The Dopamine Hypothesis of Drug Addiction: Hypodopaminergic State

Melis, Miriam; Spiga, Saturnino; Diana, Marco

doi:10.1016/s0074-7742(05)63005-x

Cited by 237 publications

(211 citation statements)

References 421 publications

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“…Specifically, GC are known to modulate the reinforcing properties of drugs and, in fact, have positive reinforcing properties of their own (43). Adding a new perspective, the present study demonstrates that iuGC triggers an impoverishment in DAergic inputs and DA levels in the NAcc, leading to increased drug-seeking behavior in adulthood; notably, hypoDAergic status is an hallmark of the "addicted brain" (44,45). Associated with their lower intra-NAcc levels of DA, animals exposed to prenatal GC expressed more Drd2 in the NAcc, potentially indicating a compensatory mechanism in this structure.…”

Section: Discussionmentioning

confidence: 57%

Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids

et al. 2011

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Section: Discussionmentioning

confidence: 57%

Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids

et al. 2011

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“…In line with these observations, a marked reduction in VTA dopamine neuron activity has been reported in ethanol-withdrawn animals (Diana et al, 1993(Diana et al, , 1996. This 'hypodopaminergic state', which can be reversed by administration of ethanol itself (Diana et al, 1993;Weiss et al, 1996), may, at least partially, contribute to the emotional/motivational component of ethanol withdrawal symptoms, such as dysphoria and anhedonia (Koob and Volkow, 2010;Melis et al, 2005;Trevisan et al, 1998). However, the cellular mechanisms underlying the hypoactivity of dopamine neurons after ethanol withdrawal remain poorly understood.…”

Section: Introductionmentioning

confidence: 77%

“…The hypodopaminergic state observed in ethanol-withdrawn animals or in detoxified alcoholics is characterized by hypoactivity of dopamine neurons and the resulting decrease in dopamine release in the NAc and striatum, together with downregulation of postsynaptic D 2 receptors in those dopamine projection areas (Martinez et al, 2005;Melis et al, 2005;Volkow et al, 2007). It has been postulated that this hypodopaminergic state contributes to the emotional/motivational component of ethanol dependence, although activation of other neurotransmitter systems, such as those involving corticotropin-releasing factor or the endogenous k-opioid dynorphin, has also been implicated (Koob, 2009;Wee and Koob, 2010).…”

Section: Enhanced D 2 Autoinhibition and Hypodopaminergic State Durinmentioning

confidence: 99%

In Vivo Ethanol Experience Increases D2 Autoinhibition in the Ventral Tegmental Area

Perra

Clements

Bernier

et al. 2011

Neuropsychopharmacol

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Alcoholism is characterized by compulsive alcohol intake after a history of chronic consumption. A reduction in mesolimbic dopaminergic transmission observed during abstinence may contribute to the negative affective state that drives compulsive intake. Although previous in vivo recording studies in rodents have demonstrated profound decreases in the firing activity of ventral tegmental area (VTA) dopamine neurons after withdrawal from long-term ethanol exposure, the cellular mechanisms underlying this reduced activity are not well understood. Somatodendritic dopamine release within the VTA exerts powerful feedback inhibition of dopamine neuron activity via stimulation of D 2 autoreceptors and subsequent activation of G protein-gated inwardly rectifying K + (GIRK) channels. Here, by performing patch-clamp recordings from putative dopamine neurons in the VTA of mouse brain slices, we show that D 2 receptor/ GIRK-mediated inhibition becomes more potent and exhibits less desensitization after withdrawal from repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 days). In contrast, GABA B receptor/GIRK-mediated inhibition and its desensitization are not affected. Chelating cytosolic Ca 2 + with BAPTA augments D 2 inhibition and suppresses its desensitization in control mice, while these effects of BAPTA are occluded in ethanol-treated mice. Furthermore, inositol 1,4,5-trisphosphate (IP 3 )-induced intracellular Ca 2 + release and Ca 2 + /calmodulin-dependent protein kinase II are selectively involved in the desensitization of D 2 , but not GABA B , receptor signaling. Consistent with this, activation of metabotropic glutamate receptors that are coupled to IP 3 generation leads to cross-desensitization of D 2 /GIRK-mediated responses. We propose that enhancement of D 2 receptor-mediated autoinhibition via attenuation of a Ca 2 + -dependent desensitization mechanism may contribute to the hypodopaminergic state during ethanol withdrawal.

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“…There are multiple lines of evidence that cocaine dependence is associated with a decrease in D 2 receptor binding [164-167], a pattern that seems to persist after disease remission [165]. Decreases in D 2 receptor binding have also been found in heroin addiction [168], alcohol dependence [169,170], methamphetamine abuse [171,172], prompting a number of researchers to posit that low D 2 receptor availability may serve as a biomarker for substance abuse, potentially reflecting an altered sensitivity to various rewards [173-175]. Although these molecular-imaging studies suggest decreased reward motivation in addiction that is consistent with the ‘reward-deficiency syndrome’ hypothesis of addiction, functional brain-activation studies paint a less consistent picture, probably due to variability in samples, task demands, patient characteristics, and unknown effects of a history of addictive behavior on functional responses to reward stimuli.…”

Section: Reviewmentioning

confidence: 99%

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Dichter

Damiano

Allen

2012

J Neurodevelop Disord

253

207

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This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.

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The Dopamine Hypothesis of Drug Addiction: Hypodopaminergic State

Cited by 237 publications

References 421 publications

Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids

Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids

In Vivo Ethanol Experience Increases D2 Autoinhibition in the Ventral Tegmental Area

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

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