Browsing by Subject "cocaine"
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Item ANTIOXIDANT COMPOUNDS INHIBIT COCAINE-CONDITIONED LOCOMOTION(2013-04-12) Nguyen, JacquesPurpose: Cocaine, a potent psychostimulant, produces various neuroadaptations that further contribute to its overall abuse. Although there currently are no known pharmacological treatments for cocaine addiction, N-acetylcysteine, a thiol-containing antioxidant, has been shown to prevent relapse in animal models of cocaine-addiction and to effect drug reward value following psychostimulant toxicity. This study evaluates the mechanisms that underlie this compound's ability to affect cocaine-conditioned locomotion and compares its efficacy to other potential intervention(s) for cocaine-induced effects. Methods: Cocaine (40mg/kg) and 0.9% saline were administered to Swiss-Webster mice via intraperitoneal injection (i.p.), in either the testing apparatus or the home cage, separated by a 2-hour time interval. When the animals were placed into the testing chambers, they were given 30 minutes to explore freely and spontaneous locomotion was monitored using Digiscan animal tracking software. On the following day, N-acetylcysteine (25, 50, 100 mg/kg), dimethylthiourea (5, 10, 25, 50 mg/kg), or vehicle control were administered prior to placement into the activity chambers. Cocaine conditioned effect was inferred by a change in horizontal activity counts, respective to controls. Results: N-acetylcysteine (100mg/kg) and dimethylthiourea (25 and 50mg/kg) successfully inhibited cocaine-conditioned locomotion. Conclusions: N-acetylcysteine and dimethylthiourea's common ability to inhibit the cocaine-conditioned locomotion suggests that pro-oxidating cellular redox state may underlie acute neuroadaptations that occur during cocaine exposure. Understanding the nature of cocaine-conditioned effects, using various pharmacological interventions, may further provide insight into the molecular mechanisms underlying these drug-induced behaviors.Item CHARACTERIZATION OF COCAINE-CONDITIONED LOCOMOTOR RESPONSES BY MODULATION OF ENVIRONMENTAL CONTEXT AND NEURAL PLASTICITY-SIGNALING PATHWAYS(2014-03) Nguyen, Jacques D.; Forster, Michael J.Rodent models are commonly used for the study of substance abuse and addiction. The objective of this study was to characterize the cocaine-conditioned locomotor response, a behavioral phenomenon observed in mice, following an acute injection of cocaine, and to determine its mechanism of action for potential therapeutic targeting. Compounds known to modulate neural plasticity were evaluated for their ability to affect the acquisition and expression of the conditioned behavior. Purpose (a): In rodents, increase in locomotion is a hallmark effect of psychostimulant exposure and conditioning that is associated with activation of mesocorticolimbic dopamine signals mediating reinforcing/rewarding actions. The objective of this study was to characterize the cocaine-conditioned locomotor response following an acute injection of cocaine, specifically the modulating roles of environmental context and plasticity-associated signals. Methods (b): Cocaine (40mg/kg) was administered to different groups of Swiss-Webster, C57Bl/6, or DBA2 mice via intraperitoneal injection (i.p.), in either a locomotor activity testing apparatus or the home cage, 2 hours following an activity test under saline. Mice placed in the testing chambers were given 30 minutes to explore freely and locomotion was monitored using a Digiscan photocell apparatus. A conditioned effect of cocaine was inferred by an increase in horizontal activity counts relative to home cage cocaine controls during a test in the same apparatus on the following day. Compounds known to modulate neural plasticity-associated signaling cascades were evaluated for their ability to affect the acquisition and expression of cocaine-conditioned locomotor response, using a two-day protocol. Mice were administered haloperidol (0.05-1 mg/kg), dizocilpine (0.01-0.25mg/kg), nifedipine (0.1-10 mg/kg), cycloheximide (2.5-10mg/kg), or vehicle, prior to placement into the activity chambers on the test day for expression or prior to acquisition day. Results (c): Haloperidol (0.25-1 mg/kg) inhibited expression of the cocaine-conditioned locomotion, though failed to alter acquisition of the behavioral response. Dizocilpine (0.05-0.25 mg/kg) attenuated acquisition and exacerbated expression. Nifedipine had no effect on the conditioned locomotor response. Cycloheximide (2.5-10 mg/kg) attenuated acquisition of the conditioned response. Conclusions (d): These findings suggest that plasticity-dependent signaling pathways mediate associations of context following acute cocaine exposure and are necessary for the acquisition and expression of the cocaine-conditioned