Elsevier

Biological Psychiatry

Volume 69, Issue 7, 1 April 2011, Pages 618-624
Biological Psychiatry

Priority Communication
Chlorzoxazone, an SK-Type Potassium Channel Activator Used in Humans, Reduces Excessive Alcohol Intake in Rats

https://doi.org/10.1016/j.biopsych.2010.11.011Get rights and content

Background

Alcoholism imposes a tremendous social and economic burden. There are relatively few pharmacological treatments for alcoholism, with only moderate efficacy, and there is considerable interest in identifying additional therapeutic options. Alcohol exposure alters SK-type potassium channel (SK) function in limbic brain regions. Thus, positive SK modulators such as chlorzoxazone (CZX), a US Food and Drug Administration–approved centrally acting myorelaxant, might enhance SK function and decrease neuronal activity, resulting in reduced alcohol intake.

Methods

We examined whether CZX reduced alcohol consumption under two-bottle choice (20% alcohol and water) in rats with intermittent access to alcohol (IAA) or continuous access to alcohol (CAA). In addition, we used ex vivo electrophysiology to determine whether SK inhibition and activation can alter firing of nucleus accumbens (NAcb) core medium spiny neurons.

Results

Chlorzoxazone significantly and dose-dependently decreased alcohol but not water intake in IAA rats, with no effects in CAA rats. Chlorzoxazone also reduced alcohol preference in IAA but not CAA rats and reduced the tendency for rapid initial alcohol consumption in IAA rats. Chlorzoxazone reduction of IAA drinking was not explained by locomotor effects. Finally, NAcb core neurons ex vivo showed enhanced firing, reduced SK regulation of firing, and greater CZX inhibition of firing in IAA versus CAA rats.

Conclusions

The potent CZX-induced reduction of excessive IAA alcohol intake, with no effect on the more moderate intake in CAA rats, might reflect the greater CZX reduction in IAA NAcb core firing observed ex vivo. Thus, CZX could represent a novel and immediately accessible pharmacotherapeutic intervention for human alcoholism.

Section snippets

Alcohol Self-Administration

Adult male Wistar rats (250–275 g, Harlan, Livermore, California) drank 20% alcohol or water under a two-bottle choice, home-cage, IAA paradigm modified from Simms et al. (12). Rats had 24-hour access to alcohol 3 days/week (starting Monday, Wednesday, and Friday) for 5–6 weeks. Rats were then switched to only 3-hour access to alcohol on the 3 days/week to simplify detection of CZX-related intake changes. After 5–6 weeks of 3-hour/day, 3-day/week IAA drinking, the effects of CZX were examined.

Results

As shown in Figure 1, IAA rats were trained to drink 20% alcohol versus water under a two-bottle choice, home-cage, intermittent access to alcohol paradigm, whereas CAA rats had continuous access to 20% alcohol concurrent with water. Chlorzoxazone significantly and dose-dependently reduced alcohol drinking in IAA rats, determined after 3 hours access to alcohol (Figure 2A) [F(3,74) = 17.45, p < .001] or 1 hour access to alcohol (Figure 2C) [F(3,74) = 20.63, p < .001]. Importantly, CZX did not

Discussion

The present study demonstrates that CZX, an FDA-approved SK activator (10) used for decades in humans as a centrally acting myorelaxant (11), reduced excessive alcohol intake in IAA rats but not moderate alcohol intake in CAA rats. CZX significantly and dose-dependently decreased alcohol intake in IAA rats, with no effect on concurrent water intake. In contrast, CZX did not reduce alcohol or water intake in CAA rats; the lack of effect of CZX in CAA rats was not due to a floor effect, because

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