Effects of Alcohol on Synaptic Transmission. Why is Alcohol Used and Abused?

Effects of Alcohol onEffects of Alcohol onSynaptic TransmissionSynaptic Transmission

Why is Alcohol Used and Abused?

Chemical Synaptic Transmission

PRESYNAPTICPRESYNAPTICTERMINALTERMINAL

POSTSYNAPTICDENDRITE

Ligand-GatedIon Channels

Key Steps in Synaptic Transmission

POSTSYNAPTICPOTENTIAL

Ca2+

channel

+++

+++

Neurotransmitteruptake

EPSP reachesaction potential

threshold

EPSPEPSP

IPSPIPSP

- 65 mV- 65 mV

- 45 mV- 45 mV

CAFFEINECAFFEINE

COCAINECOCAINE

NICOTINENICOTINE

ETHANOL???ETHANOL???

GABAGABA

--GLUTAMATEGLUTAMATE

++

AlcoholAlcohol

GABAGABA

--GLUTAMATEGLUTAMATE

++

Chronic Chronic AlcoholAlcohol

Electrophysiological MethodsElectrophysiological Methodsin Alcohol Researchin Alcohol Research

BrainBrainSliceSlice

CA1CA1PyramidalPyramidal

CellCell

++GABAGABAAA Receptor Blockers Receptor Blockers

++Glutamate ReceptorGlutamate Receptor

BlockersBlockersaCSFaCSF

GLUGLU

GABAGABA

Alcohol and GABAergic Inhibition

Model of theGABAA Receptor

Freund and Buzsaki, 1996 Trudell and Bertaccini, 2004

Acute Alcohol Exposure Potentiates GABAergic Acute Alcohol Exposure Potentiates GABAergic

Synaptic TransmissionSynaptic Transmission

RAT AMYGDALA MONKEY DENTATE GYRUS

Roberto et al, 2003 Ariwodola et al, 2003

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Presynaptic Mechanisms Contribute to Alcohol Potentiation of

GABAergic Inhibition

RAT CEREBELLAR

GRANULE CELLSRAT HIPPOCAMPAL CA1

PYRAMIDAL CELLS

Li et al, 2006

Carta et al, 2004

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Tonic vs. Phasic GABAergic Inhibition

Farrant and Nusser, 2005

mIPSC Evoked IPSC

PHASICPHASIC TONICTONIC

Wei et al, 2004

Jia et al, 2007

DENTATE GRANULE CELLS

THALAMIC NEURONSCEREBELLAR GRANULE CELLS

Carta et al, 2004

Alcohol Enhances Tonic GABAergic Inhibition

Chronic Alcohol Increases Anxiety andDecreases GABAA Receptor Function

Cagetti et al, 2003

Alcohol Potentiation of GABAergic Synapses is not Reduced After Chronic Alcohol Treatments

Roberto et al, 2004

Kang et al, 1998

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Local Amygdalar Infusion of aGABAA Agonist Reduces Alcohol Self-

Administrationin Dependent Rats

Koob, 2004

Alcohol and Glutamatergic Excitation

Lendvai et al, 2000Anderen and Soleng, 1999

Lovinger et al, 1990

Alcohol inhibition of NMDA-

evoked currents in cultured

rat hippocampal cells

Alcohol inhibition of NMDA

EPSCs in the rat ventral bed

nucleus of the stria

terminalisKash et al, 2008

Acute Alcohol Exposure

Inhibits NMDA Receptor Function

Chronic Alcohol IncreasesGlutamatergic Excitability

Hendricson et al, 2007 Lack et al, 2007

Acamprosate Decreases Alcohol Drinkingand the Neurotoxicity

Associated with Alcohol Withdrawal

Heyser et al, 1998

De Witte et al, 2005

Alcohol and Dopaminergic Signaling

Boileau et al, 2003

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Acute Alcohol Exposure Enhances Dopamine Release in the Mesolimbic “Reward” Circuit

Brodie et al, 1998

Okamoto et al, 2005

DA NEURONS IN MOUSE

MID BRAIN SLICES

DA NEURONS IN RAT VTA

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Volkow et al, 2007

Chronic Alcohol Results in Significant Perturbations in Dopamine Signaling

Naltrexone Reduces Alcohol Stimulation of Dopamine Release and Decreases Alcohol Intake

Gonzales and Weiss, 1998

• Acute alcohol exposure has profound effects on chemical synaptic transmission– Increase in synaptic and extrasynaptic GABAergic inhibition– Decrease in NMDA receptor function– Increase in the firing rate of VTA dopamine cells

• Chronic alcohol exposure and withdrawal lead to persistent changes in synaptic transmission that often oppose the acute effects of this drug– Decrease in GABAergic inhibition– Increase in glutamatergic excitation– Dopaminergic hypofunction

SUMMARY

SUMMARY (con’t)

• Although recent advances have shed considerable light on the mechanisms through which acute and chronic alcohol modulate synaptic transmission, new experimental strategies are needed to begin to address the behavioral relevance of alcohol’s many synaptic effects

• Recent preclinical and clinical studies suggest that a better understanding of the neurobiological mechanisms responsible for the acute and long term behavioral consequences of alcohol drinking will greatly facilitate the development of more effective treatment strategies for alcoholism