Long-Term Reduction in Ventral Tegmental Area Dopamine Neuron Population Activity Following Repeated Stimulant or Ethanol Treatment

Shen, Roh‐Yu; Choong, Kar-Chan; Thompson, Alexis C.

doi:10.1016/j.biopsych.2006.03.018

Cited by 47 publications

(50 citation statements)

References 36 publications

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“…The decrements were most accentuated in VS (70% lower than controls), which corroborates previous findings of reduced DA increases in VS after amphetamine in alcoholics (50% lower than controls) (Martinez et al, 2005). These findings are also in agreement with preclinical studies showing profound reductions in DA cell firing (Diana et al, 1993;Bailey et al, 1998;Shen et al, 2007) in VTA and decreased DA in NAc (Weiss et al, 1996) after withdrawal from chronic alcohol. Decreased reactivity of the DA VTA-accumbens pathway in alcoholics could put them at risk to consume large amounts of alcohol to compensate for this deficit.…”

Section: Decreased Da Release In Alcoholic Subjectssupporting

confidence: 91%

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Profound Decreases in Dopamine Release in Striatum in Detoxified Alcoholics: Possible Orbitofrontal Involvement

Volkow¹,

Wang²,

Telang³

et al. 2007

J. Neurosci.

424

295

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The value of rewards (natural rewards and drugs) is associated with dopamine increases in the nucleus accumbens and varies as a function of context. The prefrontal cortex has been implicated in the context dependency of rewards and in the fixated high value that drugs have in addiction, although the mechanisms are not properly understood. Here we test the hypothesis that the prefrontal cortex regulates the value of rewards by modulating dopamine increases in nucleus accumbens and that this regulation is disrupted in addicted subjects. We used positron emission tomography to evaluate the activity of the prefrontal cortex (measuring brain glucose metabolism with [ In all subjects, methylphenidate significantly increased dopamine in striatum. In ventral striatum (where the nucleus accumbens is located) and in putamen, dopamine increases were associated with the rewarding effects of methylphenidate (drug liking and high) and were profoundly attenuated in alcoholics (70 and 50% lower than controls, respectively). In controls, but not in alcoholics, metabolism in orbitofrontal cortex (region involved with salience attribution) was negatively associated with methylphenidate-induced dopamine increases in ventral striatum. These results are consistent with the hypothesis that the orbitofrontal cortex modulates the value of rewards by regulating the magnitude of dopamine increases in the ventral striatum and that disruption of this regulation may underlie the decreased sensitivity to rewards in addicted subjects.

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Section: Decreased Da Release In Alcoholic Subjectssupporting

confidence: 91%

“…Baseline DA D 2 /D 3 receptor availability was lower in alcoholics than in controls in VS, which corroborates previous imaging (Heinz et al, 2004;Shen et al, 2007) and postmortem (Tupala et al, 2001(Tupala et al, , 2003 studies.…”

Section: Baseline Da D 2 /D 3 Receptor Measuressupporting

confidence: 90%

Profound Decreases in Dopamine Release in Striatum in Detoxified Alcoholics: Possible Orbitofrontal Involvement

Volkow¹,

Wang²,

Telang³

et al. 2007

J. Neurosci.

424

295

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“…Consistent with the finding that increased glutamate neurotransmission in VTA DA neurons is an important cellular mechanism for increased addiction risk, exposure to psychostimulants or ethanol leads to persistent overexcitation in VTA DA neurons recorded in vivo, presumably to the degree of depolarization block (Shen and Choong, 2006;Shen et al, 2007) and enhanced sensitivity to psychostimulants (Xu and Shen, 2001). These findings suggest that overexcitation of VTA DA neurons could contribute to increased addiction risk after perinatal stress exposure.…”

Section: Introductionsupporting

confidence: 55%

“…Specifically, reduced VTA DA neuron population activity has been observed after prenatal exposure to ethanol (Choong and Shen, 2004;Shen et al, 1999;Xu and Shen, 2001) or repeated adulthood exposure to ethanol, cocaine, amphetamine, methyphenidate, or nicotine (Shen et al, 2007). In addition, the reversal effect on population activity by acute amphetamine is described after prenatal ethanol treatment (Xu and Shen, 2001).…”

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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“…Acute exposure to ethanol can increase the firing rate of VTA DA neurons (Brodie et al 1990;Diana et al 1992;Mereu et al 1984) and oral self-administration of ethanol increases DA release in a VTA target region, the nucleus accumbens (Gonzales and Weiss 1998). In contrast, withdrawal after chronic ethanol exposure decreases VTA cell firing and DA release in the nucleus accumbens for several days after removal from ethanol (Bailey et al 1998(Bailey et al , 2001Diana et al 1993;Shen 2003;Weiss et al 1996), and reexposure to ethanol during withdrawal restores nucleus accumbens DA release (Weiss et al 1996). Behavioral studies have also shown that responses to ethanol are modified by pharmacological manipulations of DA transmission.…”

Section: Introductionmentioning

confidence: 99%

Withdrawal From Intermittent Ethanol Exposure Increases Probability of Burst Firing in VTA Neurons In Vitro

Hopf¹,

Martín²,

Chen³

et al. 2007

Journal of Neurophysiology

104

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Changing the activity of ventral tegmental area (VTA) dopamine neurons from pacemaker to burst firing is hypothesized to increase the salience of stimuli, such as an unexpected reward, and likely contributes to withdrawal-associated drug-seeking behavior. Accordingly, pharmacological, behavioral, and electrophysiological data suggest an important role of the VTA in mediating alcohol-dependent behaviors. However, the effects of repeated ethanol exposure on VTA dopamine neuron ion channel function are poorly understood. Here, we repeatedly exposed rats to ethanol (2 g/kg ethanol, ip, twice per day for 5 days), then examined the firing patterns of VTA dopamine neurons in vitro after 7 days withdrawal. Compared with saline-treated animals, the function of the small conductance calcium-dependent potassium channel (SK) was reduced in ethanol-treated animals. Consistent with a role for SK in regulation of burst firing, NMDA applied during firing facilitated the transition to bursting in ethanol-treated but not saline-treated animals; NMDA consistently induced bursting only in saline-treated animals when SK was inhibited. Also, enhanced bursting in ethanol-treated animals was not a result of differences in NMDA-induced depolarization. Further, I h was also reduced in ethanol-treated animals, which delayed recovery from hyperpolarization, but did not account for the increased NMDA-induced bursting in ethanol-treated animals. Finally, repeated ethanol exposure and withdrawal also enhanced the acute locomotor-activating effect of cocaine (15 mg/kg, ip). Thus withdrawal after repeated ethanol exposure produced several alterations in the physiological properties of VTA dopamine neurons, which could ultimately increase the ability of VTA neurons to produce burst firing and thus might contribute to addiction-related behaviors.

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Long-Term Reduction in Ventral Tegmental Area Dopamine Neuron Population Activity Following Repeated Stimulant or Ethanol Treatment

Cited by 47 publications

References 36 publications

Profound Decreases in Dopamine Release in Striatum in Detoxified Alcoholics: Possible Orbitofrontal Involvement

Profound Decreases in Dopamine Release in Striatum in Detoxified Alcoholics: Possible Orbitofrontal Involvement

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

Withdrawal From Intermittent Ethanol Exposure Increases Probability of Burst Firing in VTA Neurons In Vitro

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