Involvement of Amygdala Dopamine and Nucleus Accumbens NMDA Receptors in Ethanol-Seeking Behavior in Mice

Department of Behavioral Neuroscience, Portland Alcohol Research Center, Oregon Health & Science University, Portland, OR, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 11/2008; 34(6):1443-53. DOI: 10.1038/npp.2008.179
Source: PubMed


Although progress has been made identifying neural mechanisms underlying ethanol's primary reinforcing effects, few studies have examined the mechanisms mediating ethanol-induced conditioned effects. A recent lesion study suggests that expression of ethanol-conditioned behaviors depends upon an intact amygdala and nucleus accumbens core. However, specific mechanisms within these nuclei are unknown. In the present experiments, we used site-specific microinfusions of dopamine and NMDA receptor antagonists to examine the roles of accumbens and amygdala in the expression of ethanol conditioned place preference (CPP) in mice. In experiments 1 and 2, a D1/D2/D3 receptor antagonist (flupenthixol) was infused into accumbens or amygdala before testing, whereas experiment 3 used pretest infusions of an NMDA antagonist (AP-5) to examine the role of intra-accumbens NMDA receptors. Dopamine antagonism of accumbens was without effect, but intra-amygdala infusions of flupenthixol blocked CPP expression. Moreover, this effect was dependent upon dopamine antagonism within the basolateral nucleus but not the central nucleus of the amygdala. Antagonism of NMDA receptors in accumbens also blocked CPP expression. The present findings suggest that expression of the ethanol-conditioned response depends upon amygdala dopamine and accumbens NMDA receptors. These are the first studies in any species to show a role for amygdala dopamine receptors and the first studies in mice to implicate accumbens NMDA receptors in ethanol-induced conditioned effects.

