Lack of operant ethanol self-administration in dopamine D2 receptor knockout mice

Risinger, Fred O.; Freeman, Pierre; Rubinstein, Marcelo; Low, Malcolm J.; Grandy, David K.

doi:10.1007/s002130000548

Cited by 103 publications

(65 citation statements)

References 32 publications

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“…Thus, by removing the a1 inhibitory GABAergic tone in the VTA, the integrity of the normal downstream GABA/DA circuitry in reinforcing loci such as the nucleus accumbens (NAcc) and the VP is compromised, resulting in an inability of the a1 (À/À) mice to engage in instrumental responding. It is interesting to note that while Phillips et al (1998) found that D2 receptor (À/À) mice were capable of home-cage alcohol drinking (albeit at much lower levels than their D2 ( + / + ) counterparts), Risinger et al (2000) reported that the D2 (À/À) mice demonstrated a profound reduction in EtOH-maintained responding (similar to a1 (À/À) mice in the current study). Hence, a reduction of DA neurotransmission in the a1 (À/À) mice may predispose them to a failure/reduced capacity to initiate lever-press responding for instrumental reinforcers (but see June et al, 2003).…”

Section: Hypothesized Mechanism Of Action In Reducing Etoh and Sucrossupporting

confidence: 47%

Dopamine and Benzodiazepine-Dependent Mechanisms Regulate the EtOH-Enhanced Locomotor Stimulation in the GABAA α1 Subunit Null Mutant Mice

June

Foster

Eiler

et al. 2006

Neuropsychopharmacol

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The present study investigated the role of the a1-containing GABA A receptors in the neurobehavioral actions of alcohol. In Experiment 1, mice lacking the a1 subunit (a1 (À/À)) were tested for their capacity to initiate operant-lever press responding for alcohol or sucrose. Alcohol intake in the home cage was also measured. In Experiment 2, the a1 (À/À) mice were injected with a range of alcohol doses (0.875-4.0 g/kg; i.p.) to evaluate the significance of the a1 subunit in alcohol's stimulant actions. In Experiment 3, we determined if the alcohol-induced stimulant effects were regulated via dopaminergic (DA) or benzodiazepine (BDZ)-dependent mechanisms. To accomplish this, we investigated the capacity of DA (eticlopride, SCH 23390) and BDZ (flumazenil, bCCt) receptor antagonists to attenuate the alcohol-induced stimulant actions. Compared with wild-type mice (a1 ( + / + )), the null mutants showed marked reductions in both EtOH and sucrose-maintained responding, and home-cage alcohol drinking. The null mutants also showed significant increases in locomotor behaviors after injections of low-moderate alcohol doses (1.75-3.0 g/kg). bCCt, flumazenil, eticlopride, and SCH 23390 were able to attenuate the alcohol-induced stimulation in mutant mice, in the absence of intrinsic effects. These data suggest the a1 receptor plays an important role in alcohol-motivated behaviors; however, it also appears crucial in regulating the reinforcing properties associated with normal ingestive behaviors. Deleting the a1 subunit of the GABA A receptor appears to unmask alcohol's stimulatory effects; these effects appear to be regulated via an interaction of both DA-and GABA A BDZ-dependent mechanisms. Neuropsychopharmacology (2007) 32, 137-152.

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Section: Hypothesized Mechanism Of Action In Reducing Etoh and Sucrossupporting

confidence: 47%

Dopamine and Benzodiazepine-Dependent Mechanisms Regulate the EtOH-Enhanced Locomotor Stimulation in the GABAA α1 Subunit Null Mutant Mice

June

Foster

Eiler

et al. 2006

Neuropsychopharmacol

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“…For example, SA of ethanol increases nucleus accumbens (Nac) DA release in rodents (Weiss et al, 1993(Weiss et al, , 1996Gonzales and Weiss, 1998;Nurmi et al, 1998;Olive et al, 2000;Melendez et al, 2002;Hungund et al, 2003), and DA D1 and D2 receptor agonists and antagonists modulate ethanol SA in some circumstances (Weiss et al, 1990;Hubbell et al, 1991;Dyr et al, 1993;Rassnick et al, 1993a;Ng and George, 1994;Silvestre et al, 1996;Cohen et al, 1998Cohen et al, , 1999Boyce and Risinger, 2002;D'Souza et al, 2003;Zocchi et al, 2003). In addition, genetic deletion of D1 or D2 DA receptors decreases ethanol SA (El-Ghundi et al, 1998;Phillips et al, 1998;Risinger et al, 2000). However, inconsistencies similar to those obtained in examining the DA mediation of opiate reinforcement have plagued the field.…”

