Role of α6-Nicotinic Receptors in Alcohol-Induced GABAergic Synaptic Transmission and Plasticity to Cholinergic Interneurons in the Nucleus Accumbens

Wadsworth, Hillary A.; Anderson, Elizabeth Q.; Williams, Benjamin M.; Ronström, Joakim W.; Moen, Janna K.; Lee, AM; McIntosh, J. Michael; Wu, Jie; Yorgason, Jordan T.; Steffensen, Scott C.

doi:10.1007/s12035-023-03263-5

Cited by 12 publications

(18 citation statements)

References 78 publications

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“…One pathway through which ethanol seems to mediate at least part of its DA releasing effect is via activation of accumbal CIN. 42,43 In this study, we show that CIN do…”

Section: Discussionsupporting

confidence: 61%

“…Ethanol acts on several pharmacological targets and thus mediates its rewarding properties through complex mechanisms that to a large extent are yet to be elucidated. One pathway through which ethanol seems to mediate at least part of its DA releasing effect is via activation of accumbal CIN 42,43 . In this study, we show that CIN do not regulate basal levels of DA or the GlyR agonists glycine and taurine.…”

Section: Discussionmentioning

confidence: 50%

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Regulation of ethanol‐mediated dopamine elevation by glycine receptors located on cholinergic interneurons in the nucleus accumbens

Loftén,

Adermark,

Ericson

et al. 2023

Addiction Biology

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Alcohol use disorder is one of the major psychiatric disorders worldwide, and there are many factors and effects contributing to the disorder, for example, the experience of ethanol reward. The rewarding and reinforcing properties of ethanol have been linked to activation of the mesolimbic dopamine system, an effect that appears to involve glycine receptors (GlyRs) in the nucleus accumbens. On which neuronal subtypes these receptors are located is, however, not known. The aim of this study was to explore the role of GlyRs on cholinergic interneurons (CIN) in sustaining extracellular dopamine levels and in ethanol‐induced dopamine release. To this end, CIN were ablated by anti‐choline acetyltransferase‐saporin administered locally in the nucleus accumbens of male Wistar rats. Changes in dopamine levels induced by ablation, ethanol and/or a GlyR antagonist were monitored using in vivo microdialysis. The GlyRs antagonist strychnine depressed extracellular dopamine in a similar manner independent on local ablation, suggesting that GlyRs on CIN are not important for sustaining the extracellular dopamine tone. However, a low concentration of strychnine hampered ethanol‐induced dopamine release in sham‐treated animals, whilst no reduction was seen in ablated animals, suggesting that GlyRs located on CIN are involved in ethanol‐induced dopamine release. Further, in ablated rats, ethanol‐induced increases of the extracellular levels of the GlyR agonists glycine and taurine were attenuated. In conclusion, this study suggests that CIN are not important for GlyR‐mediated regulation of basal dopamine output, but that CIN ablation blunts the ethanol‐induced dopamine release, putatively by reducing the release of GlyR agonists.

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“…One pathway through which ethanol seems to mediate at least part of its DA releasing effect is via activation of accumbal CIN. 42,43 In this study, we show that CIN do…”

Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 50%

Regulation of ethanol‐mediated dopamine elevation by glycine receptors located on cholinergic interneurons in the nucleus accumbens

Loftén,

Adermark,

Ericson

et al. 2023

Addiction Biology

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“…Accordingly, we have recently shown that VTA GABA neurons project to the CINs localized in the NAcc 41 and that α6*-nAChRs mediate EtOH effects on CIN activity, CIN plasticity with chronic EtOH, and DA release. 49 Here, we show additional immunohistochemical evidence that α6*-nAChRs are expressed on GABAergic terminals in the NAc. This was accomplished with MII-biotin labeling of VTA GABA neuron terminals in VGAT-Cre/GAD67-GFP mice (Figure 5).…”

Section: ■ Discussionsupporting

confidence: 54%

Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of α6-Nicotinic Receptors and Dopamine Transporters

Williams,

Steed,

Woolley

et al. 2024

ACS Chem. Neurosci.

