Paul J. Meyer - US grants

DESCRIPTION (provided by applicant): Understanding the effects of ethanol on simple behaviors such as locomotion provides a foundation for understanding more complex behaviors, such as ethanol self-administration and addiction. Further, studies with psychostimulants such as cocaine and amphetamine, and with ethanol as well, have revealed an overlap in the brain systems underlying both the locomotor and reinforcing effects of drugs. However, the neural substrates of ethanol-induced locomotion have not been as extensively studied. The goal of this proposal is to determine the neural bases for ethanol-induced locomotion. Brain lesions of areas within the mesolimbic dopamine system and the extended amygdala will be used to determine the neuroanatomical basis of the locomotor response to ethanol. In addition, microdialysis within these systems will be used to investigate the neurochemical events that are possibly correlated with this behavior. All of the experiments described in this proposal will utilize a genetic animal model of increased (FAST) and decreased (SLOW) sensitivity to ethanol's stimulant effects. This model of differential ethanol sensitivity is useful for examining behavioral and neurophysiological events that are genetically correlated to the locomotor response to ethanol.

? DESCRIPTION (provided by applicant): Nicotine and alcohol are the most commonly abused recreational drugs, and nicotine dependence and alcoholism have a high degree of comorbidity. For example, an estimated 90% of alcoholics also smoke, and an estimated 60% of smokers engage in binge drinking. The health consequences of alcohol and nicotine abuse are severe, including many types of cancer, cardiovascular disease, liver damage, and chronic obstructive pulmonary disease. Further, these health issues are more severe in individuals who co-abuse these drugs. Therefore, it is crucial to understand the behavioral and neurobiological mechanisms that underlie the interaction between nicotine and alcohol abuse. This information can then be used to develop treatments specifically designed address the comorbidity of addiction to these drugs. A major problem with both nicotine addiction and alcoholism is the craving and relapse induced by individuals' heightened responsivity to the people, places, and other cues associated with drinking and smoking. In addition, smoking-associated cues can trigger drinking. Preliminary studies demonstrate that nicotine enhances the response alcohol-associated cues, but it is not known whether nicotine's effects on alcohol drinking are secondary to these effects. In addition, the response to many drug-associated cues involves the brain's motivational circuit, including the nucleus accumbens and the prefrontal cortex, which affect behavior in complementary ways. It may be through activation of this system that nicotine increases the response to alcohol cues, but to date no studies have examined this possibility. The proposed work will determine whether nicotine increases alcohol intake by increasing the response to alcohol cues within this system, and whether the response to alcohol cues depends upon specific subcircuits within the brain's motivational circuitry. This project will determine th behavioral and neural basis for the ability of nicotine to increase alcohol drinking in rats, by dissociating the effects of cues during specific phases of alcohol drinking, and by measuring and manipulating the activity of neurons with the brain's motivational circuitry. To this end, two sets of experiments will determine 1) which specific aspect of alcohol drinking (including the response to alcohol cues) are affected by nicotine, and 2) which specific projections are necessary and sufficient to engender alcohol cues with motivational value. Findings from this project regarding the specific behavioral and neural points of interaction between nicotine and alcohol will allow for the development of experimental and pharmacological interventions that specifically address the effect of nicotine on alcohol intake.

PROJECT SUMMARY/ABSTRACT While many individuals are exposed to addictive drugs in their lifetimes, only a small percentage develop the patterns of drug-taking associated with addiction. It is therefore crucial to identify the genetic vulnerability factors that influence the transition from recreational to problematic drug use. Studies investigating the genetic basis of addiction often use rodent self-administration models to induce addiction-like symptoms. However, these paradigms differ in the patterns of drug-taking they produce. For example, in the long access (LgA) paradigm, rats self-administer a drug such as cocaine continuously for 6 hours or longer, and this paradigm produces escalation in drug intake over several sessions in a manner that is characteristic of addiction. In contrast, in the intermittent access (IntA) paradigm, rats' access to cocaine is restricted such that overall intake is limited, yet leads to ?spiking? brain levels of cocaine thought to be characteristic of drug-taking during binges in humans. Despite the lower level of intake relative to LgA, IntA results in larger increases in the motivational value of cocaine, as indicated by increases in the effort expended to acquire the drug, and relapse to drug- seeking after periods of abstinence. Thus, the scientific premise of this proposal is that the behavioral and neurogenetic processes driving drug- taking in these models are distinct, and comparing these processes in IntA versus LgA enable the dissociation of genes that promote escalation of intake from those that induced enhanced cocaine motivation (i.e., incentive sensitization). However, to date no studies have examined the genetic substrates of cocaine self- administration during the IntA paradigm, and no studies have compared transcriptomic changes induced by LgA and IntA. To fill these knowledge gaps and identify potentially therapeutic targets, we will conduct a genome-wide association study (GWAS) to determine the genetic variants that influence cocaine intake during IntA, and the degree to which IntA causes incentive sensitization, as measured by changes in progressive ratio breakpoint and cocaine self-administration despite negative consequences (footshock). Further, a unique feature of this application is that we have carefully designed our procedure to parallel an ongoing GWAS (U01DA043799) being conducted by Drs. Olivier George and Abraham Palmer, which allows us to use genetic correlations to compare IntA vs LgA, addressing a unique question: to what extent are the genes that influence the development of addiction-like behavior with LgA similar/different than with IntA? Finally, we will use RNA sequencing to compare how transcriptomic profiles are altered by drug exposure during IntA and LgA, enabling us to determine which gene networks are associated with (1) escalation of intake during LgA vs IntA, (2) incentive sensitization during IntA, and (3) compulsive drug intake during IntA and LgA.