Synaptic inputs to GABAA and GABAB receptors originate from discrete afferent neurons

Sugita, Shunsuke; Johnson, Steven W.; North, Richard

doi:10.1016/0304-3940(92)90518-c

Cited by 210 publications

(125 citation statements)

References 31 publications

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“…In support of the regional differences in baclofen's effectiveness, perfusion of baclofen into the SN decreased basal and nomifensine-induced extracellular dopamine levels in the SN and CPu, but infusion into the CPu did not decrease striatal dopamine levels (Westerink et al, 1992;Santiago et al, 1993;Balon et al, 2002). GABA B receptors are expressed by striatonigral, striatopallidal, and glutamatergic afferents as well as by dopamine and GABA neurons in the SN and VTA (Sugita et al, 1992;Charara et al, 2000;Boyes and Bolam, 2003). However, the amphetaminesuppressing effect of baclofen in the ventral mesencephalon is most consistent with a direct action on dopamine neurons.…”

Section: Effects Of Intracerebral Baclofen On Amphetamine-induced Behmentioning

confidence: 83%

Intracerebral Baclofen Administration Decreases Amphetamine-Induced Behavior and Neuropeptide Gene Expression in the Striatum

Zhou

Mailloux

McGinty

2004

Neuropsychopharmacol

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In a previous study, systemic administration of the GABA B receptor agonist, R-( þ )-baclofen (2.5 mg/kg, i.p.) blocked acute amphetamine (2.5 mg/kg, i.p.)-induced rearing and neuropeptide (preprodynorphin (PPD), preprotachykinin (PPT), preproenkephalin (PPE), and secretogranin II (SGII)) mRNA expression in the striatum (Zhou et al, 2004). The purpose of the present study was to investigate the site(s) of action of these baclofen effects in the dorsal and ventral striatal circuitries. Infusion of baclofen (75 ng/side) into the ventral tegmental area (VTA), substantia nigra (SN), nucleus accumbens (NA), caudate-putamen (Cpu), or medial prefrontal cortex (mPFC) had no effect on behavioral activity in saline-treated rats habituated to a photocell apparatus. However, intra-VTA infusion of baclofen (75 ng/ side) completely blocked, whereas intra-NA and intra-SN infusion of baclofen attenuated, amphetamine-induced vertical activity without affecting amphetamine-induced total distance traveled. In contrast, intramedial PFC and intra-CPu infusion of baclofen had no effect on behavioral activity in amphetamine-treated rats. Infusion of baclofen into the VTA, NA, or SN decreased amphetamine-induced neuropeptide gene expression in the striatum. These results indicate that GABA B receptor stimulation within the ventral striatal circuitry is involved in mediating acute amphetamine-induced behaviors and neuropeptide gene expression in the dorsal and ventral striatum. The present study provides information on the potential targets in the brain for baclofen in the initial behavioral and genomic response to amphetamine.

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Section: Effects Of Intracerebral Baclofen On Amphetamine-induced Behmentioning

confidence: 83%

Intracerebral Baclofen Administration Decreases Amphetamine-Induced Behavior and Neuropeptide Gene Expression in the Striatum

Zhou

Mailloux

McGinty

2004

Neuropsychopharmacol

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“…GABA is the main inhibitory neurotransmitter in the central nervous system, and GABAergic projections to the VTA are thought to synapse on dopamine neurons at GABA-B receptor sites Sugita, et al, 1992). One way that baclofen might act, therefore, would be to reduce the rewarding properties of fatty foods by inhibiting DA neurons in the VTA.…”

Section: Raclopride: Dopamine D 2 -Like Antagonistmentioning

confidence: 99%

Baclofen, raclopride, and naltrexone differentially reduce solid fat emulsion intake under limited access conditions

Rao

Wojnicki

Coupland

et al. 2008

Pharmacology Biochemistry and Behavior

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Previous work in rats has demonstrated that an Intermittent (Monday, Wednesday, Friday) schedule of access promotes binge-type consumption of 100% vegetable shortening during a 1-hour period of availability. The present study used novel shortening-derived stable solid emulsions of various fat concentrations. These emulsions were the consistency of pudding and did not demonstrate oil and water phase separation previously reported with oil-based liquid emulsions. Male Sprague-Dawley rats were grouped according to schedule of access (Daily or Intermittent) to one of three concentrations (18%, 32%, 56%) of solid fat emulsion. There were no significant Intermittent vs. Daily differences in amount consumed, due to high intakes in all groups. This indicated the acceptability of the emulsions. Baclofen (GABA-B agonist) and raclopride (D2-like antagonist) both significantly reduced emulsion intake in all Daily groups, but only in the 56% fat Intermittent group. Naltrexone (opioid antagonist), in contrast, significantly reduced 32% and 56% fat emulsion intake in the Intermittent, as well as the Daily groups. These results indicate that the fat intake reducing effects of GABA B activation and D2 blockade depend upon fat concentration and schedule of fat access, while the fat intake reducing effects of opioid blockade depend upon fat concentration but not schedule of access.

