a Ca2+-dependent nitric oxide synthase, which generates nitric oxide, which acts as a retrograde messenger by diffusing back to presynaptic neurons.
“This leads to activation of a Ca 2þ -dependent nitric oxide synthase, which generates nitric oxide, which acts as a retrograde messenger by diffusing back to presynaptic neurons.”
From NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). (2012) · cites this paper as Nugent et al. 2007
The release probability for GABA increases through a still unknown mechanism involving activation of the cGMP-dependent protein kinase, PKG.
“The release probability for GABA then increases through a still unknown mechanism involving activation of the cGMPdependent protein kinase, PKG.”
From NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). (2012) · cites this paper as Nugent et al. 2007
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- Authors
- Nugent, F. S., Penick, E. C., & Kauer, J. A.
- Affiliations
- Brown University (US)
- Corresponding author
- Kauer, Julie A.
- Venue
- Nature
- Published
- 2007-04
- Volume
- 446
- Issue
- 7139
- Pages
- 1086-1090
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2045927851
- Cited by
- 297
- References
- 1
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 2 · 2023: 11 · 2022: 12 · 2021: 12 · 2020: 23 · 2019: 5 · 2018: 19 · 2017: 14 · 2016: 18 · 2015: 17 · 2014: 22 · 2013: 18 · 2012: 22
- FWCI
- 7.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- long-term potentiation, inhibitory synapses, GABAA receptor, morphine, opioid analgesics, ventral tegmental area, dopaminergic neurons, drug addiction, nitric oxide, guanylate cyclase, NMDA receptor, heterosynaptic plasticity, synaptic plasticity, excitation-inhibition balance, presynaptic glutamate release, neural adaptation
- MeSH terms
- Analgesics, Opioid, Animals, Calcium, Dopamine, gamma-Aminobutyric Acid, Cyclic GMP, Morphine, Synaptic Transmission, Neurons, Nitric Oxide, Receptors, GABA-A, Synapses, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Ventral Tegmental Area, Long-Term Potentiation, Substance-Related Disorders, Rats, In Vitro Techniques
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