The prevailing view is that enhancement of dopamine (DA) transmission in the mesocorticolimbic system underlies the rewarding properties of alcohol and nicotine (NIC). The mesolimbic DA system consists of DA neurons in the midbrain ventral tegmental area (VTA) that innervate the nucleus accumbens (NAc). Dopamine neurotransmission is regulated by inhibitory VTA GABA neurons, whose excitability is a net effect of glutamate (GLU) and GABA neurotransmission that are modulated by NIC cholinergic receptors (nAChRs) on afferent terminals. We have shown that these neurons are excited by low-dose ethanol (Steffensen et al., 2009), but inhibited by moderate to high-dose ethanol (Gallegos et al., 1999;Ludlow et al., 2009;Steffensen et al., 2009; Stobbs et al., 2004;Yang et al., 2010), and adapt to chronic ethanol (Gallegos et al., 1999), evincing marked hyperexcitability during withdrawal. Based on our previous studies and data presented here, we propose that VTA GABA neurons are a common substrate for the acute actions of ethanol and NIC. The core thesis underlying this proposal is that ?6*-nAChRs on GABA terminals mediate acute ethanol inhibition of VTA GABA neurons and DA release in the NAc. In addition, VTA GABA neuron hyperexcitability during withdrawal from chronic ethanol results from adaptations in presynaptic ?6*-nAChRs and postsynaptic GABA(A)R-mediated inhibitory synaptic transmission to these neurons, which contributes to the dysregulation of mesolimbic DA homeostasis that accompanies dependence on ethanol and co-dependence on NIC. We will study of the role of ?6*-nAChRs in acute and chronic effects of ethanol on VTA GABA neurons and on DA release. Our proposed studies constitute a focused investigation into the role of ?6*-nAChRs in mediating acute ethanol effects on these neurons and their adaptation with alcohol dependence. Our studies will test the following specific hypotheses: 1) Acute ethanol inhibition of VTA GABA neuron activity and phasic DA release results from enhancement of GABA release via ?6*-nAChRs on GABA terminals;2) Lack of ?6*-nAChRs results in disrupted ethanol consumption and reward;and 3) Hyperexcitability of VTA GABA neurons during withdrawal from chronic ethanol results from adaptation of ?6*-nAChRs and subsequent reduction of DA release at terminals in the NAc. To test these hypotheses, we propose three Specific Aims, which involve electrophysiological, behavioral, neurochemical and molecular experiments with acute and chronic ethanol exposure in GAD GFP knock-in mice, and in wild type (WT) and ?6*-nAChR KO mice: 1) Define the role of ?6*-nAChRs in acute ethanol actions on VTA neurons and dopamine release in the NAc;2) Define the role of ?6*-nAChRs in mediating ethanol consumption and reward;and 3) Define the role of ?6-nAChRs in mediating the hyperexcitability of VTA GABA neurons and lowered dopamine release in the NAc during withdrawal from chronic ethanol. We will show preliminary evidence that ?6*-nAChRs mediate ethanol enhancement of NIC currents in recombinant nAChRs expression systems,that ethanol enhancement of GABA inhibition to VTA GABA neurons and ethanol reduction in DA release in the NAc, and compromised ethanol reward in ?6*- nAChR KO mice. The proposed studies constitute a thorough and systematic investigation into the role of VTA GABA neurons in mediating the acute effects of ethanol and NIC and the role of ?6*-nAChR in modulating GABA neurotransmission to these neurons that critically regulate DA neurotransmission in the mesolimbic system implicated in alcohol reward and dependence. Results from this study could provide a preclinical pharmacologic rationale for considering drugs that act selectively on ?6*-nAChR as putative therapeutic agents for the treatment of alcohol dependence and alcohol and NIC co-dependence.
Alcoholism and nicotine addiction are chronic relapsing disorders that have enormous impact on society. A major goal of research on addiction is to characterize the critical neural substrates that are most sensitive to the drug, adapt in association with chronic abuse and drive subsequent drug-seeking behavior. Currently, there are no evidence-based, clinically useful, pharmacotherapeutic interventions that might reverse the neuroadaptive effects of alcohol or nicotine dependence. Alcohol and NIC are the most commonly abused drugs, and a large body of evidence indicates that there is a positive correlation between their consumption. Today, smoking NIC-containing tobacco products is recognized as one of the greatest risk factors in the development of alcoholism. A major goal of addiction research is to characterize the critical neural substrates that are most sensitive to these drugs, adapt in association with chronic consumption and drive subsequent drug-seeking behavior. Alcohol and nicotine addiction share much in common, including co-dependence. The long-term objective of our research program is to advance our understanding of the neural basis of drug reward and dependence. The rationale for this proposal is predicated on the belief that advancement in the understanding the brain mechanisms underlying the recreational use and abuse potential of alcohol and nicotine will pave the way for more effective treatment strategies that could reverse dependence on these drugs and save lives and resources throughout the world.
|Jang, Eun Young; Yang, Chae Ha; Hedges, David M et al. (2016) The role of reactive oxygen species in methamphetamine self-administration and dopamine release in the nucleus accumbens. Addict Biol :|
|Jang, Eun Young; Ryu, Yeon-Hee; Lee, Bong Hyo et al. (2015) Involvement of reactive oxygen species in cocaine-taking behaviors in rats. Addict Biol 20:663-75|
|Larson, Michael J; Clayson, Peter E; Primosch, Mark et al. (2015) The Effects of Acute Dopamine Precursor Depletion on the Cognitive Control Functions of Performance Monitoring and Conflict Processing: An Event-Related Potential (ERP) Study. PLoS One 10:e0140770|
|Yorgason, Jordan T; Ferris, Mark J; Steffensen, Scott C et al. (2014) Frequency-dependent effects of ethanol on dopamine release in the nucleus accumbens. Alcohol Clin Exp Res 38:438-47|
|Vargas-Perez, Hector; Bahi, Amine; Bufalino, Mary Rose et al. (2014) BDNF signaling in the VTA links the drug-dependent state to drug withdrawal aversions. J Neurosci 34:7899-909|
|Schilaty, Nathan D; Hedges, David M; Jang, Eun Young et al. (2014) Acute ethanol inhibits dopamine release in the nucleus accumbens via Î±6 nicotinic acetylcholine receptors. J Pharmacol Exp Ther 349:559-67|
|Kim, Seol Ah; Lee, Bong Hyo; Bae, Jong Han et al. (2013) Peripheral afferent mechanisms underlying acupuncture inhibition of cocaine behavioral effects in rats. PLoS One 8:e81018|
|Ting-A-Kee, Ryan; Vargas-Perez, Hector; Mabey, Jennifer K et al. (2013) Ventral tegmental area GABA neurons and opiate motivation. Psychopharmacology (Berl) 227:697-709|
|Zhang, Die; Gao, Ming; Xu, Dan et al. (2012) Impact of prefrontal cortex in nicotine-induced excitation of ventral tegmental area dopamine neurons in anesthetized rats. J Neurosci 32:12366-75|
|Liu, Qiang; Huang, Yao; Shen, Jianxin et al. (2012) Functional Î±7Î²2 nicotinic acetylcholine receptors expressed in hippocampal interneurons exhibit high sensitivity to pathological level of amyloid Î² peptides. BMC Neurosci 13:155|