Effects of alcohol and ∆9-tetrahydrocannabinol on energy balance and cognitive behaviors

Nelson, Nnamdi G.

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Description

Title

Effects of alcohol and ∆9-tetrahydrocannabinol on energy balance and cognitive behaviors

Author(s)

Nelson, Nnamdi G.

Issue Date

2019-04-17

Director of Research (if dissertation) or Advisor (if thesis)

Liang, Nu-Chu

Doctoral Committee Chair(s)

Liang, Nu-Chu

Committee Member(s)

• Gulley, Joshua M.
• Johnson, Rodney W.
• Pepino, Yanina

Department of Study

Neuroscience Program

Discipline

Neuroscience

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Alcohol
• ∆9-tetrahydrocannabinol (THC)
• Ingestive behavior
• Glucose homeostasis
• Cognitive function
• Adolescence

Abstract

Habitual consumption of energy-dense foods is a notable contributor to the high incidence of obesity and metabolic syndrome worldwide. The extent to which calories from alcohol contribute to overweight and obesity is debatable. ∆9-tetrahydrocannabinol (THC), the main psychoactive constitute of marijuana, mainly activates cannabinoid subtype 1 and 2 receptors (CB1R and CB2R) to modulate many behavioral and metabolic processes, including feeding and glucose homeostasis. For several reasons, reports on the long-term effects of alcohol and THC use on energy balance, glucose homeostasis, and cognitive behaviors in both human and rodent studies are fraught with inconsistencies. Further, alcohol and marijuana co-use is believed to be more detrimental to health and safety, yet surprisingly little is known about the specific physiological domains impacted by such a pattern of drug use. There is also a dearth of research on the neurobiological mechanisms that mediate the unique effects of joint alcohol and THC use on metabolism and behavior. To bridge the gap in our understanding of the effects of separate or combined alcohol and THC use on feeding behavior, cognitive function, and metabolic fitness of young adults, we implemented three studies using relatively young Long-Evans rats. Chapters 1 and 2 reviewed published reports on this topic and outlined the Specific Aims of this dissertation, respectively. Chapter 3 investigated the effects of chronic moderate alcohol consumption on energy balance, cognitive behaviors, and glucose homeostasis in young male and female rats. We observed that rats who voluntarily consumed moderate doses of alcohol compensated for the calories supplied by the beverage. Intermittent moderate alcohol consumption (for 14 weeks) did not appreciably alter object recognition memory and emotion-like behavior in both sexes of rats. But such drinking pattern and duration altered glucose homeostasis in males. Chapter 4 established two rodent models of alcohol and THC co-use that differed in terms of the route of THC administration. In the first model, adolescent male rats were entrained to consume a sweetened alcohol solution immediately after receiving increasing subcutaneous THC doses. To closely capture the voluntary nature of human drug co-use and the trendy consumption of THC via edibles, we implemented a second co-use model where rats voluntarily consumed a sweetened alcohol solution and THC-laced cookies. In the first model, moderate alcohol consumption attenuated the immediate hyperphagic effect of subcutaneous THC. Separate or combined alcohol and THC use under both models did not alter daily caloric intake and learning and memory, but differently affected alcohol intake, weight gain, and sucrose consumption during abstinence. Western blot analyses uncovered insignificant changes in CB1R protein expression and basal glycogen synthase kinase-3 beta (GSK-3β) activity in the medial prefrontal cortex (mPFC; center for executive function control), mediobasal hypothalamus (MBH; energy balance regulator), and hippocampus (HIP; involved in spatial learning) during drug abstinence. GSK-3β is a ubiquitously-expressed signaling molecule in the central nervous system. CB1R and GSK-3β activity help regulate cellular homeostasis. Finally, subcutaneous THC and alcohol co-exposure modestly improved peripheral glucose homeostasis. Chapter 5 examined whether a metabolic challenge using high-fat diet (HFD; 45% kcal from fat) exposure during young adulthood would help uncover robust metabolic effects of adolescent alcohol and THC consumption. There were no effects of oral drug treatment and no interaction between drug treatment and later dietary fat consumption on all the metabolic measures examined. Interestingly, rats exposed to HFD for a short duration demonstrated a hyperphagic response that produced modest weight gain. Four days of HFD feeding altered systemic glucose tolerance as reflected by the modest hyperglycemia and hyperinsulinemia both during a brief fast and in response to an oral glucose load. Although the HFD consumers had a higher basal blood glucose concentration following a mild fast, percent visceral adiposity, and plasma leptin content compared with the chow group, both diet groups responded similarly to exogenous insulin. Collectively, this set of experiments indicated that separate or combined chronic moderate alcohol and THC use can alter energy balance and glucose homeostasis under different experimental conditions. While we detected no long-term changes in cognition, emotion-like behaviors, and neurobiology (CB1R expression and GSK-3β activity) following periods of separate or combined alcohol and THC use, studies with more sensitive analytical assays may reveal subtle detrimental effects of drug use. The adolescent alcohol and THC co-use model developed in this dissertation is the first to utilize an edible THC product to truly capture the growing pattern of human alcohol and THC co-use. Considering the lenient regulation of alcohol, the ongoing societal acceptance of marijuana, and the burden of metabolic syndrome on public health, more research to decipher the neurobiological mechanisms that mediate the effects of alcohol and cannabinoid co-use on metabolism and behavior are needed.

Graduation Semester

2019-05

Type of Resource

text

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Copyright 2019 Nnamdi Nelson

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