Nanomolar allopregnanolone potentiates rat cerebellar GABAA receptors

Fodor, László; Bı́ró, Tı́mea; Maksay, Gábor

doi:10.1016/j.neulet.2005.03.064

Cited by 23 publications

(21 citation statements)

References 21 publications

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“…Other than δ, no GABA A receptor subunits have so far been found to be exclusively extrasynaptic (Farrant and Nusser, 2005). Neurosteroids potentiate extrasynaptic GABA A receptors in nanomolar concentrations and decrease neuronal excitability by enhancing tonic conductance mediated by the δ subunit (Fodor et al, 2005;Stell et al, 2003). Some studies have shown that low concentrations of ethanol (1-30mM) potentiate extrasynaptic receptors (≤ 5% of all receptors), predominantly composed of the non-BZ sensitive α 4 , α 6 and δ subunits, but have no effect on receptors with γ 2 subunits, i.e.…”

Section: Presynaptic Postsynaptic and Extrasynaptic Receptors: Phasimentioning

confidence: 99%

The role of GABAA receptors in the development of alcoholism

Enoch

2008

Pharmacology Biochemistry and Behavior

196

181

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Alcoholism is a common, heritable, chronic relapsing disorder. GABA A receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABA A receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABA A receptors: tolerance is associated with generally decreased GABA A receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABA A receptors may be implicated in the switch from heavy drinking to dependence. GABA A receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABA A receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABA A receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.

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Section: Presynaptic Postsynaptic and Extrasynaptic Receptors: Phasimentioning

confidence: 99%

The role of GABAA receptors in the development of alcoholism

Enoch

2008

Pharmacology Biochemistry and Behavior

196

181

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“…An increase in receptors containing the c2 subunit was noted, along with a6 and bx, suggesting that c2 and d compete for assembly with these subunits in granule cells from wildtype mice (77). Functionally, a loss of modulation of sIPSCs by the neurosteroid THDOC selectively occurs in granule cells, but not stellate cells of d 0/0 mice (78), underscoring the importance of d-GABA A receptors for the in vivo action of neurosteroids (79). Behaviorally, deletion of the d subunit gene produces no overt impairment in motor function or motor learning, similarly to the a6 subunit gene (76).…”

Section: Effects Of Targeted Subunit Gene Deletion On Cerebellar Gabamentioning

confidence: 99%

Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions

Fritschy

Panzanelli

2006

Cerebellum

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GABA A receptors form heteromeric GABA-gated chloride channels assembled from a large family of subunit genes. In cerebellum, distinct GABA A receptor subtypes, differing in subunit composition, are segregated between cell types and synaptic circuits. The cerebellum therefore represents a useful system to investigate the significance of GABA A receptor heterogeneity. For instance, studies of mice carrying targeted deletion of major GABA A receptor subunit genes revealed the role of a subunit variants for receptor assembly, synaptic targeting, and functional properties. In addition, these studies unraveled mandatory association between certain subunits and demonstrated distinct pharmacology of receptors mediating phasic and tonic inhibition. Although some of these mutants have a profound loss of GABA A receptors, they exhibit only minor impairment of motor function, suggesting activation of compensatory mechanisms to preserve inhibitory networks in the cerebellum. These adaptations include an altered balance between phasic and tonic inhibition, activation of voltageindependent K + conductances, and upregulation of GABA A receptors in interneurons that are not affected directly by the mutation. Deletion of the a1 subunit gene leads to complete loss of GABA A receptors in Purkinje cells. A striking alteration occurs in these mice, whereby presynaptic GABAergic terminals are preserved in the molecular layer but make heterologous synapses with spines, characterized by a glutamatergic-like postsynaptic density. During development of a1 0/0 mice, GABAergic synapses are initially formed but are replaced upon spine maturation. These findings suggest that functional GABA A receptors are required for long-term maintenance of GABAergic synapses in Purkinje cells.

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“…Evidence shows that although ALLO can potentiate both tonic and phasic inhibition, extrasynaptic δ subunit-containing receptors may be especially sensitive to ALLO (Belelli and Lambert, 2005; Brown et al, 2002; Fodor et al, 2005). To better isolate the contribution of extrasynaptic GABA A receptors to ethanol’s reinforcing effects (which could eventually elucidate the contribution of each class of receptors to neurosteroid effects on ethanol intake), the second aim of this study was to utilize THIP, an agonist with selectivity for δ-subunit containing receptors, to examine the role of enhanced tonic inhibition on operant and limited access self-administration in mice.…”

Section: Introductionmentioning

confidence: 99%

Effect of ganaxolone and THIP on operant and limited-access ethanol self-administration

et al. 2012

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Recent evidence suggests that GABAA receptor ligands may regulate ethanol intake via effects at both synaptic and extrasynaptic receptors. For example, the endogenous neurosteroid, allopregnanolone (ALLO) has a similar pharmacological profile as ethanol, and it alters ethanol intake in rodent models. Additionally, recent evidence suggests that δ-subunit containing extrasynaptic GABAA receptors may confer high sensitivity to both ethanol and neurosteroids. The purpose of the present study was to determine the effects of ganaxolone (GAN; an ALLO analogue) and gaboxadol (THIP; a GABAA receptor agonist with selectivity for the extrasynaptic δ-subunit) on ethanol intake, drinking patterns, and bout characteristics in operant and limited access self-administration procedures. In separate studies, the effects of GAN (0 – 10 mg/kg) and THIP (2 – 16 mg/kg) were tested in C57BL/6J male mice provided with two-hour access to a two-bottle choice of water or 10% ethanol or trained to respond for 30 minutes of access to 10% ethanol. GAN had no overall significant effect on operant ethanol self-administration, but tended to decrease the latency to consume the first bout. In the limited-access procedure, GAN dose-dependently decreased ethanol intake. THIP dose-dependently decreased ethanol intake in both paradigms, altering both the consummatory and appetitive processes of operant self-administration as well as shifting the drinking patterns in both procedures. These results add to literature suggesting time-dependent effects of neurosteroids to promote the onset, and to subsequently decrease, ethanol drinking behavior, and they support a role for extrasynaptic GABAA receptor activation in ethanol reinforcement.

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Nanomolar allopregnanolone potentiates rat cerebellar GABAA receptors

Cited by 23 publications

References 21 publications

The role of GABAA receptors in the development of alcoholism

The role of GABAA receptors in the development of alcoholism

Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions

Effect of ganaxolone and THIP on operant and limited-access ethanol self-administration

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