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Iboga alkaloids, also known as coronaridine congeners, have shown promise in the treatment of alcohol and opioid use disorders. The objective of this study was to evaluate the effects of catharanthine and 18-methoxycoronaridine (18-MC) on dopamine (DA) transmission and cholinergic interneurons in the mesolimbic DA system, nicotine-induced locomotor activity, and nicotine-taking behavior. Utilizing ex vivo fast-scan cyclic voltammetry (FSCV) in the nucleus accumbens core of male mice, we found that catharanthine or 18-MC differentially inhibited evoked DA release. Catharanthine inhibition of evoked DA release was significantly reduced by both α4 and α6 nicotinic acetylcholine receptors (nAChRs) antagonists. Additionally, catharanthine substantially increased DA release more than vehicle during high-frequency stimulation, although less potently than an α4 nAChR antagonist, which confirms previous work with nAChR antagonists. Interestingly, while catharanthine slowed DA reuptake measured via FSCV ex vivo, it also increased extracellular DA in striatal dialysate from anesthetized mice in vivo in a dose-dependent manner. Superfusion of catharanthine or 18-MC inhibited the firing rate of striatal cholinergic interneurons in a concentration dependent manner, which are known to potently modulate presynaptic DA release. Catharanthine or 18-MC suppressed acetylcholine currents in oocytes expressing recombinant rat α6/α3β2β3 or α6/α3β4 nAChRs. In behavioral experiments using male Sprague-Dawley rats, systemic administration of catharanthine or 18-MC blocked nicotine enhancement of locomotor activity. Importantly, catharanthine attenuated nicotine self-administration in a dose-dependent manner while having no effect on food reinforcement. Lastly, administration of catharanthine and nicotine together greatly increased head twitch responses, indicating a potential synergistic hallucinogenic effect. These findings demonstrate that catharanthine and 18-MC have similar, but not identical effects on striatal DA dynamics, striatal cholinergic interneuron activity and nicotine psychomotor effects.

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“…We found that a6 and b3 were expressed in approximately half of all VTA glutamatergic and GABAergic cells. Although the level of a6 and b3 expression in GABA cells is much lower compared with dopamine neurons, our data adds to the recent studies that have detected and uncovered a role for a6* on GABA neurons in the regulation of alcohol effects, highlighting the involvement of nAChRs in drug effects even when expressed at low levels (Steffensen et al, 2018;Wadsworth et al, 2023;Yan et al, 2018).…”

Section: Discussionmentioning

confidence: 55%

“…Technical advances have significantly improved the detection of individual nAChR transcripts, which has led to revised data on the presence of nAChR subunits in cells that were previously thought to be lacking these subunits, such as expression of the a6 subunit in GABA neurons of the ventral tegmental area (VTA) (Charpantier et al, 1998;Steffensen et al, 2018;Wadsworth et al, 2023). nAChRs containing the a4 and/or the a6 subunits (denoted a4* and/or a6*, with * indicating the presence of other undetermined subunits in the receptor pentamer) have high affinity for nicotine.…”

Section: Introductionmentioning

confidence: 99%

Expression pattern of nicotinic acetylcholine receptor subunit transcripts in neurons and astrocytes in the ventral tegmental area and locus coeruleus

Gao

Schneider

Mulloy

et al. 2023

Preprint

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Acetylcholine is the endogenous agonist for the neuronal nicotinic acetylcholine receptor (nAChR) system, which is involved in attention, memory, affective behaviors, and substance use disorders. Brain nAChRs are highly diverse with 11 different subunits that can form multiple receptor subtypes, each with distinct receptor and pharmacological properties. Different neuronal cell types can also express different nAChR subtypes, resulting in highly complex cholinergic signaling. Identifying which nAChR subunit transcripts are expressed in cell types can provide an indication of which nAChR combinations are possible and which receptor subtypes may be most pharmacologically relevant to target. In addition to differences in expression across cell types, nAChRs also undergo changes in expression levels from adolescence to adulthood. In this study, we used fluorescent in situ hybridization to identify and quantify the expression of α4, α5, α6, β2 and β3 nAChR subunit transcripts in dopaminergic, GABAergic, glutamatergic, and noradrenergic neurons and astrocytes in the ventral tegmental area (VTA) and locus coeruleus (LC) in adult and adolescent, male and female C57BL/6J mice. There were distinct differences in the pattern of nAChR subunit transcript expression between the two brain regions. LC noradrenergic neurons had high prevalence of α6, β2 and β3 expression, with very low expression of α4, suggesting the α6(non-α4)β2β3 receptor as a main subtype in these neurons. VTA astrocytes from adult mice showed greater prevalence of α5, α6, β2 and β3 transcript compared with adolescent mice. These data highlight the complex nAChR expression patterns across brain region and cell type.

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Role of α6-Nicotinic Receptors in Alcohol-Induced GABAergic Synaptic Transmission and Plasticity to Cholinergic Interneurons in the Nucleus Accumbens

Cited by 12 publications

References 78 publications

Regulation of ethanol‐mediated dopamine elevation by glycine receptors located on cholinergic interneurons in the nucleus accumbens

Regulation of ethanol‐mediated dopamine elevation by glycine receptors located on cholinergic interneurons in the nucleus accumbens

Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of α6-Nicotinic Receptors and Dopamine Transporters

Expression pattern of nicotinic acetylcholine receptor subunit transcripts in neurons and astrocytes in the ventral tegmental area and locus coeruleus

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