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    • "The acquisition and reinstatement of MDMA CPP were blocked by antagonism of NMDAR. There are no previous studies on the involvement of these receptors in the rewarding effects of MDMA, but several studies have showed that memantine blocks the acquisition of CPP induced by morphine (Popik and Danysz, 1997; Popik et al., 2003, 2006; Ribeiro Do Couto et al., 2004, 2005; Aguilar et al., 2009b), cocaine (Kotlinska and Biala, 2000; Maldonado et al., 2007) and ethanol (Gremel and Cunningham, 2009), as well as the reinstatement of CPP induced by morphine (Ribeiro Do Couto et al., 2005; Popik et al., 2006) and cocaine (Maldonado et al., 2007). "
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    ABSTRACT: Some 3,4-methylenedioxymethamphetamine (MDMA) users become dependent as a result of chronic consumption. A greater understanding of the neurobiological basis of the rewarding effects of MDMA could contribute to developing effective pharmacotherapies for MDMA-related problems. The present study evaluated the role of N-methyl-D-aspartate (NMDA) glutamate receptors (NMDARs) in the acquisition and reinstatement of conditioned place preference (CPP) induced by MDMA. Adolescent male mice were conditioned with 1 or 10 mg/kg MDMA and pretreated with 5 or 10 mg/kg of the NMDAR antagonist memantine during acquisition of conditioning (experiment 1), or before a reinstatement test (experiment 2). In addition, the effects of memantine on acquisition of chocolate-induced CPP and the effects of memantine and MDMA on a passive avoidance task were evaluated. Memantine did not exert any motivational effects, but blocked the acquisition of MDMA-induced CPP. Moreover, following acquisition and extinction of MDMA-induced CPP, memantine did not induce reinstatement but blocked reinstatement of the CPP induced by priming with MDMA. Memantine did not block the CPP induced by chocolate, and it partially reversed the impairing effects of MDMA on memory. Our results demonstrate that NMDARs are involved in acquisition of the conditioned rewarding effects of MDMA and in priming-induced reinstatement of CPP following extinction. Moreover, they suggest the validity of memantine for the treatment of MDMA abuse.
    Behavioural pharmacology 05/2015; 26(5). DOI:10.1097/FBP.0000000000000138 · 2.15 Impact Factor
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    • "Chronic ethanol exposure and withdrawal produce morphological adaptations in the size and density of dendritic spines (Carpenter-Hyland and Chandler, 2006; Moonat et al., 2011; Pandey et al., 2008; Zhou et al., 2007) and elevate the synaptic expression of GluN1 and GluN2B subunits of the NMDA receptor in a number of regions in the addiction circuitry (Carpenter-Hyland et al., 2004; Clapp et al., 2010; Hendricson et al., 2007; Kash et al., 2009; Mulholland et al., 2011; Qiang et al., 2007; Roberto et al., 2004). Enhanced activation and number of NAc NMDA receptors and elevated extracellular glutamate levels actively regulate expression of ethanol-seeking behaviors (Gremel and Cunningham, 2009, 2010; Obara et al., 2009; Szumlinski et al., 2008). These neuroadaptations in glutamatergic processes in the NAc shell are associated with a potentiation of NMDA receptor-dependent excitatory postsynaptic currents and a metaplastic shift from long-term depression to longterm potentiation (Jeanes et al., 2011). "
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    ABSTRACT: Small-conductance, calcium-activated potassium (K(Ca)2) channels influence neuronal firing properties, intrinsic excitability, and NMDA receptor-dependent synaptic responses and plasticity. In this mini-review, we discuss new evidence that chronic alcohol-associated plasticity critically involves K(Ca)2 channels in hippocampus, ventral tegmental area, and nucleus accumbens. K(Ca)2 channel activity can modulate the magnitude of excitation of midbrain dopamine neurons induced by acute alcohol exposure. Emerging evidence indicates that K(Ca)2 channels regulate neuroadaptations to chronic alcohol that contribute to withdrawal hyperexcitability and escalation of voluntary alcohol consumption. Restoring K(Ca)2 channel activity can attenuate the severity of the alcohol withdrawal syndrome in vivo and withdrawal-associated neurotoxicity in vitro. Pharmacological modulation of K(Ca)2 channels can bi-directionally influence drinking behavior in rat and mouse models of voluntary alcohol consumption. Collectively, these studies using various rodent models have clearly indicated a central role for K(Ca)2 channels in the neuroplasticity of chronic alcohol exposure. In addition, accumulating evidence suggests that K(Ca)2 channels are a novel therapeutic target to alleviate the symptoms of alcohol withdrawal and reduce high amounts of alcohol drinking.
    Alcohol (Fayetteville, N.Y.) 03/2012; 46(4):309-15. DOI:10.1016/j.alcohol.2011.11.002 · 2.01 Impact Factor
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    • "Expression of drug/alcohol-induced CPP is considered to be a measurement of drug/alcohol seeking (Tzschentke, 2007; Gremel and Cunningham, 2009). Next, we determined whether GDNF in the VTA affects the expression of CPP to alcohol . "
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    ABSTRACT: We previously showed that infusion of glial cell line-derived neurotrophic factor (GDNF) into the ventral tegmental area (VTA) rapidly reduces alcohol intake and relapse (Carnicella et al., 2008, 2009a), and increases dopamine (DA) levels in the nucleus accumbens (NAc) of alcohol-naive rats (Wang et al., 2010). Withdrawal from excessive alcohol intake is associated with a reduction in NAc DA levels, whereas drug-induced increases in NAc DA levels are associated with reward. We therefore tested whether GDNF in the VTA reverses alcohol withdrawal-associated DA deficiency and/or possesses rewarding properties. Rats were trained for 7 weeks to consume high levels of alcohol (5.47 ± 0.37 g/kg/24 h) in intermittent access to 20% alcohol in a two-bottle choice procedure. Using in vivo microdialysis, we show that 24 h withdrawal from alcohol causes a substantial reduction in NAc DA overflow, which was reversed by intra-VTA GDNF infusion. Using conditioned place preference (CPP) paradigm, we observed that GDNF on its own does not induce CPP, suggesting that the growth factor is not rewarding. However, GDNF blocked acquisition and expression of alcohol-CPP. In addition, GDNF induced a downward shift in the dose-response curve for operant self-administration of alcohol, further suggesting that GDNF suppresses, rather than substitutes for, the reinforcing effects of alcohol. Our findings suggest that GDNF reduces alcohol-drinking behaviors by reversing an alcohol-induced allostatic DA deficiency in the mesolimbic system. In addition, as it lacks abuse liability, the study further highlights GDNF as a promising target for treatment of alcohol use/abuse disorders.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2011; 31(27):9885-94. DOI:10.1523/JNEUROSCI.1750-11.2011 · 6.34 Impact Factor
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