locomotor response.Item Sensitization to Cocaine: Behavioral and Genetic Characterization(1998-04-01) Odom, Linda Ann; Michael Forster; Glenn Dillon; Harbans LalOdom, Linda Ann, Sensitization to Cocaine: Behavioral and Genetic Characterization. Doctor of Philosophy (Pharmacology). April 1998, 141 pages, 2 tables, 23 figures, 89 references. Conditioned associations between environmental context and cocaine effects may play a significant role in acquisition and maintenance of cocaine dependence. Conditioning may also contribute significantly to cocaine sensitization, a leftward shift in the cocaine dose-response curve that is attributable to cocaine pre-exposure. Both studies examined the sensitization of cocaine’s behavioral effects after one or four prior exposures to cocaine in two distinct environments, allowing evaluation of the acquisition and magnitude of sensitization to cocaine and the contribution of conditioning to sensitization. An extinction component was added to the second study to allow determination of persistence of context-dependent sensitization in C57BL/6 and DBA/2 mice. The purpose of the first study was to fully characterize the quantity and quality of the sensitized behavioral response to cocaine in Swiss Webster mice and to determine parameters for sensitization in the second study. Results of this study indicated that pairing cocaine to the testing environment resulted in a leftward shift of the dose-response curves for both horizontal and stereotypy measures and a concurrent decrease in maximal effect of cocaine on horizontal distance and an increase in maximal effect of cocaine on horizontal distance and an increase in maximal effect of cocaine on stereotypy. The multivariate behavior profile indicated that the sensitized response to cocaine was best observed in response to 1 to 5 mg/kg cocaine, and that the conditioned response elicited by saline following cocaine pre-exposure closely resembled the 10 mg/kg acute cocaine response. The overall purpose of the second study was to determine if genetic differences in various aspects of such conditioned associations could contribute to individual differences in cocaine dependence. It was determined that, although DBA/2 mice had a faster rate of acquisition of context-dependent sensitization to cocaine than C57/BL6 mice, the multivariate behavior profile of the conditioned response of C57BL/6 mice resembled the behavior observed with a higher dose of acute cocaine and had greater magnitude and greater persistence than that of DBA/2 mice, which may explain in part the susceptibility of the C57BL/6 mice to cocaine dependence.Item The Influence of CNS stimulants, opioid antagonists and an NMDA antagonist on the reinforcing effect of cocaine using a progressive-ratio schedule(1996-07-01) Li, Donghang; Forster, Michael J.; Martin, Michael; Luedtke, Robert R.It has been hypothesized that there is a common dopaminergic pathway mediating the reward properties of abused drugs, and that dopamine is involved in tolerance to the reinforcing effect of cocaine. The progressive-ratio (PR) schedule can be used to test both potentiation and reduction of the reinforcing effects of cocaine by other factors. Under the PR schedule, an increasing number of responses is required to obtain each subsequent cocaine injection, and failure to complete the required number of responses within 1 h of the previous cocaine injection terminates the session. The number of total reinforcers obtained during a session is defined as “the breaking point” and was used as the primary dependent measure. Fisher F344 male rats acquired the self-administration task under the PR schedule within forty sessions and showed a stable daily acquisition baseline. The breaking point and inter-reinforcer time (ISRT) were positively correlated within each ratio. A motor-incapacitating side effect of a pretreatment can be determined by a change in the relationship between the ISRT and the breaking point. d-Amphetamine pretreatment (0.32-3.2 mg/kg, i.p., 30 min) potentiates the reinforcing effect of cocaine as demonstrated by a higher breaking point of self-administration without changing the ISRT. Morphine pretreatment (0.32-3.2 mg/kg, i.p., 30 min failed to change the breaking point of cocaine self-administration but it did increase the ISRT. These results support an additive reinforcing effect for amphetamines and cocaine, but do not support an additive reinforcing effect of morphine and cocaine. The reinforcing effect of cocaine was reduced by pretreatment with ketamine (0.032-0.32 mg/kg, i.p., 20 min) as indicated by a reduction in the breaking point. In a concurrent experiment, animals were trained to self-administer cocaine under a fixed ratio 2 schedule (FR2). Ketamine pretreatment did not modify the ISRT in FR2 trained animals