Biochemical actions of chronic ethanol exposure in the mesolimbic dopamine system

Abstract

In previous studies, we have demonstrated that chronic administration of morphine or cocaine produces some common biochemical adaptations in the ventral tegmental area (VTA) and nucleus accumbens (NAc), components of the mesolimbic dopamine system implicated in the reinforcing actions of these and other drugs of abuse. Since this neural pathway is also implicated in the reinforcing actions of ethanol, it was of interest to determine whether chronic ethanol exposure results in similar biochemical adaptations. Indeed, as seen for chronic morphine and cocaine treatments, we show here that chronic ethanol treatment increased levels of tyrosine hydroxylase and glial fibrillary acidic protein immunoreactivity, and decreases levels of neurofilament protein immunoreactivity, in the VTA. Also like morphine and cocaine, ethanol increases levels of cyclic AMP-dependent protein kinase activity in the NAc. These actions of ethanol required long-term exposure to the drug, and were in most cases not seen in the substantia nigra or caudateputamen, components of the nigrostriatal dopamine system studied for comparison. Altered levels of tyrosine hydroxylase in catecholaminergic cells frequently reflect altered states of activation of the cells. Moreover, increasing evidence indicates that ethanol produces many of its acute effects on the brain by regulating NMDA glutamate and GABAA receptors. We therefore examined the influence of chronic ethanol treatment on levels of expression of specific glutamate and GABA receptor subunits in the VTA. It was found that long-term, but not short-term, ethanol exposure increased levels of immunoreactivity of the NMDAR1 subunit, an obligatory component of NMDA glutamate receptors, and of the GluR1 subunit, a component of many AMPA glutamate receptors; but at the same time, long-term ethanol exposure decreased immunoreactivity levels of the alpha 1 subunit of the GABAA receptor complex. These changes are consistent with an increased state of activation of VTA neurons inferred from the observed increase in tyrosine hydroxylase (TH) expression. These results demonstrate that chronic ethanol exposure results in several biochemical adaptations in the mesolimbic dopamine system, which may underlie prominent changes in the structural and functional properties of this neural pathway related to alcohol abuse and alcoholism.

NMDA Receptors Regulate Nicotine-Enhanced Brain Reward Function and Intravenous Nicotine Self-Administration: Role of the Ventral Tegmental Area and Central Nucleus of the Amygdala

“…We found that the expression of NMDA receptor subunits (NR2A, NR2B, and/or NR1) was increased in the VTA and CeA, decreased in the PFC, and unaltered in the NAcc, BLA, or CPu, of nicotine self-administering rats compared with controls. Importantly, similar increases in NMDA receptor subunit expression in the VTA and CeA and decreases in the PFC have been observed in rats self-administering cocaine, opiates, or alcohol and in post-mortem brain tissues from human cocaine users (Ortiz et al, 1995;Ghasemzadeh et al, 1999;Lu et al, 2003Lu et al, , 2005Tang et al, 2003;Turchan et al, 2003;Roberto et al, 2006;Ben-Shahar et al, 2007). The effects of self-administered nicotine on NMDA receptor subunit expression were far more pronounced in the CeA compared with the VTA.…”

Prenatal Stress Exposure Increases the Excitation of Dopamine Neurons in the Ventral Tegmental Area and Alters Their Reponses to Psychostimulants

“…For example, enhancing the expression in GluR2-lacking AMPARs in the VTA DA neurons leads to increased sensitivity to drug reward (Carlezon et al, 2000), whereas blocking glutamate receptors in the VTA during psychostimulant pre-exposure prevents enhanced psychostimulant self-administration (Suto et al, 2003). Exposure to psycho-stimulants, ethanol, or stress leads to augmented AMPA receptor function and greater glutamate synaptic strength in VTA DA neurons (Argilli et al, 2008;Bellone and Luscher, 2006;Borgland et al, 2004;Chen et al, 2008;Churchill et al, 1999;Fitzgerald et al, 1996;Ortiz et al, 1995;Saal et al, 2003;Stuber et al, 2008;Ungless et al, 2001;Zhang et al, 1997). Therefore, increased glutamate neurotransmission might contribute to PSE-induced overexcitation/depolarization block in VTA DA neurons and mediate the increased responding to psychostimulants and addiction risk.…”

“…For example, intra-VTA administration of psychostimulants enhances the subsequent cocaine self-administration (Suto et al, 2003) and reinstates drug-seeking behavior (Shaham et al, 2003). In addition, numerous studies report increased glutamate synaptic transmission in VTA DA neurons after psychostimulant, ethanol, or stress exposure, the conditions known to increase addiction risk (Borgland et al, 2004;Fitzgerald et al, 1996;Ortiz et al, 1995;Saal et al, 2003;Ungless et al, 2001;White et al, 1995;Zhang et al, 1997). Directly enhancing and blocking glutamate receptor expression in VTA DA neurons lead to increased responding to drug reward (Carlezon et al, 2000), and prevent enhanced psychostimulant self-administration (Suto et al, 2003), respectively.…”

Nucleus accumbens AGS3 expression drives ethanol seeking through Gβγ

“…13). Results from human alcoholics have, however, produced mixed but suggestive evidence of lasting perturbations in G protein signaling (49,50) that, in some studies, were not apparent without an abstinence period (51,52). In addition, decreased availability and function of D 2 dopamine receptors in the ventral striatum after repeated alcohol ingestion and subsequent abstinence (53) has been correlated with transynaptic network activation that may support craving (26); high AGS3 expression can impair signaling through D 2 dopamine receptors (13,16).…”