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“…GABA B receptors on VTA DA neurons are selectively activated by GABAergic inputs from the ventral pallidum, and inhibiting these afferents increases the population activity of VTA DA neurons and DA release in the NAc (52,53). Thus, the potentiation of GABA B -GIRK coupling by ethanol would reduce VTA DA neuron firing and DA efflux in the NAc, and, as proposed above, the phenotype of GIRK3 KO mice could be explained by stronger activation of GIRK currents coupled to GABA B receptors.…”

Section: Girk3 Deletion Prevents Ethanol-induced Release Of Da In Thementioning

confidence: 99%

GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol

Herman

Sidhu

Stouffer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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G protein-gated inwardly rectifying potassium (GIRK) channels are critical regulators of neuronal excitability and can be directly activated by ethanol. Constitutive deletion of the GIRK3 subunit has minimal phenotypic consequences, except in response to drugs of abuse. Here we investigated how the GIRK3 subunit contributes to the cellular and behavioral effects of ethanol, as well as to voluntary ethanol consumption. We found that constitutive deletion of GIRK3 in knockout (KO) mice selectively increased ethanol bingelike drinking, without affecting ethanol metabolism, sensitivity to ethanol intoxication, or continuous-access drinking. Virally mediated expression of GIRK3 in the ventral tegmental area (VTA) reversed the phenotype of GIRK3 KO mice and further decreased the intake of their wild-type counterparts. In addition, GIRK3 KO mice showed a blunted response of the mesolimbic dopaminergic (DA) pathway to ethanol, as assessed by ethanol-induced excitation of VTA neurons and DA release in the nucleus accumbens. These findings support the notion that the subunit composition of VTA GIRK channels is a critical determinant of DA neuron sensitivity to drugs of abuse. Furthermore, our study reveals the behavioral impact of this cellular effect, whereby the level of GIRK3 expression in the VTA tunes ethanol intake under binge-type conditions: the more GIRK3, the less ethanol drinking.protein-gated inwardly rectifying potassium (GIRK) channels mediate slow inhibitory postsynaptic potentials following activation of G i/o -coupled receptors, thereby regulating membrane excitability in neuronal, cardiac, and endocrine cells. In neurons, GIRK channels exist as GIRK2 homotetramers or heterotetramers of GIRK1, GIRK2, and/or GIRK3 (reviewed in ref. 1). Despite overlapping distributions in the central nervous system, the three subunits exhibit cell type-specific patterns of expression within some brain regions (2-7). In particular, in the ventral tegmental area (VTA), dopaminergic (DA) neurons express only GIRK2 and GIRK3, whereas non-DA neurons also express GIRK1, a discrepancy that drives differential sensitivity of the two cell populations to G i/o -coupled receptor (e.g., GABA B receptor) activation (8-10).In addition to their activation by G i/o -coupled receptors, GIRK channels also can be directly activated by ethanol (11-14). The behavioral significance of GIRK channel activation by ethanol (either directly or through G proteins) is poorly understood, however. GIRK2 knockout (KO) mice are less sensitive to ethanol's rewarding and aversive effects, as measured in conditioned place preference and conditioned taste aversion tests (15). Ethanol-induced locomotor stimulation, anxiolytic-like effect, and withdrawal severity are also blunted in the absence of GIRK2 (16). Constitutive GIRK2 deletion produces numerous behavioral abnormalities, however, including increased seizure susceptibility, reduced anxiety-like behavior, hyperactivity, hyperalgesia, and enhanced operant response for food, making it difficult to interpre...

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Synaptic inputs to GABAA and GABAB receptors originate from discrete afferent neurons

Cited by 210 publications

References 31 publications

Intracerebral Baclofen Administration Decreases Amphetamine-Induced Behavior and Neuropeptide Gene Expression in the Striatum

Intracerebral Baclofen Administration Decreases Amphetamine-Induced Behavior and Neuropeptide Gene Expression in the Striatum

Baclofen, raclopride, and naltrexone differentially reduce solid fat emulsion intake under limited access conditions

GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol

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