Erik B. Oleson - US grants

[unreadable] DESCRIPTION (provided by applicant): This application proposes to use a newly developed self-administration paradigm and fast-scan cyclic voltammetry to characterize two unique models. The two models of interest are the long-access and the break-point escalation models. The long-access escalation model reflects the escalating nature of responding and overall consumption observed in cocaine addicts. The break-point escalation model reflects the incease in motivation to take cocaine reported by addicts. The self-administration paradigm that I have developed and refined measures the lowest possible dose that will maintain cocaine responding. In this proposal, my newly developed self-administration paradigm will be used to measure changes in an animal's propensity to binge at extremely low cocaine doses following training under either the long-access escalation, break-point escalation, or a stable short-access control training model. Investigating the lowest dose for which an animal will respond following exposure to different training histories will provide novel information pertaining to the motivational aspects of cocaine self-administration in these models. The neurobiological adaptations underlying changes in the reinforcing efficacy of cocaine in either the breakpoint or the long-access escalation model remains unknown. Fast-scan cyclic volumetric allows for the high-temporal detection of extremely low levels of dopamine, which is a neurochemical that is well-accepted to be involved in the acute reinforcing effects of cocaine. Our laboratory has reported that high consumption self-administration training can result in an increased rate of dopamine reuptake at the dopamine transporter in response to cocaine. The current application further proposes to use fast scan cyclic voltammetry in order to investigate changes that may occur in dopamine reuptake in the unique models of cocaine addiction in vivo. Cocaine is one of the most addictive and highly abused drugs in the United States. Characterizing animal models can help in our neurobiological understanding of cocaine addiction, and will enable a better investigation of potential treatments for cocaine addicts. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant: Adolescent marijuana-use is a prominent health concern that may confer increased susceptibility to psychosis and addiction in vulnerable individuals. We, and others, have characterized an animal model of the co-morbid development of psychosis and addiction. Here, I will test whether adolescent marijuana exposure exacerbates behavior and neurobiological adaptations occurring in this unique animal model. Two symptoms are of interest, deficits in sensorimotor gating and reward learning. I will test for deficits in sensorimotor gating using prepulse inhibition of the acoustic startle response;I will test for deficits in reward learning by measuring changes in response-latency across trials in previously described conditioned reward learning task. Both of these behaviors are known to involve subsecond dopamine signaling. Using a cutting edge neurochemical technique called fast-scan cyclic voltammetry, I will measure whether adolescent marijuana exposure changes subsecond dopamine release evoked by either acoustic-stimuli or conditioned stimuli during performance in these behavioral tasks. Our ability to detect precise changes in dopamine release accompanying the expression of psychotic symptoms will provide novel information concerning the neurobiological mechanisms through which adolescent marijuana exposure might confer increased vulnerability to psychosis and addiction. PUBLIC HEALTH RELEVANCE: According to the NIDA-funded 2008 Monitoring the Future Study, 24% of 10th graders and 32.4% of 12th graders abuse marijuana each year. This is alarming due to a growing literature suggesting that adolescent marijuana exposure may confer increased risk for psychosis and addiction. The proposed study will provide new information concerning the neural mechanisms through which adolescent marijuana exposure may increase the risk for psychosis and addiction. This information will facilitate the development of future pharmacotherapies designed to treat symptoms of these conditions.

? DESCRIPTION (provided by applicant): Of the 3 million people who used an illicit drug in 2010, 17.3% reported the non-medical use of pain relievers (2010 NSDUH); an alarming statistic, as nonmedical opioid abusers show a high prevalence to develop dependence (2 million in 2010), explore alternative routes of drug administration (e.g., intravenous), and seek out potentially dangerous opiate sources on the street. During a hallmark feature of opiate dependence, withdrawal, environmental stimuli become associated with a drug-induced negative emotional state and develop the power to modify natural reward seeking. The aims of this project are to elucidate how the opiate dependent brain computes behaviorally relevant stimuli during conditioned withdrawal and to identify pharmacotherapeutic approaches that alleviate these maladaptations. Previous studies indicate that the mesolimbic dopamine pathway is generally depressed during opiate withdrawal and systemically increasing endocannabinoids-known neuromodulators of mesolimbic function-reduce overt withdrawal symptomatology. However, it remains unknown how dopamine neurons represent transiently present withdrawal associated stimuli that are capable of suppressing reward seeking and how endocannabinoids improve withdrawal symptoms. Here we will monitor near real-time dopamine release events during conditioned withdrawal induced suppression of food seeking and further assess the potentially therapeutic effects of increasing distinct endocannabinoids within the mesolimbic pathway. The innovative nature of the experiments proposed herein will allow us to achieve an unprecedented analysis of mesolimbic pathway neuromodulation during conditioned opiate withdrawal. Combining a cutting-edge electrochemical technique-fast-scan cyclic voltammetry, drug microinfusions and operant behavior will allow, for the first time, a near real-time assessment of how dopamine computes environmental stimuli during conditioned withdrawal and whether endocannabinoids rectify suppressed mesolimbic function in opiate dependence. These results will elucidate a potentially interactive role of endocannabinoids and mesolimbic dopamine in conditioned withdrawal that may lead to the development novel pharmacotherapies to prevent relapse in opiate addicts.