RGS2 modulates coupling between GABAB receptors and GIRK channels in dopamine neurons of the ventral tegmental area

Dopamine D2 autoreceptors located on the midbrain dopaminergic neurons modulate dopamine (DA) neuron firing, DA release, and DA synthesis through a negative-feedback mechanism. Dysfunctional D2 autoreceptors following repeated drug exposure could lead to aberrant DA activity in the ventral tegmental area (VTA) and projection areas such as nucleus accumbens (NAcc), promoting drugseeking and -taking behavior. Therefore, it is important to understand molecular mechanisms underlying drug-induced changes in D2 autoreceptors. Here, we reported that 5 days of amphetamine (AMPH) self-administration reduced the ability of D2 autoreceptors to inhibit DA release in the NAcc as determined by voltammetry. Using the antibody-capture [ 35 S]GTPgS scintillation proximity assay, we demonstrated for the first time that midbrain D2/D3 receptors were preferentially coupled to Gai2, whereas striatal D2/D3 receptors were coupled equally to Gai2 and Gao for signaling. Importantly, AMPH abolished the interaction between Gai2 and D2/D3 receptors in the midbrain while leaving striatal D2/D3 receptors unchanged. The disruption of the coupling between D2/D3 receptors and Gai2 by AMPH is at least partially explained by the enhanced RGS2 (regulator of G-protein signaling 2) activity resulting from an increased RGS2 trafficking to the membrane. AMPH had no effects on the midbrain expression and trafficking of other RGS proteins such as RGS4 and RGS8. Our data suggest that midbrain D2/D3 receptors are more susceptible to AMPH-induced alterations. Reduced D2 autoreceptor function could lead to enhanced DA signaling and ultimately addiction-related behavior. RGS2 may be a potential non-dopaminergic target for pharmacological intervention of dysfunctional DA transmission and drug addiction.

Section: Amph Self-administration Selectively Promoted Membrane Transsupporting

confidence: 84%

Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

Calipari

Sun

Eldeeb

et al. 2014

“…The VTA DA neuron GIRK channel (GIRK2/GIRK3) is unique, as most neuronal GIRK channels contain GIRK1 (Cruz et al, 2004;Koyrakh et al, 2005;Labouebe et al, 2007). Interestingly, Girk2 ablation yields a complete loss of VTA DA neuron GIRK channel activity (Beckstead et al, 2004;Cruz et al, 2004), whereas Girk3 ablation yields increased sensitivity of the residual channel (GIRK2 homomer) to receptor activation (Labouebe et al, 2007;Lunn et al, 2007).…”

Section: Girk-dependent Inhibitory Feedback and Cocaine Reinforcementmentioning

confidence: 99%

“…Interestingly, Girk2 ablation yields a complete loss of VTA DA neuron GIRK channel activity (Beckstead et al, 2004;Cruz et al, 2004), whereas Girk3 ablation yields increased sensitivity of the residual channel (GIRK2 homomer) to receptor activation (Labouebe et al, 2007;Lunn et al, 2007). The opposing contributions of GIRK2 and GIRK3 are also sensed at the behavioral level, where loss of GIRK2 in DA neurons correlates with increased locomotor effects of cocaine and morphine, while constitutive Girk3 ablation correlates with decreased locomotor-stimulatory effect of morphine (Arora et al, 2010;Kotecki et al, 2015).…”

Section: Girk-dependent Inhibitory Feedback and Cocaine Reinforcementmentioning

confidence: 99%

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

McCall

Kotecki

Domínguez-López

et al. 2016

Self Cite

The increase in dopamine (DA) neurotransmission stimulated by in vivo cocaine exposure is tempered by G protein-dependent inhibitory feedback mechanisms in DA neurons of the ventral tegmental area (VTA). G protein-gated inwardly rectifying K + (GIRK/Kir3) channels mediate the direct inhibitory effect of GABA B receptor (GABA B R) and D 2 DA receptor (D 2 R) activation in VTA DA neurons. Here we examined the effect of the DA neuron-specific loss of GIRK channels on D 2 R-dependent regulation of VTA DA neuron excitability and on cocaine-induced, reward-related behaviors. Selective ablation of Girk2 in DA neurons did not alter the baseline excitability of VTA DA neurons but significantly reduced the magnitude of D 2 R-dependent inhibitory somatodendritic currents and blunted the impact of D 2 R activation on spontaneous activity and neuronal excitability. Mice lacking GIRK channels in DA neurons exhibited increased locomotor activation in response to acute cocaine administration and an altered locomotor sensitization profile, as well as increased responding for and intake of cocaine in an intravenous self-administration test. These mice, however, showed unaltered cocaine-induced conditioned place preference. Collectively, our data suggest that feedback inhibition to VTA DA neurons, mediated by GIRK channel activation, tempers the locomotor stimulatory effect of cocaine while also modulating the reinforcing effect of cocaine in an operant-based self-administration task.

“…Previous studies have shown that D 2 autoreceptormediated inhibition of VTA dopamine neurons is reduced after repeated psychostimulant exposure (Henry et al, 1989;Marinelli et al, 2003;Wolf et al, 1993), whereas the GABA B receptor-GIRK channel coupling efficiency is increased after repeated exposure to morphine or the GABA B agonist g-hydroxybutyrate (Labouebe et al, 2007). In this study, by performing patch-clamp recordings from putative dopamine neurons in the VTA of mouse brain slices, we show that repeated in vivo exposure to ethanol induces sensitization of D 2 -mediated inhibition without affecting GABA Bmediated inhibition.…”

Section: Introductionmentioning

confidence: 98%

“…It is well known that activation of dopamine D 2 receptors and GABA B receptors can mediate powerful inhibition of dopamine neurons both in vitro (Beckstead et al, 2004;Labouebe et al, 2007;Lacey et al, 1987) and in vivo (Erhardt et al, 2002;White and Wang, 1984). These receptors are coupled to the activation of G protein-gated inwardly rectifying K + (GIRK) channels via G i/o G proteins, resulting in membrane hyperpolarization and suppression of neuronal excitability (Luscher and Slesinger, 2010).…”

Section: Introductionmentioning

confidence: 99%

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

Perra

Clements

Bernier

et al. 2011

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.