effects of alcohol on synaptic transmission. why is alcohol used and abused?
TRANSCRIPT
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Effects of Alcohol onEffects of Alcohol onSynaptic TransmissionSynaptic Transmission
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Why is Alcohol Used and Abused?
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Chemical Synaptic Transmission
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PRESYNAPTICPRESYNAPTICTERMINALTERMINAL
POSTSYNAPTICDENDRITE
Ligand-GatedIon Channels
Key Steps in Synaptic Transmission
POSTSYNAPTICPOTENTIAL
Ca2+
channel
+++
+++
Neurotransmitteruptake
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EPSP reachesaction potential
threshold
EPSPEPSP
IPSPIPSP
- 65 mV- 65 mV
- 45 mV- 45 mV
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CAFFEINECAFFEINE
COCAINECOCAINE
NICOTINENICOTINE
ETHANOL???ETHANOL???
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GABAGABA
--GLUTAMATEGLUTAMATE
++
AlcoholAlcohol
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GABAGABA
--GLUTAMATEGLUTAMATE
++
Chronic Chronic AlcoholAlcohol
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Electrophysiological MethodsElectrophysiological Methodsin Alcohol Researchin Alcohol Research
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BrainBrainSliceSlice
CA1CA1PyramidalPyramidal
CellCell
++GABAGABAAA Receptor Blockers Receptor Blockers
++Glutamate ReceptorGlutamate Receptor
BlockersBlockersaCSFaCSF
GLUGLU
GABAGABA
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Alcohol and GABAergic Inhibition
Model of theGABAA Receptor
Freund and Buzsaki, 1996 Trudell and Bertaccini, 2004
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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
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Wei et al, 2004
Jia et al, 2007
DENTATE GRANULE CELLS
THALAMIC NEURONSCEREBELLAR GRANULE CELLS
Carta et al, 2004
Alcohol Enhances Tonic GABAergic Inhibition
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Chronic Alcohol Increases Anxiety andDecreases GABAA Receptor Function
Cagetti et al, 2003
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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
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Alcohol and Glutamatergic Excitation
Lendvai et al, 2000Anderen and Soleng, 1999
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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
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Chronic Alcohol IncreasesGlutamatergic Excitability
Hendricson et al, 2007 Lack et al, 2007
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Acamprosate Decreases Alcohol Drinkingand the Neurotoxicity
Associated with Alcohol Withdrawal
Heyser et al, 1998
De Witte et al, 2005
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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
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Naltrexone Reduces Alcohol Stimulation of Dopamine Release and Decreases Alcohol Intake
Gonzales and Weiss, 1998
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• 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
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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