Glutamate-mediated transmission, alcohol, and alcoholism

Dodd, Peter R.; Beckmann, Alison M.; Davidson, Marks S; Wilce, Peter A.

doi:10.1016/s0197-0186(00)00061-9

Cited by 172 publications

(88 citation statements)

References 272 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This possibility does not seem likely given that most of the published evidence indicates that EtOH enhances GABAergic transmission in the CNS (Mihic, 1999;Aguayo et al, 2002;Roberto et al, 2003); however, an EtOH-induced decrease in glutamatergic input to basket, stellate, or Lugaro cells could indirectly decrease GABAergic tone, as we recently detected in interneuron-to-CA1 pyramidal neurons in the hippocampus (Carta et al, 2003). Alternatively, EtOH could increase excitatory input to Golgi cells, although evidence from a myriad of laboratories suggests that EtOH typically reduces glutamatergic input (Woodward, 1999;Dodd et al, 2000;Roberto et al, 2004). Moreover, we report here that EtOH does not affect spontaneous glutamate release at mossy fiber-to-granule cell synapses, suggesting that it is also ineffective at mossy fiber-to-Golgi cell synapses.…”

Section: Discussionmentioning

confidence: 87%

Alcohol Enhances GABAergic Transmission to Cerebellar Granule Cells via an Increase in Golgi Cell Excitability

Carta¹,

Mameli²,

Valenzuela³

2004

J. Neurosci.

206

243

View full text Add to dashboard Cite

Alcohol intoxication alters coordination and motor skills, and this is responsible for a significant number of traffic accident-related deaths around the world. Although the precise mechanism of action of ethanol (EtOH) is presently unknown, studies suggest that it acts, in part, by interfering with normal cerebellar functioning. An important component of cerebellar circuits is the granule cell. The excitability of these abundantly expressed neurons is controlled by the Golgi cell, a subtype of GABAergic interneuron. Granule cells receive GABAergic input in the form of phasic and tonic currents that are mediated by synaptic and extrasynaptic receptors, respectively. Using the acute cerebellar slice preparation and patch-clamp electrophysiological techniques, we found that ethanol induces a parallel increase in both the frequency of spontaneous IPSCs and the magnitude of the tonic current. EtOH (50 mM) did not produce this effect when spontaneous action potentials were blocked with tetrodotoxin. Recordings in the loose-patch cell-attached configuration demonstrated that ethanol increases the frequency of spontaneous action potentials in Golgi cells. Taken together, these findings indicate that ethanol enhances GABAergic inhibition of granule cells via a presynaptic mechanism that involves an increase in action potential-dependent GABA release from Golgi cells. This effect is likely to have an impact on the flow of information through the cerebellar cortex and may contribute to the mechanism by which acute ingestion of alcoholic beverages induces motor impairment.

show abstract

Section: Discussionmentioning

confidence: 87%

Alcohol Enhances GABAergic Transmission to Cerebellar Granule Cells via an Increase in Golgi Cell Excitability

Carta¹,

Mameli²,

Valenzuela³

2004

J. Neurosci.

206

243

View full text Add to dashboard Cite

show abstract

“…Many of the physiological, biochemical, and behavioral effects of ethanol are known to involve iGluR function (Dodd et al, 2000;Mihic, 1999;Aschner et al, 2001;Woodward, 1999;Tabakoff and Hoffman, 1993;Littleton et al, 2001;Weight et al, 1993;Costa et al, 2000). In addition to its effects on iGluRs, however, ethanol also modulates general metabotropic receptor activity as evidenced by its ability to reduce basal and stimulated phosphoinositide hydrolysis (Gonzales et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological and Anatomical Evidence for an Interaction Between mGluR5- and GABAA α1-Containing Receptors in the Discriminative Stimulus Effects of Ethanol

Besheer

Hodge

2004

Neuropsychopharmacol

View full text Add to dashboard Cite

The discriminative stimulus properties of ethanol are mediated in part by positive modulation of GABA A receptors. Recent evidence indicates that metabotropic glutamate receptor subtype 5 (mGluR5) activity can influence GABA A receptor function. Therefore, the purpose of this work was to examine the potential involvement of mGluR5 in the discriminative stimulus effects of ethanol. In rats trained to discriminate ethanol (1 g/kg, intragastric gavage (i.g.)) from water, 2-methyl-6-(phenylethyl)-pyridine (MPEP) (1-50 mg/kg, i.p.) a selective noncompetitive antagonist of the mGlu5 receptor did not produce ethanol-like stimulus properties. However, pretreatment with MPEP (30 mg/kg) reduced the stimulus properties of ethanol as indicated by significant reductions in ethanol-appropriate responding, specifically at 0.5 and 1 g/kg ethanol, and a failure of ethanol test doses (1 and 2 g/kg) to fully substitute for the ethanol training dose. To test whether mGluR5 antagonism altered the GABA A receptor component of the ethanol stimulus, the ability of MPEP to modulate pentobarbital and diazepam substitution for ethanol was assessed. Pentobarbital substitution (1-10 mg/kg, i.p.) for ethanol was not altered by MPEP pretreatment. However, MPEP pretreatment inhibited the ethanol-like stimulus properties of diazepam (5 mg/ kg, i.p.). To examine a potential anatomical basis for these pharmacological findings, expression patterns of mGluR5-and benzodiazepinesensitive GABA A a1-containing receptors were examined by dual-label fluorescent immunohistochemistry with visualization by confocal microscopy. Results indicated that mGluR5-and GABA A a1-containing receptors were both coexpressed in limbic brain regions and colocalized on the same cells in specific brain regions including the amygdala, hippocampus, globus pallidus, and ventral pallidum. Together, these findings suggest an interaction between mGluR5-and benzodiazepine-sensitive GABA A receptors in mediating ethanol discrimination.

show abstract

“…On the other hand, excitatory N-methyl-Daspartate (NMDA) glutamate receptors are up-regulated in alcohol dependence. Abrupt cessation of alcohol intake results in withdrawal syndrome when this neuroadaptation is unmasked 31 . The role of benzodiazepines in alcohol detoxification is to re-establish the balance and suppress the predominance of glutamate by enhancing GABA transmission.…”

Section: Etiopathogenesismentioning

confidence: 99%