except at the highest dose (0.32 mg/kg, i.p., 20 min), where significant motor incoordination was observed. Both chronic treatment with cocaine (20 mg/kg/ 8hr x 7 days, iv) or amphetamine (3.2 mg/kg /12 hr x 7 days, i.p.) resulted in a reduction in breaking point at any given dose, providing direct evidence of tolerance and cross-tolerance to the reinforcing effects of cocaine. Chronic treatment with ketamine (0.32 mg/kg/8hr x 7 days, i.v.) failed to modify either the breaking point under a PR schedule of reinforcement or the ISRT under a FR2 schedule of reinforcement. Co-administration of ketamine (0.32 mg/kg/8hr x 7 days, i.v.) with chronic cocaine (20 mg/kg/8hr x 7days, i.v.) failed to prevent tolerance to the reinforcing effect of cocaine as indicated by either the breaking point under a PR schedule of reinforcement of the ISRT under an FR2 schedule of reinforcement. These data indicate that the breaking point in the PR schedule is more sensitive to changes in the dopamine reward system, whereas changes in rate of response are not consistently related to the changes in the dopamine reward system. These data support the use of PR schedule as a better method than FR schedule for determining reward properties of drugs of abuse with fewer complications due to the central nervous system inhibitory effects of some drugs of abuse.Item The Interaction of Psychostimulant Intake With Brain Aging: Effects On Behavioral Capacity, Oxidative Damage and Dopaminergic Markers(2009-05-01) Hilburn, Craig R.; Forster, Michael J.Frequent abuse of psychostimulants is known to induce changes in brain neurochemistry that are most profound in dopaminergic neurons. These changes could both impair dopamine neurotransmission and adversely affect psychomotor and cognitive functions. One hypothesized cause of these impairments is the adverse effects of psychostimulant-induced increases in oxidative stress. The current studies addressed the general hypothesis that chronic administration of cocaine and methamphetamine would create a change in neurochemistry in dopaminergic neurons and, as a consequence, increase oxidative damage. This would result in decreases in dopaminergic functions specifically in the nigrostriatal region and cause impairments in psychomotor functions. To test this hypothesis we utilized an in vivo rodent model involving continuous chronic administration of cocaine or methamphetamine. Separate groups of mice were exposed to a 30-day treatment, involving continuous infusion of saline, 40 mg/kg of cocaine, or 2 mg/kg of methamphetamine. After discontinuation of the drug treatment, separate groups of the mice were tested for cognitive and psychomotor function at 11, 14, or 16 months of age i.e., 1 week, 3 months, or 5 months after treatment. The test used in this study included spatial learning and memory (swim maze), coordinated running ability (accelerating rotorod), muscle and grip strength (wire suspension) and balance and coordination (bridge walking). Following completion of the behavioral tests brain regions were dissected. The regions we analyzed were the cortex, striatum, cerebellum, hippocampus, midbrain, and hindbrain. These regions were analyzed for carbonyl and thiobarbituric acid reactive substances concentrations to measure levels of protein and lipid oxidation, and Western blotting procedures to address dopaminergic protein expression. Overall, both chronic administration of cocaine and methamphetamine resulted in significant impairments to psychomotor functions. These impairments were evident for both groups on wire hanging tests, bridge walking, and rotating rod tests, both initially following the treatment phase and throughout the age ranges that were analyzed. In addition, the cocaine treatment administered led to profound impairments on cognitive function in the 14-month-old age groups. This impairment was most evident on the reversal phase of the spatial swim maze tests. The biochemical tests revealed that chronic cocaine and methamphetamine administration induced significant increases in protein oxidative damage in the striatum initially following the treatment phase. Psychostimulant-induced lipid oxidative damage was evident in the striatum in both the 14 and 16 month old age groups. Age related declines were evident in the midbrain, cortex and striatum. Overall neither treatment had any effect on the expression of the dopaminergic proteins that were analyzed. The results from these studies warrant the conclusion that chronic cocaine and methamphetamine administration causes an increase in intracellular oxidative damage in the nigrostriatal neurons which decrease dopamine-mediated psychomotor functions. Overall there was not enough evidence to conclude that chronic abuse of these drugs induce impairments that would increase during senescence.