Ethanol experience induces metaplasticity of NMDA receptor-mediated transmission in ventral tegmental area dopamine neurons


Ethanol experience induces metaplasticity of NMDA receptor-mediated transmission in ventral tegmental area dopamine neurons

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dc.contributor.advisor Morikawa, Hitoshi
dc.creator Bernier, Brian Ernest 2011-10-31T19:17:04Z 2011-10-31T19:17:04Z 2011-08 2011-10-31 August 2011
dc.description.abstract Addiction is thought to arise, in part, from a maladaptive learning process in which enduring memories of drug-related experiences are formed, resulting in persistent and uncontrollable drug-seeking behavior. However, it is well known that both acute and chronic alcohol (ethanol) exposures impair various types of learning and memory in both humans and animals. Consistent with these observations, both acute and chronic exposures to ethanol suppress synaptic plasticity, the major neural substrate for learning and memory, in multiple brain areas. Therefore, it remains unclear how powerful memories associated with alcohol experience are formed during the development of alcoholism. The mesolimbic dopaminergic system is critically involved in the learning of information related to rewards, including drugs of abuse. Both natural and drug rewards, such as ethanol, cause release of dopamine in the nucleus accumbens and other limbic structures, which is thought to drive learning by enhancing synaptic plasticity. Accumulating evidence indicates that plasticity of glutamatergic transmission onto dopamine neurons may play an important role in the development of addiction. Plasticity of NMDA receptor (NMDAR)-mediated transmission may be of particular interest, as NMDAR activation is necessary for dopamine neuron burst firing and phasic dopamine release in projection areas that occurs in response to rewards or reward-predicting stimuli. NMDAR plasticity may, therefore, drive the learning of stimuli associated with rewards, including drugs of abuse. This dissertation finds that repeated in vivo ethanol exposure induces a metaplasticity of NMDAR-mediated transmission in mesolimbic dopamine neurons, expressed as an increased susceptibility to the induction of NMDAR LTP. Enhancement of NMDAR plasticity results from an increase in the potency of inositol 1,4,5- trisphosphate (IP3) in producing the facilitation of action potential-evoked Ca2+ signals critical for LTP induction. Interestingly, amphetamine exposure produces a similar enhancement of IP3R function, suggesting this neuroadaptation may be a common response to exposure to multiple drugs of abuse. Additionally, ethanol-treated mice display enhanced learning of cues associated with cocaine exposure. These findings suggest that metaplasticity of NMDAR LTP may contribute to the formation of powerful memories related to drug experiences and provide an important insight into the learning component of addiction.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.subject Addiction
dc.subject Dopamine
dc.subject Reward learning
dc.subject Synaptic plasticity
dc.subject Alcohol
dc.subject Ethanol
dc.subject IP3
dc.subject NMDA
dc.title Ethanol experience induces metaplasticity of NMDA receptor-mediated transmission in ventral tegmental area dopamine neurons 2011-10-31T19:17:23Z
dc.identifier.slug 2152/ETD-UT-2011-08-3764
dc.contributor.committeeMember Harris, R. A.
dc.contributor.committeeMember Aldrich, Richard
dc.contributor.committeeMember Koester, Helmut
dc.contributor.committeeMember Valenzuela, Fernando
dc.description.department Neuroscience
dc.type.genre thesis
dc.type.material text Neuroscience Neuroscience University of Texas at Austin Doctoral Doctor of Philosophy

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