piperidines and Alcohol-Related-Disorders

We have previously demonstrated that the neurokinin-1 receptor (NK1R) is upregulated in the central nucleus of the amygdala of alcohol preferring (P) rats and that this receptor mediates escalated alcohol consumption in this strain. However, it is unclear if non-genetic models of escalated consumption are also mediated by NK1R signaling, and if so, what brain regions govern this effect. In the experiments presented here, we use two methods of inducing escalated alcohol intake in outbred Wistar rats: yohimbine pretreatment and intermittent alcohol access (Monday, Wednesday, and Friday availability; 20% alcohol). We found that escalated alcohol consumption induced by both yohimbine injection and intermittent access is attenuated by systemic administration of the NK1R antagonist L822429. Also, when compared to continuous alcohol access or access to water alone, NK1R expression was increased in the nucleus accumbens (NAC) and dorsal striatum, but not the amygdala. Escalated consumption induced by intermittent access was attenuated when the NK1R antagonist L822429 was infused directly into the dorsal striatum, but not when infused into the NAC. Taken together, these results suggest that NK1R upregulation contributes to escalated alcohol consumption that is induced by genetic selection, yohimbine injection, and intermittent access. However there is a dissociation between the regions involved in these behaviors with amygdalar upregulation contributing to genetic predisposition to escalated consumption and striatal upregulation driving escalation that is induced by environmental exposures.

Topics: Adrenergic alpha-2 Receptor Antagonists; Alcohol Deterrents; Alcohol Drinking; Alcohol-Related Disorders; Amygdala; Animals; Animals, Outbred Strains; Corpus Striatum; Disease Models, Animal; Gene Expression Regulation; Male; Neurokinin-1 Receptor Antagonists; Nucleus Accumbens; Piperidines; Rats, Wistar; Receptors, Neurokinin-1; Yohimbine

Neurokinin-1 receptors (NK1Rs) have been shown to mediate alcohol and opiate, but not cocaine reward in rodents. We recently reported that NK1R antagonism also blocks stress-induced reinstatement of alcohol seeking in rats, but it is presently unknown whether these antirelapse properties extend to other drug classes. Although some work has suggested that intracranial substance P (SP) infusion reinstates cocaine seeking following extinction, no studies have indicated a direct role for the NK1R in reinstatement of cocaine seeking. Here, we explored the effect of the NK1R antagonist L822429 on yohimbine-induced reinstatement of alcohol or cocaine seeking in Long-Evans rats. Consistent with our previous findings with footshock-induced reinstatement of alcohol seeking in Wistar rats, we found that L822429 attenuates yohimbine-induced reinstatement of alcohol seeking, but does not affect baseline alcohol self-administration. We observed a similar suppression of yohimbine-induced reinstatement of cocaine seeking by L822429, and found that Long-Evans rats exhibit greater sensitivity to NK1R antagonism than Wistar rats. Accordingly, Long-Evans rats exhibit differences in the expression of NK1Rs in some subcortical brain regions. Combined, our findings suggest that while NK1R antagonism differentially influences alcohol- and cocaine-related behavior, this receptor mediates stress-induced seeking of both drugs.

Topics: Adrenergic alpha-2 Receptor Antagonists; Alcohol-Related Disorders; Animals; Behavior, Addictive; Brain; Central Nervous System Depressants; Cocaine; Cocaine-Related Disorders; Dopamine Uptake Inhibitors; Ethanol; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Rats; Rats, Long-Evans; Rats, Wistar; Receptors, Neurokinin-1; Recurrence; Saccharin; Species Specificity; Stress, Psychological; Yohimbine

A 75-year old man with a 40-year history of alcoholism was admitted to the hospital for intoxication and inability to care for himself. He had been admitted frequently in the past for detoxification and rehabilitation. The patient had no family history of Alzheimer's disease, no history of head injury, and single-photon emission computed tomography showed no typical findings of Alzheimer's disease. His cognitive function was impaired. He was treated with donepezil for alcohol-related dementia, and 3 months later, his cognitive function had improved. More research is needed to confirm donepezil's role in treating alcohol-related dementia.

Topics: Aged; Alcohol-Related Disorders; Cognition Disorders; Donepezil; Drug Administration Schedule; Humans; Indans; Injections; Male; Piperidines; Time Factors; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency