Dhaher R, Finn DA, Oberbeck DL, Yoneyama N, Snelling CC, Wu W et al. Electrolytic lesions of the medial nucleus accumbens shell selectively decrease ethanol consumption without altering preference in a limited access procedure in C57BL/6J mice. Pharmacol Biochem Behav 92: 335-342

Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR 97239, United States.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 05/2009; 92(2):335-42. DOI: 10.1016/j.pbb.2008.12.024
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The central extended amygdala (cExtA) is a limbic region proposed to play a key role in drug and alcohol addiction and to contain the medial nucleus accumbens shell (MNAc shell). The aim of this study was to examine the involvement of the MNAc shell in ethanol and sucrose consumption in a limited and free access procedure in the C57BL/6J (B6) mouse. Separate groups of mice received bilateral electrolytic lesions of the MNAc shell or sham surgery, and following recovery from surgery, were allowed to voluntarily consume ethanol (15% v/v) in a 2 h limited access 2-bottle-choice procedure. Following 1 week of limited access ethanol consumption, mice were given 1 week of limited access sucrose consumption. A separate group of lesioned and sham mice were given free access (24 h) to ethanol in a 2-bottle choice procedure and were run in parallel to the mice receiving limited access consumption. Electrolytic lesions of the MNAc shell decreased ethanol (but not sucrose) consumption in a limited access procedure, but did not alter free access ethanol consumption. These results suggest that the MNAc shell is a component of the underlying neural circuitry contributing to limited access alcohol consumption in the B6 mouse.

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    • "However, animals in free access paradigms have large fluctuations in blood ethanol concentration that only rarely reach pharmacologically significant levels, raising questions about the validity of these models for studying addictive behavior (Dole and Gentry, 1984). A more recent study by Dhaher et al (2009) using electrolytic lesions of the medial NAc shell compared 24-h free access to a 2-h limited access paradigm, finding that lesioned animals had a nonsignificant trend toward increased consumption in free access but a significant decrease in consumption in the limited access paradigm. Our results differ slightly from Dhaher et al in that we saw no difference in ethanol consumption in 2-h limited access, but we did see a significant decrease in ethanol consumption during 4-h limited access. "
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    ABSTRACT: Bilateral stereotactic lesioning of the nucleus accumbens core reduces relapse rates in alcohol dependent patients but may cause irreversible cognitive deficits. Deep brain stimulation has similar effects but requires costly implanted hardware and regular surgical maintenance. Therefore, there is considerable interest in refining these approaches to develop reversible, minimally invasive treatments for alcohol dependence. Toward this end, we evaluated the feasibility of a reverse pharmacogenetic approach in a preclinical mouse model. We first assessed the predictive validity of a limited access ethanol consumption paradigm by confirming that electrolytic lesions of the nucleus accumbens core decreased ethanol consumption, recapitulating the effects of similar lesions in humans. We then used this paradigm to test the effect of modulating activity in the nucleus accumbens using the Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) hM3Dq and hM4Di. We found that increasing activity with hM3Dq had no effect, but suppressing activity with hM4Di reduced alcohol consumption to a similar extent as lesioning without affecting consumption of water or sucrose. These results may represent early steps toward a novel neurosurgical treatment modality for alcohol dependence that is reversible and externally titratable, yet highly targetable and less invasive than current approaches such as lesioning or deep brain stimulation.Neuropsychopharmacology accepted article preview online, 1 August 2013. doi:10.1038/npp.2013.184.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2013; 39(2). DOI:10.1038/npp.2013.184 · 7.05 Impact Factor
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    • "Conversely, psychosocial stress did not alter EtOH preference of saline treated subjects. It should be noted that EtOH intake and EtOH preference do not necessarily follow the same pattern, and may involve different mechanisms (e.g., Dhaher et al., 2009). "
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    ABSTRACT: Studies of socially housed rodents have provided significant information regarding the consequences of exposure to stressors. Psychosocial stressors are known to alter the ingestion of ethanol and the activity of the dopaminergic neuronal system. Since both stressors and ethanol are known to affect the function of dopaminergic neurons, we employed amphetamine to assess the role of this neural system on the ingestion of ethanol by psychosocially stressed male rats. Male rats housed two per cage were designated as dominant or subdominant rats based on evaluations of agonistic behavior and body weight changes. The dyad-housed rats and a group of single-housed rats were sequentially assessed for ethanol intake after injections of saline or amphetamine (0.3, 0.9 or 2.7 mg/kg i.p.) both prior to dyad housing and subsequently again during dyad-housing. Prior to dyad housing ethanol intake of future subdominant rats was higher than that of future dominant rats. Dyad-housing significantly increased ethanol intake of dominant rats. Pre-dyad the highest dose of amphetamine potently depressed ethanol ingestion. Sensitivity to amphetamine's depressant effect on ethanol intake was higher at the dyad test in all subjects, most prominently in single-housed rats. In contrast to the single-housed rats, the dyad-housed rats displayed saccharin anhedonia. It can be concluded that dopaminergic system modulates, at least partially, the psychosocial stress-induced changes in ethanol intake. Furthermore, the level of ethanol ingestion at the pre-dyad test was predictive of future hierarchical status.
    Pharmacology Biochemistry and Behavior 01/2012; 101(3):417-26. DOI:10.1016/j.pbb.2012.01.010 · 2.78 Impact Factor
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    • "For example, alterations in glutamatergic transmission (Kapasova & Szumlinski 2008) and serotonergic transmission (Jankowska & Kostowski 1995; Hoplight, Sandygren & Neumaier 2006) in the shell region are reported to modulate ethanol intake. In addition, electrolytic lesions of the medial shell in mice reduced ethanol self-administration (Dhaher et al. 2009). Together, these studies point to a role of the medial shell in regulation of ethanol intake. "
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    ABSTRACT: The α4βδ gamma-aminobutyric acid A receptor (GABA(A) R) has been proposed to mediate the rewarding effects of low-to-moderate concentrations of alcohol (ethanol) that approximate those achieved by social drinking. If this is true, then this receptor should be necessary for the reinforcing effects of ethanol as assessed in an instrumental self-administration procedure in which rats are trained to lever press for oral ethanol. We used viral-mediated RNA interference to transiently reduce expression of the α4 GABA(A) R subunit in the shell region of the nucleus accumbens (NAc). We found that responding for ethanol was significantly reduced after α4 reductions in the NAc shell, but not NAc core. This reduction was specific to ethanol, as responding for sucrose was not altered. The presence of ethanol was also required as unreinforced responding for ethanol in subjects previously trained to respond for ethanol (i.e. responding during an extinction test) was not altered. In addition, responding during reinforced sessions was not altered during the initial 5 minutes of the session, but decreased after 5 minutes, following multiple reinforced responses. Together, these findings indicate that the α4 GABA(A) R subunit in the NAc shell is necessary for the instrumental reinforcing effects of oral ethanol, further supporting a role for α4-containing GABA(A) Rs in the rewarding/reinforcing effects of ethanol. Possible pharmacological and non-pharmacological explanations for these effects are considered.
    Addiction Biology 04/2011; 17(2):309-21. DOI:10.1111/j.1369-1600.2011.00333.x · 5.36 Impact Factor
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