Voluntary Ethanol Intake Enhances Excitatory Synaptic Strength in the Ventral Tegmental Area

Stuber, Garret D.; Hopf, F. Woodward; Hahn, Junghyun; Cho, Saemi L.; Guillory, Anitra M.; Bonci, Antonello

doi:10.1111/j.1530-0277.2008.00749.x

Cited by 122 publications

(82 citation statements)

References 44 publications

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“…In rats, high-dose ethanol exposure increases both ethanol self-administration and ethanol preference (Camarini & Hodge, 2004;Crabbe et al, 2012;Griffi n et al, 2009;O'Dell et al, 2004;Rimondini et al, 2002Rimondini et al, , 2003Timberlake et al, 2009), even when evidence of tolerance is absent (Alaux-Cantin et al, 2013;Cox et al, 2013;Stuber et al, 2008). We have established that rats reliably consume enough ethanol in a gelatin vehicle within an hour to result in brain ethanol levels of 8-10 mM (Li et al, 2010;Peris et al, 2006;Rowland et al, 2005), which is remarkably similar to that achieved after one to two alcoholic beverages over the same period in humans (Brick 2006).…”

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confidence: 57%

Intermittent High-Dose Ethanol Exposure Increases Ethanol Preference in Rats

Peris¹,

Rhodes²,

McCullough³

et al. 2015

J. Stud. Alcohol Drugs

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ABSTRACT. Objective: Alcohol use disorders have both high social and economic costs and are among the leading causes of preventable death in the United States. Understanding the factors that contribute to escalation of alcohol intake is important in developing effective treatments for this problem. This study further characterizes the effects of limited intermittent exposure to high levels of alcohol on the preference for alcohol consumption over other incentives. Method: Fourteen male, Sprague-Dawley rats were trained to consume ethanol in a gelatin vehicle. They were then given free access to both ethanol gelatin and plain gelatin during daily choice periods interspersed with nonchoice periods (only plain gelatin access). After baseline ethanol preference was established, half of the rats were given eight injections of 3 g/kg ethanol during nonchoice periods (spread out over about 2 months), and the other half received saline injections. Ethanol preference was measured during subsequent choice periods. Results: Intermittent ethanol injections increased ethanol preference from 21% (SEM = 2.3%) of their total gelatin consumption during the fi rst choice period to 46.8% (SEM = 3.4%) during the third choice period. The saline-treated rats had no signifi cant change in ethanol preference. In addition, the ethanoltreated rats exhibited higher ethanol intake than saline-treated rats when ethanol gelatin was the only choice available. Conclusions: The results indicate that intermittent exposure to sedative doses of ethanol leads to an increased ethanol preference in rats. This suggests that occasional high-dose alcohol exposure could be an important contributor to the development of enhanced ethanol intake, which may affect the incidence of chronic alcoholism. (J. Stud. Alcohol Drugs, 76, 165-173, 2015)

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mentioning

confidence: 57%

Intermittent High-Dose Ethanol Exposure Increases Ethanol Preference in Rats

Peris¹,

Rhodes²,

McCullough³

et al. 2015

J. Stud. Alcohol Drugs

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“…Drugs of abuse increase levels of the rate-limiting enzyme in dopamine synthesis, Th (tyrosine hydroxylase), and augment firing rates of VTA dopamine neurons via direct and indirect mechanisms (Nestler, 2005;Stuber et al, 2008). Importantly, CLOCK is involved in regulating dopaminergic transmission.…”

Section: Discussionmentioning

confidence: 99%

The Role of Clock in Ethanol-Related Behaviors

Ozburn

Falcón

Mukherjee

et al. 2013

Neuropsychopharmacol

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Mice with a mutation in the Clock gene (ClockD19) exhibit increased preference for stimulant rewards and sucrose. They also have an increase in dopaminergic activity in the ventral tegmental area (VTA) and a general increase in glutamatergic tone that might underlie these behaviors. However, it is unclear if their phenotype would extend to a very different class of drug (ethanol), and if so, whether these systems might be involved in their response. Continuous access voluntary ethanol intake was evaluated in ClockD19 mutants and wild-type (WT) mice. We found that ClockD19 mice exhibited significantly increased ethanol intake in a two-bottle choice paradigm. Interestingly, this effect was more robust in female mice. Moreover, chronic ethanol experience resulted in a long-lasting decrease in VTA Clock expression. To determine the importance of VTA Clock expression in ethanol intake, we knocked down Clock expression in the VTA of WT mice via RNA interference. We found that reducing Clock expression in the VTA resulted in significantly increased ethanol intake similar to the ClockD19 mice. Interestingly, we also discovered that ClockD19 mice exhibit significantly augmented responses to the sedative effects of ethanol and ketamine, but not pentobarbital. However, their drinking behavior was not affected by acamprosate, an FDA-approved drug for the treatment of alcoholism, suggesting that their increased glutamatergic tone might underlie the increased sensitivity to the sedative/hypnotic properties of ethanol but not the rewarding properties of ethanol. Taken together, we have identified a significant role for Clock in the VTA as a negative regulator of ethanol intake and implicate the VTA dopamine system in this response.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Hausknecht

Haj‐Dahmane

Shen

2012

Neuropsychopharmacol

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Prenatal stress exposure (PSE) is known to increase addiction risk. Dopamine (DA) neurons in the ventral tegmental area (VTA) play an important role in addiction. In order to understand the cellular mechanisms underlying PSE-induced increase in addiction risk, we examined the effects of PSE on the electrical impulse activity of VTA DA neurons using the in vivo extracellular single-unit recording technique. Amphetamine self-administration was also conducted to confirm increased addiction risk after PSE. The PSE was carried out by restraining pregnant dams from GD 11 to 20. Adult male offspring (3-6 months old) were used in the experiments. Animals with PSE showed enhanced amphetamine self-administration compared with controls when amphetamine dose was reduced after acquisition. The number of spontaneously active VTA DA neurons was also reduced in PSE rats. The reduction was reversed by acute apomorphine that normally inhibits the impulse activity of DA neurons. The reversal effect suggests that PSE-induced reduction in the number of spontaneously active VTA DA neurons is caused by overexcitation to the extent of depolarization block. Furthermore, the reduced number of spontaneously active VTA DA neurons was also reversed by acute psychostimulants (eg, amphetamine; cocaine), which in control rats inhibited the activity of VTA DA neurons. The reversal effect on VTA DA neuron in PSE animals represents an actual increase in the impulse activity. This effect might contribute to increased responding to psychostimulants and mediate increased addiction risk after PSE.

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Voluntary Ethanol Intake Enhances Excitatory Synaptic Strength in the Ventral Tegmental Area

Cited by 122 publications

References 44 publications

Intermittent High-Dose Ethanol Exposure Increases Ethanol Preference in Rats

Intermittent High-Dose Ethanol Exposure Increases Ethanol Preference in Rats

The Role of Clock in Ethanol-Related Behaviors

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

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