GIRK Channels as Candidate Targets for the Treatment of Substance Use Disorders

Substance use disorders (SUDs) are chronic, lifelong disorders that have serious consequences. Repeated substance use alters brain function. G-protein-activated inwardly rectifying potassium (GIRK) channels are expressed widely in the brain, including the reward system, and regulate neuronal excitability. Functional GIRK channels are identified as heterotetramers of GIRK subunits (GIRK1–4). The GIRK1, GIRK2, and GIRK3 subunits are mainly expressed in rodent brain regions, and various addictive substances act on the brain through GIRK channels. Studies with animals (knockout and missense mutation animals) and humans have demonstrated the involvement of GIRK channels in the effects of addictive substances. Additionally, GIRK channel blockers affect behavioral responses to addictive substances. Thus, GIRK channels play a key role in SUDs, and GIRK channel modulators may be candidate medications. Ifenprodil is a GIRK channel blocker that does not have serious side effects. Two clinical trials were conducted to investigate the effects of ifenprodil in patients with alcohol or methamphetamine use disorder. Although the number of participants was relatively low, evidence of its safety and efficacy was found. The present review discusses the potential of GIRK channel modulators as possible medications for addiction. Therapeutic agents that target GIRK channels may be promising for the treatment of SUDs

Involvement of GluD2 in Fear-Conditioned Bradycardia in Mice.

Lesions in the cerebellar vermis abolish acquisition of fear-conditioned bradycardia in animals and human patients. The δ2 glutamate receptor (GluD2) is predominantly expressed in cerebellar Purkinje cells. The mouse mutant ho15J carries a spontaneous mutation in GluD2 and these mice show a primary deficiency in parallel fiber-Purkinje cell synapses, multiple innervations of Purkinje cells by climbing fibers, and impairment of long-term depression. In the present study, we used ho15J mice to investigate the role of the cerebellum in fear-conditioned bradycardia. We recorded changes in heart rate of ho15J mice induced by repeated pairing of an acoustic (conditioned) stimulus (CS) with an aversive (unconditioned) stimulus (US). The mice acquired conditioned bradycardia on Day 1 of the CS-US phase, similarly to wild-type mice. However, the magnitude of the conditioned bradycardia was not stable in the mutant mice, but rather was exaggerated on Days 2-5 of the CS-US phase. We examined the effects of reversibly inactivating the cerebellum by injection of an antagonist against the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR). The antagonist abolished expression of conditioned responses in both wild-type and ho15J mice. We conclude that the GluD2 mutation in the ho15J mice affects stable retention of the acquired conditioned bradycardia

Extinction of conditioned bradycardia.

<p>Shown is the daily mean change in heart rate (beats/min) during the 5 s CS collapsed across daily 20 trials during the five days of the extinction phase.</p

The effects of NBQX injection on mean heart rate.

<p>(A) Mean heart rate for the wild-type (saline), wild-type (NBQX) and <i>ho15J</i> (NBQX) mice during Days 2–4 of the CS-US phase. NBQX was injected into the wild-type (NBQX) and <i>ho15J</i> (NBQX) mice on Day 3 of the CS-US phase. The wild-type (saline) mice were injected with saline. (B) Baseline heart rate for the wild-type (saline), wild-type (NBQX) and <i>ho15J</i> (NBQX) mice during Day 3 of the CS-US phase.</p

Injection site and diffusion of NBQX in the cerebellum.

<p>(A) Schematic showing the injection site and diffusion of pontamine sky blue in a dorsal view of the cerebellum. The black dot in the blue area indicates the injection site and the blue area shows the extent of diffusion of pontamine sky blue. The pontamine sky blue was confirmed to extend from the cerebellar vermis to the intermediate cerebellum. (B) Schematic showing the injection site and diffusion of pontamine sky blue in a sagittal section of the cerebellum. Arrow shows the injection site. Pontamine sky blue was confirmed to extend from cerebellar lobules III to VI. (C) Sagittal section was selected at 0.48 mm from midline. Blue dye is pontamine sky blue and red dye is Neutral Red.</p

Conditioned bradycardia during the CS-US phase.

<p>(A) Mean heart rate for the wild-type and <i>ho15J</i> mice during 5 consecutive days of the CS-US phase. (B) Probabilities of conditioned bradycardia for wild-type and <i>ho15J</i> mice during the 5 days of the CS-US phase. (C) The conditioned bradycardia for each second-block on each of the 5 consecutive days of the CS-US phase is shown for the wild type and the <i>ho15J</i> mice. The mean heart rate change relative to the pre-CS level is shown. (D) The mean heart rate change of the last 10 trials (trial 41–50) on each day and that of the first 10 trials (trial 1–10) on the following day for each type of mouse during the 5 days of the CS-US phase is indicated by the bars. The mean heart rate change relative to the pre-CS level is shown. *<i>p</i> < 0.05.</p

The acquisition of conditioned bradycardia on Day 1 of the CS-US phase.

<p>Shown is the mean heart rate change from the pre-CS baseline through the 5 s CS collapsed across 50 trials on Day 1 of the CS-US phase. The wild-type (open circles) and <i>ho15J</i> mice (filled circles) demonstrated progressively increasing bradycardia throughout the CS period.</p

Heart rate responses following a tail shock and responses to pain stimuli.

<p>(A) Topography of heart rate responses following application of a tail-shock as the US, during US-alone testing. Mean changes in heart rate (beats/min) during each 1 s period of the 6 s following the offset of the US collapsed across 20 trials. (B) Tail-flick test. Wild-type and <i>ho15J</i> mice received 2 levels of thermal stimulus (80°C or 110°C).</p