Christopher M. Olsen - US grants

Project Summary/Abstract: Novelty/sensation seeking as a construct in human personality inventories has been extensively associated with drug use. Novelty and sensation seeking have also been associated with elevated drug intake in rodent populations, suggesting an overlap in the neural substrates that encode the reinforcing values of both of these constructs. Further examination of novel stimuli has also supported the relationship with drugs of abuse. Novel stimuli can increase mesolimbic dopamine (DA) activity and produce reinforced behavior in rodents, suggesting that the study of novelty/sensation seeking can provide insight into processes related to addiction. Preliminary data in this proposal demonstrates that dynamic visual stimuli are reinforcing in mice, as they will perform an operant response to obtain it (a task we have termed operant sensation seeking (OSS)). Additionally, they exhibit persistent operant behavior when the stimuli are taken away, a phenomenon common to operant studies using drugs of abuse. Acute and long-term effects of OSS relative to food and cocaine will be characterized using immunohistochemistry and electrophysiology. These experiments will provide insight into how natural and drug reinforcers are encoded in the brain. The role of the glutamate mGluR5 receptor in OSS will be examined using novel pharmacological and genetic tools. This receptor is involved in mediating the reinforcing effects of drug abuse and may be important in OSS as well. Finally, the influence of genetics on OSS will be assessed by screening recombinant inbred strains of mice (BXDs) that are divergent in limbic structure, stress responsivity, and exploratory behavior. These data will reveal the contributions of genetic factors that underlie reinforcement and persistent seeking behavior following removal of OSS stimuli. Understanding how genetics can contribute to these behaviors may improve our knowledge of which people are especially at risk for addiction.

? DESCRIPTION (provided by applicant): Substance use disorder (SUD) is a frequent comorbidity following traumatic brain injury (TBI), even in patients without a previous history of drug use. However, the extent to which the neurological effects of TBI contribute to the development of SUD is unknown. The long-term goal is to understand how brain injury alters neurological and psychiatric function. The objective of the proposed research is to elucidate the relationship between mild TBI (mTBI), addictive phenotypes, and mesocorticolimbic function. The central hypothesis is that mTBI results in elevated risk for drug addiction and changes in mesocorticolimbic circuitry. This hypothesis is supported by correlative data from human studies and by preliminary imaging data using a preclinical mTBI model. The rationale for the proposed research is that understanding the neurological consequences of mTBI will aid in the development of therapeutic strategies for mTBI patients. To isolate neurological effects, we propose a rodent model to enable investigation of the effects of mTBI in drug naïve organisms with similar environmental histories. Our hypothesis is supported by epidemiological and preliminary data and will be tested in two specific aims: 1) Identify the impact of mTBI on drug self-administration, seeking, and relapse; and 2) Determine the effects of mTBI and cocaine on brain networks implicated in drug seeking. In Aim 1, cocaine self-administration and drug seeking will be measured in rats following mild TBI induced by blast forces. In Aim 2, structural and functional imaging studies will be performed before and after mTBI and cocaine self-administration. The approach is innovative because it will contribute translational imaging and behavioral data from a controlled and reproducible preclinical model to a field of study that has been dominated by human imaging and correlative studies. The project is significant because it will initiate a course of research that will reveal mechanisms of TBI sequelae and how these sequelae can influence drug intake and drug seeking behaviors. This work is expected to contribute to a body of basic research that will aid in the development of treatments for co-morbid psychological and psychiatric disorders following TBI.

