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

McCall, Nora M.; Kotecki, Lydia; Domínguez-López, Sergio; Velasco, Ezequiel Marrón Fernández de; Carlblom, Nicholas; Sharpe, Amanda L.; Beckstead, Michael J.; Wickman, Kevin

doi:10.1038/npp.2016.138

Cited by 41 publications

(50 citation statements)

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“…In cocaine self-administration experiments, GIRK2 DA KO mice exhibit an increased number of cocaine infusions, particularly at low doses, and an increase in total intake of cocaine [76]. Interestingly, conditioned place preference with cocaine is unaffected by GIRK2 knockout [76]. Overall, these conditional GIRK2 knockout experiments support the view that expression of GIRK channels in VTA DA neurons plays an important modulatory role in the behavioral responses to cocaine and morphine.…”

Section: Effects Of Girk Knockouts On Addictive Behaviorsmentioning

confidence: 84%

“…Studies with a cell-type specific ablation of GIRK2 in DA neurons (DAT-Cre +/− : Girk2 fl/fl or GIRK2 DA KO mice) reveal enhanced acute and chronic locomotor response to cocaine [76]. In cocaine self-administration experiments, GIRK2 DA KO mice exhibit an increased number of cocaine infusions, particularly at low doses, and an increase in total intake of cocaine [76]. Interestingly, conditioned place preference with cocaine is unaffected by GIRK2 knockout [76].…”

Section: Effects Of Girk Knockouts On Addictive Behaviorsmentioning

confidence: 99%

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G Protein-Gated Potassium Channels: A Link to Drug Addiction

Rifkin

Moss

Slesinger

2017

Trends in Pharmacological Sciences

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G protein-gated inwardly rectifying potassium (GIRK) channels are regulators of neuronal excitability in the brain. Knockout mice lacking GIRK channels display altered behavioral responses to multiple addictive drugs, implicating GIRK channels in addictive behaviors. Here, we review the effects of GIRK subunit deletions on the behavioral response to psychostimulants, such as cocaine and methamphetamine. Additionally, exposure of mice to psychostimulants produces alterations in surface expression of GIRK channels in multiple types of neurons within the brain’s reward system. We compare the subcellular mechanisms by which drug exposure appears to alter GIRK expression in multiple cell types and provide an outlook on future studies examining the role of GIRK channels in addiction. A greater understanding of how GIRK channels are regulated by addictive drugs may enable the development of therapies to prevent or treat drug abuse.

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Section: Effects Of Girk Knockouts On Addictive Behaviorsmentioning

confidence: 84%

Section: Effects Of Girk Knockouts On Addictive Behaviorsmentioning

confidence: 99%

G Protein-Gated Potassium Channels: A Link to Drug Addiction

Rifkin

Moss

Slesinger

2017

Trends in Pharmacological Sciences

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“…Work with knockout mice suggests that behavioral sensitivity to cocaine is inversely proportional to the strength of GIRKdependent signaling in DA neurons. Girk2 Ϫ / Ϫ mice exhibit increased locomotor responses to cocaine and morphine (Arora et al, 2010;Kotecki et al, 2015) and altered cocaine self-administration (Morgan et al, 2003), as do mice lacking GIRK channels in DA neurons (DATCre(ϩ):Girk2 fl/fl mice) (Kotecki et al, 2015;McCall et al, 2017). However, Girk2 Ϫ / Ϫ mice exhibit an array of other behavioral phenotypes (Signorini et al, 1997;Blednov et al, 2001Blednov et al, , 2003Marker et al, 2004Marker et al, , 2005Costa et al, 2005;Pravetoni and Wickman, 2008), as well as adaptations in excitatory and inhibitory neurotransmission in multiple rewardassociated neuron populations (Arora et al, 2010;Hearing et al, 2013), making it challenging to attribute changes in cocainerelated behavior to a specific population.…”

Section: Introductionmentioning

confidence: 99%

GIRK Channel Activity in Dopamine Neurons of the Ventral Tegmental Area Bidirectionally Regulates Behavioral Sensitivity to Cocaine

McCall¹,

Velasco

Wickman

2019

J. Neurosci.

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Dopamine (DA) neurons of the VTA have been widely implicated in the cellular and behavioral responses to drugs of abuse. Inhibitory G protein signaling mediated by GABA B receptors (GABA B Rs) and D 2 DA receptors (D 2 Rs) regulates the excitability of VTA DA neurons, DA neurotransmission, and behaviors modulated by DA. Most of the somatodendritic inhibitory effect of GABA B R and D 2 R activation on DA neurons reflects the activation of G protein-gated inwardly rectifying K ϩ (GIRK) channels. Furthermore, GIRK-dependent signaling in VTA DA neurons can be weakened by exposure to psychostimulants and strengthened by phasic DA neuron firing. The objective of this study was to determine how the strength of GIRK channel activity in VTA DA neurons influences sensitivity to cocaine. We used a Cre-dependent viral strategy to overexpress the individual GIRK channel subunits in VTA DA neurons of male and female adult mice, leading to enhancement (GIRK2) or suppression (GIRK3) of GIRK channel activity. Overexpression of GIRK3 decreased somatodendritic GABA B R-and D 2 R-dependent signaling and increased cocaine-induced locomotor activity, whereas overexpression of GIRK2 increased GABA B R-dependent signaling and decreased cocaine-induced locomotion. Neither manipulation impacted anxiety-or depressionrelated behavior, despite the link between such behaviors and DA signaling. Together, these data show that behavioral sensitivity to cocaine in mice is inversely proportional to the strength of GIRK channel activity in VTA DA neurons and suggest that direct activators of the unique VTA DA neuron GIRK channel subtype (GIRK2/GIRK3 heteromer) could represent a promising therapeutic target for treatment of addiction.

