Booze Totally Screws the Brain — At the Molecular Level

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This is a bit geeky, but look up words you don’t know.  It is very mechanical and not infinitely complex. Take Away – Pretty much the g-protein receptors get fried.  lol, well, that is pretty geeky

Alcoholism is a disease of chronic relapse, consisting of repeated bouts of excessive intake and abstinence, resulting in withdrawal symptoms that contribute to the resumption of heavy drinking…human alcoholics report increased anxiety and compulsive behaviors during abstinence periods, which correlate with escalated ethanol consumption …Examination of these symptoms in a mouse model of alcohol use disorders showed …escalated ethanol intake during abstinence.

…Dopamine transmission is markedly attenuated after chronic ethanol exposure …A previous study reported reduced dopamine terminal function in the nucleus accumbens (NAc) …suggesting a link between attenuated accumbal function and augmented ethanol intake. As the dopamine system has been implicated as an important regulator of ethanol drinking and anxiety/compulsive- like behaviors, it is possible that dysregulated dopamine transmission may underlie chronic ethanol-induced increases in these behaviors.

…Dopamine transmission in the NAc is regulated by a variety of receptors, including kappa opioid receptors (KORs). Intra-accumbal pharmacological activation of KORs reduces dopamine release in this region, while blockade transiently increases extracellular levels of dopamine. Consistent with these data, administration of a KOR agonist … increases brain reward thresholds, as measured by intra-cranial self-stimulation, suggesting that KOR activation reduces mesocorticolimbic signaling and produces negative affect. Notably:

  • KORs on mesolimbic dopamine neurons mediate place aversion to KOR agonists, supporting a modulatory role of KORs on mesolimbic dopamine system function that influences hedonic state.
  • Further, withdrawal from ethanol and cocaine increases brain reward thresholds, an effect that is blocked with KOR antagonists
  • Thus, KOR blockade may attenuate the negative reinforcing effects of ethanol by regulating dopamine transmission.

Of interest to this particular study are data demonstrating the utility of KORs as a potential pharmacotherapeutic target to alleviate the symptoms of ethanol withdrawal.

heavy drinking-exposed rats routinely demonstrate increased ethanol self-administration after a period of abstinence …it is possible that changes in KOR function and dopamine transmission drive heavy drinking-induced behavioral changes observed during ethanol abstinence.

Discussion

The present work showed that heavy drinking induced behavioral changes in mice were associated with augmented sensitivity of KORs on dopamine terminals and reduced dopamine transmission in the NAc.

…showed that heavy drinking reduced dopamine release, increased rates of dopamine uptake, and augmented the inhibitory effects of KORs on dopamine release, promoting a hypodopaminergic state of the NAc.

These data suggest that accumbal hypodopaminergia may be partially driven by increased KOR function, leading, at least in part, to the potentiation of ethanol intake and anxiety/compulsive-like behaviors during ethanol abstinence.

…Together, these data suggest that KORs play a role in ethanol withdrawal-associated negative affective symptoms and augmented drinking and suggest that pharmacological blockade of KORs could potentially serve a therapeutic role in withdrawn alcoholics. Increased anxiety/compulsive-like behavior, opioid receptor signaling, and dopamine transmission following prolonged ethanol exposure are strikingly similar to studies examining different sources of negative affective states. In particular, negative affective states engendered by chronic stress or drug exposure have been tied to elevated KOR activity.

For example, symptoms of withdrawal from ethanol or cocaine, social isolation rearing, social defeat stress, and separation of pair-bonded prairie voles are rescued with KOR blockade. It is likely that KOR activity may be a ubiquitous mediator of negative affect and stress, although elevated KOR activity is a part of an extensive stress response system that also includes elevated levels of cortocotropin releasing factor (CRF). In fact, the CRF and KOR systems often play similar roles in stress responses, which has led to the hypothesis that the CRF and KOR systems are functionally linked

Ethanol and Opioids Acute ethanol administration increases both endorphin and dynorphin levels, activating both mu opioid receptors (MORs) and KORs simultaneously. This would result in opposing effects on the mesolimbic dopamine system, as MOR activation increases and KOR activation reduces accumbal dopamine transmission. Augmented accumbal dopamine levels in response to acute ethanol are due, in part, to increased inhibitory MOR activity on ventral tegmental area GABAergic interneurons, which causes a disinhibition of dopaminergic neurons in this region. Conversely, chronic ethanol exposure reduces MOR activity while augmenting KOR signaling.

As a G-protein coupled receptor, there are multiple signaling cascades associated with KORs, and changes in the function of one or more of these downstream effectors may be driving augmented KOR function…Increased KOR function and reduced dopamine transmission may promote an overall deficiency in reward system function. The neurochemical changes associated with chronic ethanol exposure may produce negative affective symptoms specifically by increasing KOR sensitivity and reducing dopamine system function.

The present data support this hypothesis, as reduced dopamine transmission and increased KOR signaling are associated with augmented anxiety/compulsive- like behavior and ethanol intake after a period of abstinence and further because KOR blockade reduces heavy drinking-induced changes in behavior to control levels.

Currently, only one opioid receptor antagonist, naltrexone, is approved for alcohol use disorders by the Food and Drug Administration. Naltrexone is an antagonist of all 3 classical opioid receptors (MOR, KOR, delta [DOR]). Because of the opposing functional effects of MORs, DORs, and KORs, the utility of a pan-opioid antagonist in treating alcoholics may be reduced, as inhibition of all opioid receptors may decrease the positive reinforcing effects of natural rewards as well as ethanol, thus decreasing compliance.

For example, in humans, naltrexone decreased reward related brain activation in response to palatable foods as well as overall food and sweets intake. Additionally, naltrexone produces an aversive state in monkeys, healthy humans, and alcoholics. Since the present data show that KOR blockade is sufficient to reduce anxiety/compulsive-like behavior and ethanol drinking in heavy drinking exposed mice to nondependent levels, a KOR-specific antagonist may be fully efficacious at reducing relapse drinking in the human population while sparing the positive reinforcing salience of natural rewards

The Effects of heavy drinking Exposure on Accumbal Dopamine Transmission

Chronic ethanol exposure consistently reduces dopamine system function. For example, previous work from our laboratory showed that heavy drinking exposure of mice and rats attenuates dopamine transmission by reducing dopamine release and increasing the rate of dopamine uptake, which is congruent with findings of reduced limbic system function in human alcoholics….

Conclusions

Human alcoholics report relapse to alcohol drinking in an effort to reduce withdrawal symptoms experienced during abstinence. As mounting evidence supports the involvement of accumbal KORs in the development of anxiety/compulsive-like behaviors and dependence-induced ethanol drinking, chronic ethanol-induced reductions in dopamine transmission and increased KOR sensitivity in the NAc may promote the development of negative affective behavioral phenotypes associated with ethanol withdrawal. As such, our work supports a growing body of literature suggesting the potential utility of a KOR-antagonist to rescue chronic drinking.

 

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