? DESCRIPTION (provided by applicant): Substance use disorder (SUD) is a devastating psychopathology that is without FDA-approved drug therapies. One promising target for pharmacological intervention are CB2 cannabinoid receptors (CB2R). Previous studies have demonstrated that CB2R agonists reduce intravenous self-administration (SA) of cocaine and inhibit cocaine-induced hyperlocomotion. Since CB2R agonists have very few overt behavioral effects, they represent a promising new avenue for the treatment of SUD. Unfortunately, a lack of good experimental tools for their study inhibits further progress in uncovering the potential fo manipulation of CB2R signaling to treat SUDs. We have recently developed a transgenic mouse in which CB2R expression is coupled to eGFP expression and the CB2R gene is floxed, thus can be conditionally deleted (CB2Rtg). This mouse model allows for enhanced detection and enables conditional deletion of the CB2R. Exposure to cocaine is accompanied by microglial activation and reduced microglial activation is associated with reduced cocaine seeking. Microglia express CB2R, which is increased upon microglial activation. Microglial CB2R promote a neuroprotective phenotype, including suppressed release of pro-inflammatory cytokines. Recent studies also demonstrate that CB2R are expressed in DA neurons and function to inhibit DA release. We will test two hypotheses with the experiments in this proposal: that chronic cocaine exposure increases expression of microglial CB2R and that CB2R agonists act via microglial and DA neuronal CB2R to reduce cocaine SA. We will test these hypotheses with two aims. In aim one, we will use the eGFP reporter feature of the CB2Rtg to determine the effects of cocaine on CB2R expression. In aim two, we will use the floxed feature of the CB2Rtg to specifically delete CB2R from microglia and DA neurons; then apply a subtraction approach to explore the cellular site of action of CB2R agonists to reduce locomotor activity and cocaine SA. Successful completion of these studies will impact understanding of the effects of cocaine on neuroinflammation and CB2R expression; and the roles of CB2R in regulating cocaine intake through clarification of the cell types(s) that are involved in the inhibitory actions of CB2R agonists. We will also establish conditional CB2R-/- mouse lines for further studies of the role of this very interesting receptor in brain function. Thus, these studies will impact mechanistic examination of cocaine effects on the brain and provide important new tools for the study of the CB2R in the brain.

ABSTRACT Cocaine addiction is a chronically relapsing disorder with no current FDA-approved drugs available. A major contributor to relapse is that drug-related stimuli and environments have the ability to powerfully elicit cravings and trigger relapse. Thus, a goal of current treatment plans is to reduce craving evoked by drug-related stimuli. Psychosocial enrichment has been shown to diminish cocaine craving and activation of the medial prefrontal cortex (mPFC) in response to drug-related stimuli, and in a rodent model, environmental enrichment (EE) also reduces cocaine seeking and the ability of drug-related stimuli to activate the mPFC. Despite the robust ability of environmental factors to reduce behavioral and physiological responses to drug stimuli, the mechanisms of this phenomenon are not known. It is possible that EE directly modulates a specific ensemble of neurons that is engaged by exposure to a previous drug-taking environment. One such drug-seeking ensemble resides in the mPFC, a region where enrichment reduces drug stimuli-elicited activity. Our studies will focus on these ensemble neurons to determine if EE affects their ability to become re-activated by exposure to a drug environment, if EE alters cocaine-associated plasticity in these neurons, and if inhibition or excitation of this ensemble alters other mPFC-dependent behaviors.

ABSTRACT Opioid addiction is a chronically relapsing disorder, and chronic pain is a highly prevalent condition that is thought to be a potential trigger for drug relapse. A major contributor to relapse is that drug-related stimuli and environments have the ability to powerfully elicit cravings and trigger relapse. Thus, a goal of current treatment plans is to reduce craving evoked by drug-related stimuli and stressors, such as chronic pain. Psychosocial enrichment has been shown to diminish drug craving and activation of the medial prefrontal cortex (mPFC) in response to drug-related stimuli, and in a rodent model, environmental enrichment (EE) also reduces drug seeking and the ability of drug-related stimuli to activate the mPFC. Despite the robust ability of environmental factors to reduce behavioral and physiological responses to drug stimuli, the mechanisms of this phenomenon are not known. It is possible that EE directly modulates a specific ensemble of neurons that is engaged by exposure to a previous opioid-taking environment. One such drug-seeking ensemble resides in the mPFC, a region where enrichment reduces drug stimuli-elicited activity. Our studies will focus on these ensemble neurons to determine if EE affects their ability to become re-activated by exposure to a drug environment, if EE alters oxycodone-associated plasticity in these neurons, and if chronic neuropathic pain increases opioid seeking and activity of neurons within the mPFC drug seeking ensemble.