Loss of Feedback Inhibition via D2 Autoreceptors Enhances Acquisition of Cocaine Taking and Reactivity to Drug-Paired Cues

Abstract

A prominent aspect of drug addiction is the ability of drug-associated cues to elicit craving and facilitate relapse. Understanding the factors that regulate cue reactivity will be vital for improving treatment of addictive disorders. Low availability of dopamine (DA) D2 receptors (D2Rs) in the striatum is associated with high cocaine intake and compulsive use. However, the role of D2Rs of nonstriatal origin in cocaine seeking and taking behavior and cue reactivity is less understood and possibly underestimated. D2Rs expressed by midbrain DA neurons function as autoreceptors, exerting inhibitory feedback on DA synthesis and release. Here, we show that selective loss of D2 autoreceptors impairs the feedback inhibition of DA release and amplifies the effect of cocaine on DA transmission in the nucleus accumbens (NAc) in vitro. Mice lacking D2 autoreceptors acquire a cued-operant self-administration task for cocaine faster than littermate control mice but acquire similarly for a natural reward. Furthermore, although mice lacking D2 autoreceptors were able to extinguish self-administration behavior in the absence of cocaine and paired cues, they exhibited perseverative responding when cocaine-paired cues were present. This enhanced cue reactivity was selective for cocaine and was not seen during extinction of sucrose self-administration. We conclude that low levels of D2 autoreceptors enhance the salience of cocaine-paired cues and can contribute to the vulnerability for cocaine use and relapse.

Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice

“…For example, the RNAi-mediated suppression of D 2 R in the rat VTA enhanced motivation to work for cocaine as assessed using progressive ratio scheduling, whereas not altering acquisition of cocaine self-administration or fixed ratio responding (de Jong et al, 2015). Moreover, mice lacking D 2 R in DA neurons acquired cocaine self-administration more quickly than control subjects, while other parameters, including intake, motivation, and sensitivity, were normal (Holroyd et al, 2015). Interestingly, these mice also exhibited enhanced cocaine CPP at low doses (Bello et al, 2011), whereas we detected no CPP phenotype in GIRK2 DA KO mice.…”

“…The cocaineinduced increase in VTA DA levels activates autoreceptors (D 2 R) that, together with GABA B R-dependent feedback (Waddington and Cross, 1978;Wolf et al, 1978), temper VTA DA neuron excitability (Einhorn et al, 1988). Pharmacological blockade or genetic suppression of G protein-dependent inhibitory feedback pathways in midbrain DA neurons alters behavioral effects of cocaine, including locomotor activation and self-administration (Steketee and Kalivas, 1991;Bello et al, 2011;Holroyd et al, 2015;de Jong et al, 2015). Moreover, inhibitory G protein signaling mediated by GABA B R and D 2 R is decreased following cocaine administration (Ackerman and White, 1990;Kushner and Unterwald, 2001;Arora et al, 2011), highlighting the reciprocal relationship between cocaine and inhibitory G protein signaling in DA neurons.…”

Mesocorticolimbic dopamine functioning in primary psychopathy: A source of within-group heterogeneity

“…It has been reported in rodents that D2S-and D2L-receptor subsensitivity, higher levels of DA synthesis, and higher extracellular DA are related to novelty-seeking, addictive behaviors, aggression, behavioral sensitization, incentive motivation, response perseveration, and lower levels of anxiety (Mällo et al, 2007;De Miguel et al, 2011;Beiderbeck et al, 2013;Tournier et al, 2013;Lehner et al, 2014;De Jong et al, 2015;Holroyd et al, 2015), suggesting that the A1-allele of the TaqIA-ANKK1 SNP may relate to analogous traits in humans. In agreement, A1-allele carriers display higher levels of childhood antisocial behavior, bipolar disorder with low anxiety, impulsivity, novelty/stimulus seeking, aggression, antisocial/borderline traits, faster habituation to positive feedback (decoupling behavior from experience), and substance abuse/dependence but also adaptive traits such as extraversion, behavioral activation, low depression or harm avoidance, and improved cognitive performance (Noble et al, 1998;Bartrés-Faz et al, 2002;Eisenberg et al, 2007;Hoenicka et al, 2007;Ponce et al, 2008 ;Althaus et al, 2009;Esposito-Smythers et al, 2009;Ponce et al, 2009;Barskiĭ et al, 2010;Nemoda et al, 2010;Smillie et al, 2010;Stelzel et al, 2010;Thaler et al, 2012;Kazantseva et al, 2011;Lu et al, 2012;Zai et al, 2012;Wang et al, 2013aWang et al, , 2014.…”

High and low doses of cocaine intake are differentially regulated by dopamine D2 receptors in the ventral tegmental area and the nucleus accumbens

“…In human, decreased availability of D2Rs in the midbrain parallels enhanced dopamine release in striatum and is correlated to greater impulsivity and craving for amphetamine [4]. Moreover, reduced D2R levels in mice and rats enhance dopamine release, cocaine-induced locomotor activity and conditioned place preference, and increase incentive motivation for cocaine under the progressive-ratio schedule and the salience of cocaine-paired cues [5, 13, 14]. However, it is puzzling that reduced D2R levels in the VTA of rodents do not affect fixed-ratio responding to high doses of cocaine treatment in recent reports [13, 14].…”

“…Moreover, reduced D2R levels in mice and rats enhance dopamine release, cocaine-induced locomotor activity and conditioned place preference, and increase incentive motivation for cocaine under the progressive-ratio schedule and the salience of cocaine-paired cues [5, 13, 14]. However, it is puzzling that reduced D2R levels in the VTA of rodents do not affect fixed-ratio responding to high doses of cocaine treatment in recent reports [13, 14]. It is possible that low levels of D2 autoreceptors may cause a left-ward shift in cocaine sensitivity to low, but not high, doses of cocaine.…”