Caffeine modulation of ethanol: Effects on intake, metabolism, and adenosine receptor-mediated dopamine neurotransmission in the medial prefrontal cortex of alcohol-preferring (p) rats
Abstract
The consumption of caffeinated alcoholic beverages has shown increased prevalence in recent years. Research suggests that combining these drugs may lead to different effects, compared to consumption of either drug alone. However, minimal research has been performed to look explicitly at behavioral, metabolic, and neurochemical changes that result from consuming caffeinated cocktails. The aim of the current study is to examine some of the effects that result from co-administration of caffeine and ethanol (EtOH) in a selectively-bred rodent model of alcoholism, the Alcohol-preferring (P) rat. In particular, this study sought to examine the actions of combining caffeine and EtOH on neurotransmission in the medial prefrontal cortex (mPFC), an area highly associated with executive functioning. The objective of Specific Aim 1 was to examine the acute systemic effects of caffeine and EtOH co-administration on dopamine (DA) neurotransmission in the mPFC of female P rats. This study showed that caffeine co-administration blocked a bi-modal increase in mPFC extracellular DA levels, following intraperitoneal (i.p) exposure to low-dose EtOH exposure. This finding suggests that caffeine administration may inhibit, in part, excitatory DA neurotransmission induced by low dose EtOH. Specific Aim 2 employed subcutaneous microdialysis to examine the effects of caffeine on EtOH metabolism in female P rats. This study showed a low dose of caffeine increased the EtOH elimination rates in female P rats, following acute i.p. exposure to a low-dose of EtOH. This finding indicates that caffeine likely increases EtOH metabolism. However, this effect is highly dose-specific. The goal of the Preliminary Caffeine Drinking Study was to assess caffeine intake in the high alcohol-drinking P rats, compared to their outbred Wistar rat counterparts. This study showed that P rats consumed more caffeine compared to Wistar rats. P rats showed a trend toward consuming more caffeine at the low concentration. In contrast, Wistar rats consumed more of the high-concentration caffeine. These results suggest that P rats may be more sensitive to the taste or pharmacologic properties of caffeine, compared to Wistar rats. Further, the findings suggest that female P rats may present a better model for looking at the effects of caffeine administration, compared to outbred subjects. Specific Aim 3 compared caffeine, EtOH, caffeine+EtOH (CE), or water intake, in female P rats, during 14 days of one-hour limited access drinking. This study showed that drug intake was greater than water for all solutions. Further, both EtOH and caffeine intake was greater in the CE group, compared to the single-drug groups. These findings suggest that caffeine and EtOH consumption lead to increased intake. This finding may have great implications for development of alcoholism. Finally, Specific Aim 4 examined the concentration-dependent effects of perfusion with selective adenosine A1 or A2A antagonist on extracellular DA levels in the mPFC of female P rats, following the drinking experience described in Specific Aim 3. These studies showed that CE experience increased basal extracellular DA levels (nM) compared to water. Evidence showed that DA response to the A1 antagonist was greater in the CE group, compared to the water or EtOH groups. However, this finding likely was mediated by high basal extracellular DA levels. Further analyses showed that EtOH experience may block caffeine-induced potentiation of extracellular DA levels during A1 receptor antagonist perfusion. Examination of the DA response to application of an adenosine A2A receptor antagonist in the mPFC suggests that EtOH experience may diminish the number or sensitivity of A2A receptors. However, co-administration of caffeine may, in part, inhibit these effects of EtOH. Together, the above findings suggest that high alcohol drinking rats can be used to model EtOH and caffeine co-administration. Further, both acute and chronic combination of caffeine and EtOH may have effects that are incongruent to effects seen with either drug alone. Overall, the results of the current study suggest that caffeine coadministration likely blocks some of the inhibitory effects of EtOH. Further, the finding that co-administration of caffeine increases intake of both drugs suggests that these inhibitory effects may underlie some of the rewarding effects of EtOH. In addition, caffeine may alter some of the pharmacokinetic properties of EtOH at low doses, through increasing the rate of EtOH elimination. However, the current study shows that these effects are highly dose-specific. Future studies are necessary to identify the dosespecificity and extent of effects that result from consumption of caffeinated cocktails.
Degree
Ph.D.
Advisors
Murphy, Purdue University.
Subject Area
Psychobiology|Neurobiology|Experimental psychology
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