Ethanol-Induced Suppression of G Protein-Gated Inwardly Rectifying K-Dependent Signaling in the Basal Amygdala.

Background: The basolateral amygdala (BLA) regulates mood and associative learning and has been linked to the development and persistence of alcohol use disorder. The GABAR (gamma-aminobutyric acid B receptor) is a promising therapeutic target for alcohol use disorder, and previous work suggests that exposure to ethanol and other drugs can alter neuronal GABAR-dependent signaling. The effect of ethanol on GABAR-dependent signaling in the BLA is unknown.

RGS6 negatively regulates inhibitory G protein signaling in dopamine neurons and positively regulates binge-like alcohol consumption in mice.

Background And Purpose: Drugs of abuse, including alcohol, increase dopamine in the mesocorticolimbic system via actions on dopamine neurons in the ventral tegmental area (VTA). Increased dopamine transmission can activate inhibitory G protein signalling pathways in VTA dopamine neurons, including those controlled by GABA and D receptors. Members of the R7 subfamily of regulator of G protein signalling (RGS) proteins can regulate inhibitory G protein signalling, but their influence on VTA dopamine neurons is unclear.

GIRK channel activity in prelimbic pyramidal neurons regulates the extinction of cocaine conditioned place preference in male mice.

Drug-induced neuroadaptations in the prefrontal cortex (PFC) have been implicated in drug-associated memories that motivate continued drug use. Chronic cocaine exposure increases pyramidal neuron excitability in the prelimbic subregion of the PFC (PL), an adaptation that has been attributed in part to a suppression of inhibitory signalling mediated by the GABA receptor (GABA R) and G protein-gated inwardly rectifying K (GIRK/Kir3) channels. Although reduced GIRK channel activity in PL pyramidal neurons enhances the motor-stimulatory effect of cocaine in mice, the impact on cocaine reward and associated memories remains unclear.

Bidirectional Influence of Limbic GIRK Channel Activation on Innate Avoidance Behavior.

Systemic administration of ML297, a selective activator of G-protein-gated inwardly rectifying K (GIRK) channels, decreases innate avoidance behavior in male C57BL/6J mice. The cellular mechanisms mediating the ML297-induced suppression of avoidance behavior are unknown. Here, we show that systemic ML297 administration suppresses elevated plus maze (EPM)-induced neuronal activation in the ventral hippocampus (vHPC) and basolateral amygdala (BLA) and that ML297 activates GIRK1-containing GIRK channels in these limbic structures.

Impact of Acute and Persistent Excitation of Prelimbic Pyramidal Neurons on Motor Activity and Trace Fear Learning.

Drug-induced neuroadaptations in the mPFC have been implicated in addictive behaviors. Repeated cocaine exposure has been shown to increase pyramidal neuron excitability in the prelimbic (PL) region of the mouse mPFC, an adaptation attributable to a suppression of G protein-gated inwardly rectifying K (GIRK) channel activity. After establishing that this neuroadaptation is not seen in adjacent GABA neurons, we used viral GIRK channel ablation and complementary chemogenetic approaches to selectively enhance PL pyramidal neuron excitability in adult mice, to evaluate the impact of this form of plasticity on PL-dependent behaviors.

Mechanisms and Regulation of Neuronal GABA Receptor-Dependent Signaling.

γ-Aminobutyric acid B receptors (GABARs) are broadly expressed throughout the central nervous system where they play an important role in regulating neuronal excitability and synaptic transmission. GABARs are G protein-coupled receptors that mediate slow and sustained inhibitory actions via modulation of several downstream effector enzymes and ion channels. GABARs are obligate heterodimers that associate with diverse arrays of proteins to form modular complexes that carry out distinct physiological functions.