Ventral tegmental area interneurons revisited: GABA and glutamate projection neurons make local synapses

Published: Aug. 7, 2024

The ventral tegmental area (VTA) contains projection neurons that release the neurotransmitters dopamine, GABA, and/or glutamate from distal synapses. VTA also GABA synapse locally on to dopamine neurons, synapses widely credited a population of so-called interneurons. Interneurons in cortex, striatum, and elsewhere have well-defined morphological features, physiological properties, molecular markers, but such features not been clearly described VTA. Indeed, there is scant evidence local originate separate populations neurons. In this study we tested whether several markers expressed non-dopamine are selective interneurons, defined as distally. Challenging previous assumptions, found genetically by expression parvalbumin, somatostatin, neurotensin, or mu-opioid receptor project known targets including nucleus accumbens, pallidum, lateral habenula, prefrontal cortex. Moreover, provide make functional inhibitory excitatory within These findings suggest collaterals could mediate functions prior attributed This underscores need for refined understanding connectivity explain how heterogeneous circuits diverse related reward, motivation, addiction.

Language: Английский

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Key differences in regulation of opioid receptors localized to presynaptic terminals compared to somas: Relevance for novel therapeutics

Neuropharmacology, Journal Year: 2022, Volume and Issue: 226, P. 109408 - 109408

Published: Dec. 28, 2022

Opioid receptors are G protein-coupled (GPCRs) that regulate activity within peripheral, subcortical and cortical circuits involved in pain, reward, aversion processing. expressed both presynaptic terminals where they inhibit neurotransmitter release postsynaptic locations act to hyperpolarize neurons reduce activity. Agonist activation of at the plasma membrane signal via ion channels or cytoplasmic second messengers. binding initiates regulatory processes include phosphorylation by protein receptor kinases (GRKs) recruitment beta-arrestins desensitize internalize receptors. also couple effectors from endosomes activating intracellular enzymes kinases. In contrast opioid receptors, localized resistant desensitization such there is no loss signaling continuous presence opioids over same time scale. Thus, balance expressing pre- shifted toward inhibition during exposure. The functional implication this shift not often acknowledged behavioral studies. This review covers what currently understood about regulation opioid/nociceptin with an emphasis on pain reward circuits. Importantly, critical gaps understanding area, as well opportunities further understand brain article part Special Issue "Opioid-induced changes addiction circuits".

Language: Английский

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GABAergic projections to the ventral tegmental area govern cocaine‐conditioned reward

Addiction Biology, Journal Year: 2021, Volume and Issue: 26(4)

Published: Feb. 26, 2021

Abstract Elevated dopamine (DA) levels in the reward system underlie various drug‐related behaviors, including addiction. As a major DA source system, ventral tegmental area (VTA) is highly regulated by GABAergic inputs projected from different brain regions. It was previously shown that cocaine exposure reduces GABA A ‐mediated inhibitory postsynaptic currents (IPSCs) VTA neurons; however, specific input underlying this effect remains unknown. Here, using optogenetics, we separately activate and characterize afferents innervating VTA, focusing on rostromedial nucleus (RMTg) accumbens (NAc). IPSCs were recorded neurons, of DA‐induced inhibition measured an afferent‐specific manner. In addition, to examine enhanced tone rewarding properties cocaine, exogenously activated during acquisition phase conditioned place preference (CPP). We found acute strongly attenuates neurons both sources. Furthermore, exogenous light activation RMTg NAc cocaine‐CPP significantly reduced cocaine. This behavioral observation correlated with reduction neuronal activity as expression c‐fos. Together, these results emphasize critical role modulating potentially interrupting reward.

Language: Английский

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Opioids Induce Bidirectional Synaptic Plasticity in a Brainstem Pain Center in the Rat

Journal of Pain, Journal Year: 2023, Volume and Issue: 24(9), P. 1664 - 1680

Published: May 6, 2023

Opioids are powerful analgesics commonly used in pain management. However, opioids can induce complex neuroadaptations, including synaptic plasticity, that ultimately drive severe side effects, such as hypersensitivity and strong aversion during prolonged administration or upon drug withdrawal, even following a single, brief administration. The lateral parabrachial nucleus (LPBN) the brainstem plays key role emotional processing; yet, effects of on plasticity this area remain unexplored. Using patch-clamp recordings acute slices from male female Sprague Dawley rats, we demonstrate concentration-dependent, bimodal effect excitatory transmission LPBN. While lower concentration DAMGO (0.5 µM) induced long-term depression strength (low-DAMGO LTD), abrupt termination higher (10 potentiation (high-DAMGO LTP) subpopulation cells. LTD involved metabotropic glutamate receptor (mGluR)-dependent mechanism; contrast, LTP required astrocytes N-methyl-D-aspartate (NMDAR) activation. Selective optogenetic activation spinal periaqueductal gray matter (PAG) inputs to LPBN revealed that, while was expressed at all synapses tested, restricted spino-parabrachial synapses. Thus, uncovered previously unknown forms opioid-induced potentially modulate some adverse opioids. PERSPECTIVE: We found unrecognized site nucleus, region for processing. Unraveling adaptations function might facilitate identification new therapeutic measures addressing opioid discontinuation hyperalgesia aversion.

Language: Английский

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Ventral tegmental area interneurons revisited: GABA and glutamate projection neurons make local synapses

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 8, 2024

Abstract The ventral tegmental area (VTA) contains projection neurons that release the neurotransmitters dopamine, GABA, and/or glutamate from distal synapses. VTA also GABA synapse locally on to dopamine neurons, synapses widely credited a population of so-called interneurons. Interneurons in cortex, striatum, and elsewhere have well-defined morphological features, physiological properties, molecular markers, but such features not been clearly described VTA. Indeed, there is scant evidence local originate separate populations neurons. In this study we tested whether several markers expressed non-dopamine are selective interneurons, defined as distally. Challenging previous assumptions, found genetically by expression parvalbumin, somatostatin, neurotensin, or mu-opioid receptor project known targets including nucleus accumbens, pallidum, lateral habenula, prefrontal cortex. Moreover, provide make functional inhibitory excitatory within These findings suggest collaterals could mediate functions prior attributed This underscores need for refined understanding connectivity explain how heterogeneous circuits diverse related reward, motivation, addiction. Significance statement key regulators considered central mechanisms which opioids other drugs abuse can induce Conventionally, these abundant VTA, it unclear if represent populations. We enriched Mu-opioid receptor, thus interneuron markers. collateralize where they data challenge notion only serve previously

Language: Английский

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