Inhalants are a large and diverse group of substances loosely defined by route of administration. Despite clear scientific evidence of their negative effects on human health, the abuse of inhalants remains a worldwide medical problem. Predicting whether an inhalant will be abused as well as developing treatments for inhalant abuse requires suitable experimental procedures which model different aspects of the addiction process. This proposal will investigate basic behavioral procedures for assessing abuse-related effects of two prototypic inhalants in these procedures: toluene and nitrous oxide. Our first goal will be to examine the acute rewarding effects of these inhalants. Two groups of 16 C57BL6/J mice will be implanted with chronic bipolar electrodes into their medial forebrain bundle. Mice will then be trained to respond for electrical stimulation under air exposure conditions. After a baseline has been established half the mice will be exposed to increasing or decreasing concentrations of toluene or nitrous oxide while being allowed to respond for ICSS. Changes in the rewarding effects of ICSS will be assessed both by examining shifts in ICSS frequency-response curve, a progressive ratio schedule of responding, and finally baseline threshold shifts. Mechanistically we will explore the contribution of both GABA and NMDA mediated facilitation of ICSS by pretreatment with selective agents to block facilitation. Dependence and withdrawal effects associated with abuse such as anhedonia and anxiety are critical components of addiction. Therefore we will examine if withdrawal from chronic inhalant exposure produces anhedonic effects as measured by changes in ICSS thresholds and anxiety-like effects as measured by performance in an elevated plus maze and light/dark box exploration. Three groups of 16 C57BL6/J mice will be implanted with chronic bipolar ICSS electrodes and trained to respond for ICSS until stable. The mice will then be exposed to 10 days of 24 hour/day exposure to toluene or nitrous oxide at a concentration just below that which produces overt acute behavioral effects. The third group will serve as a control and only be exposed to air under identical conditions. During the subsequent withdrawal period, ICSS thresholds will be determined at 4, 8, 24 and 48 hours after discontinuing inhalant exposure. Elevated plus maze and light/dark box performance will also be examined after each ICSS session. Lastly, we will examine persistent changes in brain reward circuitry produced by inhalants which are believed to be a major factor in relapse, the same mice used in the chronic exposure study will be examined for long-term changes in ICSS performance as a result of chronic exposure. ICSS tests will be conducted daily under air exposure conditions and compared to the ICSS frequency-response curves generated prior to chronic inhalant exposure as well as to the air control group. We believe that this project which models multiple components of the addiction process in humans has great promise for better understanding the abuse-related effects of inhalants as well as producing a model suitable for the examination of the mechanism(s) and potential treatment medications for inhalant abuse.
Predicting whether an inhalant will be abused as well as treating inhalant abuse requires suitable experimental procedures. This proposal seeks to develop and characterize the intracranial-self-stimulation (ICSS) procedure to address the absence of a basic behavioral procedure which can assess the rewarding effects of inhalants. We will also determine if ICSS, light-dark box exploration and elevated plus maze can detect withdrawal effects following chronic inhalant exposure.
|Tracy, Matthew E; Banks, Matthew L; Shelton, Keith L (2016) Negative allosteric modulation of GABAA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice. Psychopharmacology (Berl) 233:715-25|
|Tracy, Matthew E; Slavova-Hernandez, Galina G; Shelton, Keith L (2014) Assessment of reinforcement enhancing effects of toluene vapor and nitrous oxide in intracranial self-stimulation. Psychopharmacology (Berl) 231:1339-50|