Section: Ne and Ethanol Samentioning

confidence: 99%

“…For example, chemical lesions of the NE system, blocking NE synthesis via DBH inhibitors, or genetic deletion of DBH will reduce voluntary ethanol intake, whereas DA lesions do not Kiianmaa et al, 1979;Rassnick et al, 1993b;Weinshenker et al, 2000). Again, evidence does suggest that pharmacologic or genetic manipulation of D1 and D2 receptors can modulate ethanol SA in some circumstances (Weiss et al, 1990;Hubbell et al, 1991;Dyr et al, 1993;Rassnick et al, 1993a;Ng and George, 1994;Silvestre et al, 1996;Cohen et al, 1998Cohen et al, , 1999El-Ghundi et al, 1998;Phillips et al, 1998;Risinger et al, 2000;Boyce and Risinger, 2002;D'Souza et al, 2003;Zocchi et al, 2003). Further research teasing out the specific mechanisms of noradrenergic modulation of opioid and ethanol reward will be required to distinguish between DA-dependent and DA-independent pathways.…”

Section: Some Effects Of Ne On Drug Responses May Be Independent Of Damentioning

confidence: 99%

There and Back Again: A Tale of Norepinephrine and Drug Addiction

Weinshenker

Schroeder

2006

Neuropsychopharmacol

323

277

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Fueled by anatomical, electrophysiological, and pharmacological analyses of endogenous brain reward systems, norepinephrine (NE) was identified as a key mediator of both natural and drug-induced reward in the late 1960s and early 1970s. However, reward experiments from the mid-1970s that could distinguish between the noradrenergic and dopaminergic systems resulted in the prevailing view that dopamine (DA) was the primary 'reward transmitter' (a belief holding some sway still today), thereby pushing NE into the background. Most damaging to the NE hypothesis of reward were studies demonstrating that NE receptor antagonists and NE reuptake inhibitors failed to impact drug self-administration. In recent years new tools, such as genetically engineered mice, and new experimental paradigms, such as reinstatement of drug seeking following withdrawal, have propelled NE back into the awareness of addiction researchers. Of particular interest is disulfiram, an inhibitor of the NE biosynthetic enzyme dopamine b-hydroxylase, which has demonstrated promising efficacy in the treatment of cocaine dependence in preliminary clinical trials. The purpose of this review is to synthesize the new data linking NE to critical aspects of DA signaling and drug addiction, with a focus on psychostimulants (eg, cocaine), opiates (eg, morphine), and alcohol.

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“…Although this has been studied primarily for psychostimulants such as cocaine and methamphetamine, acute ethanol exposure also increases dopamine release and locomotor activity in rodents (Dar and Wooles, 1984;Imperato and Di Chiara, 1986). Genetic or pharmacologic manipulations that interfere with mesolimbic dopamine systems block not only the stimulant effects of ethanol, but also the rewarding properties (Phillips and Shen, 1996;Phillips et al, 1998;Cunningham et al, 2000;Risinger et al, 2000); however, other neurochemic systems and brain regions are also involved in drug reinforcement (reviewed in Wise, 2000).…”

Section: Role Of Dopaminergic Systems In Acute Ethanol Responses In Dmentioning

confidence: 99%

Invertebrate models of drug abuse

2002

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Susceptibility to drug addiction depends on genetic and environmental factors and their complex interactions. Studies with mammalian models have identified molecular targets, neurochemical systems, and brain regions that mediate some of the addictive properties of abused drugs. Yet, our understanding of how the primary effects of drugs lead to addiction remains incomplete. Recently, researchers have turned to the invertebrate model systems Drosophila melanogaster and Caenorhabditis elegans to dissect the mechanisms by which abused drugs modulate behavior. Due to their sophisticated genetics, relatively simple anatomy, and their remarkable molecular similarity to mammals, these invertebrate models should provide useful insights into the mechanisms of drug action. Here we review recent behavioral and genetic studies in flies and worms on the effects of ethanol, cocaine, and nicotine, three of the most widely abused drugs in the world.

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Lack of operant ethanol self-administration in dopamine D2 receptor knockout mice

Abstract: Reduced responding in the KO mice for several reinforcers including ethanol indicates a more general role for dopamine D2 receptors in motivated responding rather than a specific role in ethanol reinforcement.

Cited by 103 publications

References 32 publications

Dopamine and Benzodiazepine-Dependent Mechanisms Regulate the EtOH-Enhanced Locomotor Stimulation in the GABAA α1 Subunit Null Mutant Mice

Dopamine and Benzodiazepine-Dependent Mechanisms Regulate the EtOH-Enhanced Locomotor Stimulation in the GABAA α1 Subunit Null Mutant Mice

There and Back Again: A Tale of Norepinephrine and Drug Addiction

Invertebrate models of drug abuse

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