Repeated Ethanol Intoxication Induces Behavioral Sensitization in the Absence of a Sensitized Accumbens Dopamine Response in C57BL/6J and DBA/2J Mice

Zapata, Agustín; Gonzales, Rueben A.; Shippenberg, Toni S.

doi:10.1038/sj.npp.1300833

Cited by 97 publications

(96 citation statements)

References 56 publications

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“…For instance, ethanol increases extracellular dopamine levels in the NAc of mice sensitive to the locomotor stimulant effects of ethanol, including FAST mice (Meyer and Phillips, 2004), DBA/2J mice (Zapata et al, 2006) and outbred NMRI mice (Larsson et al, 2002). In addition, administration of a dopamine D2 receptor antagonist, or combined D1-D2 receptor antagonism, attenuates the locomotor stimulant response to ethanol in FAST mice (Shen et al, 1995a).…”

Section: Discussionmentioning

confidence: 99%

GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol

Holstein

Phillips²

2006

Pharmacology Biochemistry and Behavior

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Mice selectively bred for divergent sensitivity to the locomotor stimulant effects of ethanol (FAST and SLOW) also differ in their locomotor response to morphine. The GABA B receptor has been implicated in the mediation of locomotor stimulation to both ethanol and morphine, and a reduction in ethanol-induced stimulation has been found with the GABA B receptor agonist baclofen in FAST mice. We hypothesized that GABA B receptor activation would also attenuate the locomotor stimulant responses to morphine in these mice. In order to test this hypothesis, baclofen was administered to FAST-1 and FAST-2 mice 15 min prior to morphine, and activity was recorded for 30 min. Baclofen attenuated stimulation to 32 mg/kg morphine in FAST-1 mice, but only at a dose that also reduced saline activity. There was no stimulant response to 32 mg/kg morphine in FAST-2 mice, or to 16 mg/kg or 48 mg/kg morphine in FAST-1 mice, but the combination of baclofen with these morphine doses accentuated locomotor activity. Therefore, it appears that GABA B receptor activation is not a common mechanism for the locomotor stimulant responses to ethanol and morphine in FAST mice; however, these data suggest that GABA B receptor activation may instead enhance some of the behavioral effects of morphine.

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Section: Discussionmentioning

confidence: 99%

GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol

Holstein

Phillips²

2006

Pharmacology Biochemistry and Behavior

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“…Furthering this role, NAC Homer2b overexpression in B6 mice is sufficient to enhance the dopamine and glutamate response to acute alcohol and to augment alcohol-induced neurochemical sensitization ( Figure 5). Thus, as observed for behavior, NAC Homer2b overexpression 'presensitizes' the capacity of alcohol to elevate NAC levels of dopamine and glutamate in B6 miceFa neurochemical phenotype akin to that produced by repeated alcohol experience (eg Doyon et al, 2005;Melendez et al, 2002;Middaugh et al, 2003;Szumlinski et al, 2006aSzumlinski et al, , 2007Weiss et al, 1993; but see Zapata et al, 2006). Whether the alcohol 'presensitized' neurochemical phenotype produced by NAC Homer2b overexpression relates to an upregulation in mGluR-Homer2-NMDA signaling cannot be discerned from the present study.…”

Section: Accumbens Homer2b Upregulation Promotes Alcohol Rewardmentioning

confidence: 99%

Accumbens Homer2 Overexpression Facilitates Alcohol-Induced Neuroplasticity in C57BL/6J Mice

Szumlinski

Ary

Lominac

et al. 2007

Neuropsychopharmacol

178

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Homer proteins are integral components of the postsynaptic density that are necessary for alcohol-induced neuroplasticity within the nucleus accumbens (NAC). In this report, we describe the effects of chronic alcohol consumption upon NAC Homer expression and investigate the functional consequences of mimicking the alcohol-induced changes in Homer expression vis-à-vis alcohol-induced changes in NAC neurochemistry and behavior. Chronic alcohol consumption under continuous access (3 months; daily intake E11.271.5 g/kg/ day) produced a robust increase in NAC Homer2 protein levels that was apparent at 2 days, 2 weeks, and 2 months following withdrawal from alcohol drinking. The increased Homer2 expression was accompanied by a less enduring elevation in total mGluR1 and NR2b levels that were evident at 2 days and 2 weeks but not at the 2-month time point. Mimicking the alcohol-induced increase in Homer2 levels by viral transfection of NAC neurons in alcohol-preferring C57BL/6J inbred mice enhanced behavioral output for alcohol reinforcement and increased alcohol intake under both preprandial and postprandial conditions. Moreover, NAC Homer2 overexpression facilitated the expression of an alcohol-conditioned place preference, as well as the development of motor tolerance. Finally, NAC Homer2 overexpression facilitated NAC glutamate and dopamine release following an acute alcohol injection and augmented alcohol-induced dopamine and glutamate sensitization, but did not affect NAC g-aminobutyric acid levels. Thus, an upregulation in NAC mGluR-Homer2-N-methyl-D-aspartic acid receptor signaling appears to be an important molecular adaptation to alcohol that promotes neuroplasticity facilitating motivational drive for alcohol and the development of alcoholism-related behaviors.

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“…Although the VTA is critical for the development of sensitization for many abused drugs, the direct role of the VTA in expression of sensitization may depend on the particular drug of abuse, where a clearer role for opiates but a less clear role for psychostimulants has been described ( Leite-Morris et al 2004;Vanderschuren and Kalivas 2000). In addition, a recent study showed that ethanol-related sensitization in mice can be apparent without increased dopamine release, perhaps dissociating the dopaminergic system from enhanced locomotor activation by ethanol after repeated ethanol exposure in mice (Zapata et al 2006). Although little is known about the cellular mechanisms underlying enhanced locomotor activation after repeated ethanol exposure, reduced SK and facilitation of NMDA-induced bursting might contribute to the enhanced locomotor activation by cocaine after repeated ethanol exposure that we and others (Itzhak and Martin 1999) have observed.…”

Section: Repeated Ethanol Treatment Enhanced Locomotor Activation By mentioning

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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Repeated Ethanol Intoxication Induces Behavioral Sensitization in the Absence of a Sensitized Accumbens Dopamine Response in C57BL/6J and DBA/2J Mice

Cited by 97 publications

References 56 publications

GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol

GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol

Accumbens Homer2 Overexpression Facilitates Alcohol-Induced Neuroplasticity in C57BL/6J Mice

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

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