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“…Inwardly rectifying potassium channels are activated by neurotransmitters and hormones as well as by other messengers such as kinases and G-proteins (Dascal, 1997). The G protein-activated potassium (GIRK) channels can be directly activated by ethanol (Aryal et al , 2009) and have been found to play a role in drug addiction (Herman et al , 2015; McCall et al , 2016; Munoz et al , 2016; Rifkin et al , 2017). Here we show that ethanol-induced CPP increases the excitability of vBNST neurons by potentially blocking inwardly-rectifying potassium channels.…”

Section: Discussionmentioning

confidence: 99%

Ethanol-induced conditioned place preference and aversion differentially alter plasticity in the bed nucleus of stria terminalis

Pati

Pina

Kash

2019

Preprint

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1Contextual cues associated with drugs of abuse, such as ethanol, can trigger craving and drug 2 seeking behavior. Pavlovian procedures, such as place conditioning, have been widely used to 3 study the rewarding/aversive properties of drugs and the association between environmental 4 cues and drug seeking. Previous research has shown that ethanol as an unconditioned stimulus 5 can induce a strong conditioned place preference (CPP) or aversion (CPA) in rodents. However, 6 the neural mechanisms underlying ethanol induced reward and aversion have not been 7 thoroughly investigated. The bed nucleus of the stria terminalis (BNST), an integral part of the 8 extended amygdala, is engaged by both rewarding and aversive stimuli and plays a role in 9 ethanol seeking behavior. Here, we used ex-vivo slice physiology to probe learning-induced 10 synaptic plasticity in the BNST following ethanol-induced CPP and CPA. Male DBA/2J mice (2-3 11 months old) were conditioned using previously reported ethanol-induced CPP/CPA procedures. 12Ethanol-induced CPP was associated with increased neuronal excitability in the ventral BNST 13 (vBNST). Conversely, ethanol-induced CPA resulted in a significant decrease in spontaneous 14 glutamatergic transmission without alterations in GABAergic signaling. Ethanol-CPA also led to 15 significant increase in paired pulse ratio at excitatory synapses, suggestive of a decrease in 16 presynaptic glutamate release. Collectively, these data demonstrate that the vBNST is involved 17 in the modulation of contextual learning associated with both the rewarding and the aversive 18 properties of ethanol in mice. 1920 33 Schuckit et al, 2004). Therefore, alcohol use can be seen as a function of the balance between 34 reward and aversion wherein alcohol's rewarding properties promote its use while its aversive 35 properties limit its use (Verendeev and Riley, 2012). Thus, understanding the neuroadaptations 36 that underlie these associative memories is integral to the development of better treatment 37 strategies. 38A critical neural structure that is widely implicated in associative learning and stress-induced 39 drug seeking is the bed nucleus of the stria terminalis (BNST). BNST is a sexually dimorphic, 40 limbic forebrain region that regulates stress and anxiety states, as well as aversive and reward-41 related behaviors (for review, see Lebow and Chen, 2016; Vranjkovic et al, 2017). It is a 42 complex structure comprising several sub nuclei and heterogenous cell populations (Dong et al, 43 2001a, 2001b, Dong and Swanson, 2006a, 2006b). The anterior commissure divides the BNST 44 into dorsal and ventral (vBNST) divisions. The vast majority of neurons in the BNST are 45 GABAergic in phenotype scattered with a sparse population of glutamatergic cells (Poulin et al,48 Cassell, 1993). Dense glutamatergic inputs arise from the prefrontal cortex, the basal amygdala, 49 the hippocampus and the insular cortex (Canteras and Swanson, 1992; Cullinan et al, 1993; 50 Vertes, 2004). Also, both dorsal and vBNST send pr...

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

Cited by 41 publications

References 42 publications

G Protein-Gated Potassium Channels: A Link to Drug Addiction

G Protein-Gated Potassium Channels: A Link to Drug Addiction

GIRK Channel Activity in Dopamine Neurons of the Ventral Tegmental Area Bidirectionally Regulates Behavioral Sensitivity to Cocaine

Ethanol-induced conditioned place preference and aversion differentially alter plasticity in the bed nucleus of stria terminalis

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