These binges of continuous methamphetamine use may underlie the development of many of the deviant behaviors observed in long-term methamphetamine addicts. They then usually repeat this cycle if methamphetamine is available.
Human methamphetamine addicts typically follow a “binge-pattern” of use, with 3-15 days of continual drug use followed by a “crash” period of 1-3 days, often consisting of continuous sleep. Chronic methamphetamine use is also associated with crime, aggression, and violent, deviant and risky sexual behaviors. LSU Health Sciences Center, Shreveport, USAīackground: In 2009, the economic cost of methamphetamine use to society was estimated at $16.2 - $48.3 billion. Decreased drinking in BK β1 deficient mice suggests a key role of BK channels in the initial neuroadaptations to ethanol within the reward system. Absence of the β1 subunit in knockout mice may, on the other hand, promote counter-adaptive changes downstream of BK channel overstimulation by ethanol and exacerbate withdrawal. We also found that knockout and heterozygous mice self-administered less ethanol than their wild-type littermates.ĭiscussion: These findings suggest that the β1 subunit may be recruited upon chronic intoxication to dampen ethanol-induced potentiation of BK currents, thereby minimizing behavioral responses to ethanol. Moreover, knockout and heterozygous mice experienced an earlier and more intense physical withdrawal syndrome than wild-type counterparts. Chronic intermittent exposure to ethanol vapor produced tolerance to these effects in wild-type mice, but the extent of tolerance was reduced in knockout mice. Results: We found that sensitivity to ethanol-induced ataxia, sedation and hypothermia was similar between BK β1 wild-type, heterozygous and knockout male mice. An independent cohort of mice was subjected to a limited-access (2 h /day, starting 3 h into the dark phase) two-bottle choice model of voluntary ethanol drinking. Ethanol-induced ataxia, sedation, and hypothermia were measured approximately 26 h into withdrawal to assess the development of tolerance. Mice were exposed to chronic intermittent ethanol vapor in inhalation chambers for 3 cycles of 8-h intoxication / 16-h withdrawal, and a time-course of handling-induced convulsions was conducted to evaluate dependence. The hypnotic effect of a high dose of ethanol (4 g/kg) was measured in the loss-of-righting-reflex test, along with hypothermia. Methods: Adult male BK β1 wild-type, heterozygous and knockout mice were trained and tested following the injection ofa low dose of ethanol (1.5 g/kg) in the accelerating rotarod assay of motor coordination. In the present study, we investigated how deficiency in BK β1 subunit affects ethanol intoxication, tolerance, dependence and drinking in mice. Interestingly, association of the auxiliary β1 subunit with the pore-forming α subunit precludes ethanol-induced potentiation of BK currents in vitro.
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Ethanol is a potent activator of BK channel gating, but in vivo evidence for a causal relationship between BK channel potentiation and ethanol's behavioral effects is scarce. BK channels are highly expressed in the brain and play a key role in several aspects of neuronal physiology. One of the well-established molecular targets of ethanol is the large conductance calcium-activated potassium (BK) channel. Development of more efficient alcoholism treatments requires a better understanding of the molecular mechanisms mediating the intoxicating and motivational effects of ethanol. The Scripps Research Institute, Committee on the Neurobiology of Addictive Disorders, La Jolla, USAīackground: Alcohol abuse disorders have devastating health and societal consequences.