The mesolimbic dopaminergic system originating in the midbrain ventral tegmental area (VTA) is critically involved in the development of alcoholism. During the previous round of funding of this project, two types of neuroadaptive changes were identified in VTA dopamine neurons after repeated alcohol (ethanol) exposure: 1) enhanced synaptic plasticity of NMDA receptor-mediated glutamatergic transmission and 2) increased dopamine-induced autoinhibition of dopamine neuron activity mediated by somatodendritic D2 autoreceptors. These changes will promote the development of alcoholism by 1) facilitating the formation of powerful and enduring memories of ethanol-associated stimuli and 2) causing reduced dopaminergic output during withdrawal, which drives compulsive ethanol intake to compensate for dopamine deficits via ethanol stimulation of dopamine neuron activity. Clinical and preclinical evidence indicates that negative life experiences, such as prolonged social isolation or compulsive eating of calorie-dense palatable food, especially during early stages of life, increase an individual's risk of developing alcoholism both concurrently and in the future. However, the neurobiological mechanisms underlying the effects of these experiences are not well understood. The current proposal will investigate how VTA dopamine neurons are affected by prolonged social isolation (Aims 1 and 2) and extended access to high fat/carbohydrate palatable food ('cafeteria diet') (Aims 3 and 4) during early adolescence in rats. The overriding hypothesis is that these experiences will increase alcoholism vulnerability by enhancing NMDA receptor plasticity and dopamine-induced autoinhibition in the VTA. Brain slice experiments (Aims 1 and 3) will employ patch-clamp electrophysiology, confocal fluorescence imaging, and photolytic application of signaling molecules to determine the cellular and molecular mechanisms involved. These ex vivo methodologies will be combined with behavioral assays (Aims 2 and 4) to elucidate the neurobiological mechanisms underlying the vulnerability to develop alcoholism.

Public Health Relevance

Negative early life experiences increase an individual's risk of developing alcoholism, both concurrently and later in life. This project aims to uncover the neurobiological underpinnings of alcoholism vulnerability resulting from defective social and dietary experiences (prolonged social isolation and overconsumption of calorie-dense palatable food) during early adolescence. The findings obtained from this project may lead to effective prevention and treatment strategies for alcoholism using environmental and behavioral manipulations in combination with pharmacotherapies.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Cui, Changhai
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University of Texas Austin
Schools of Arts and Sciences
United States
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Cui, Changhai; Noronha, Antonio; Morikawa, Hitoshi et al. (2013) New insights on neurobiological mechanisms underlying alcohol addiction. Neuropharmacology 67:223-32
Clements, Michael A; Swapna, Immani; Morikawa, Hitoshi (2013) Inositol 1,4,5-triphosphate drives glutamatergic and cholinergic inhibition selectively in spiny projection neurons in the striatum. J Neurosci 33:2697-708
Whitaker, Leslie R; Degoulet, Mickael; Morikawa, Hitoshi (2013) Social deprivation enhances VTA synaptic plasticity and drug-induced contextual learning. Neuron 77:335-45
Perra, Simona; Clements, Michael A; Bernier, Brian E et al. (2011) In vivo ethanol experience increases D(2) autoinhibition in the ventral tegmental area. Neuropsychopharmacology 36:993-1002
Blednov, Y A; Benavidez, J M; Geil, C et al. (2011) Activation of inflammatory signaling by lipopolysaccharide produces a prolonged increase of voluntary alcohol intake in mice. Brain Behav Immun 25 Suppl 1:S92-S105
Morikawa, H; Paladini, C A (2011) Dynamic regulation of midbrain dopamine neuron activity: intrinsic, synaptic, and plasticity mechanisms. Neuroscience 198:95-111
Theile, J W; Morikawa, H; Gonzales, R A et al. (2011) GABAergic transmission modulates ethanol excitation of ventral tegmental area dopamine neurons. Neuroscience 172:94-103
Morikawa, Hitoshi; Harris, R Adron (2011) Small K channels: big targets for treating alcoholism? Biol Psychiatry 69:614-5
Bernier, Brian E; Whitaker, Leslie R; Morikawa, Hitoshi (2011) Previous ethanol experience enhances synaptic plasticity of NMDA receptors in the ventral tegmental area. J Neurosci 31:5205-12
Morikawa, Hitoshi; Morrisett, Richard A (2010) Ethanol action on dopaminergic neurons in the ventral tegmental area: interaction with intrinsic ion channels and neurotransmitter inputs. Int Rev Neurobiol 91:235-88

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