The development and persistence of cocaine dependence are greatly influenced by emotional affect and cocaine associative learning. Cocaine is known to enhance nucleus accumbens (NAcc) dopamine, serve as a positive reinforcer and produce negative effects, such as anxiety that may influence cocaine intake behavior. In the first study, I investigated the effects of the anxiolytic, diazepam on NAcc dopamine levels and cocaine self-administration behavior. These are two factors associated with cocaine rewarding effects. Diazepam has no effect on NAcc dopamine, but affects cocaine self-administration. This supports the notion that decreasing the anxiogenic effects of cocaine increases the rewarding value in a dopamine independent manner. Therefore, increasing the aversive effects of cocaine might be a novel approach to fight cocaine dependence. In the second study, I studied cocaine-induced associative learning and changes in affect during cocaine conditioning and extinction. 50-kHz ultrasonic vocalizations (USVs) in rats are thought to reflect positive affect and occur upon appetitive stimuli and with cocaine delivery. First, I explored whether USVs might be elicited in anticipation of impending drug delivery. Shortly into conditioning, rats elicited USVs when placed in the cocaine-associated environment. USVs progressively increased, indicating a growing learned association between cocaine intake and cocaine-associated cues. This suggests that USVs may be a useful model for investigating cocaine craving and serve as a pharmacological target for interventions aimed to reduce cocaine craving and relapse. I then examined the effects of short-term deprivation of cocaine and cocaine cues on cocaine-conditioned USVs, which were both exaggerated after abstinence. The results may have clinical implications, in that intermittently avoiding cues or context may enhance drug cue salience and increase the probability of relapse. Motivational aspects of cocaine were assessed comparing commonly measured lever response rate and locomotion with cocaine-induced USVs during cocaine administration and extinction. In agreement with prevailing findings, lever responding for cocaine and cocaine-induced locomotor activity increased across conditioning sessions. However, the number of USVs evoked in response to cocaine infusion decreased with cocaine experience. These findings suggest growing tolerance to the rewarding properties of cocaine. These studies underscore the value of USV assessment during drug dependence studies. / text

Dopamine increases in the nucleus accumbens after contingent and noncontingent ethanol administration in rats, but the contributions of the core, coreshell border, and shell subregions to this response are unclear. Also, it is not fully understood if increases in dopamine under these circumstances are due to the pharmacological effects of ethanol, stimuli associated with administration, or both. The studies presented in this dissertation were conducted to investigate dopamine’s role in each of these accumbal regions during ethanol administration and presentation of associated stimuli. Using microdialysis, ethanol and dopamine concentrations in accumbal subregions were measured every five minutes before, during, and after either experimenter-delivered intravenous ethanol or operant ethanol self-administration. After intravenous ethanol infusions, the increase in dopamine in the shell of the accumbens was significantly higher than that observed in the core. During operant ethanol self-administration, the core, core-shell border, and shell, all exhibited significant increases in dopamine during transfer of the animal into the operant chamber, with animals trained to drink sucrose + ethanol showing significantly higher increases when compared to those trained to drink sucrose alone. Dopamine increased significantly only in the core-shell border during ethanol consumption, and dopamine levels in the core and shell responded in a similar manner during all phases of the experiment. Together, these results suggest that dopamine responses to intravenous ethanol infusions and operant ethanol self-administration are subregion specific. Also, while increases in dopamine resulting from intravenous ethanol infusions in naïve animals appear to be due to the pharmacological effects of the drug, increases in ethanol-experienced animals during transfer into the operant chamber, and during ethanol consumption, may also be due to stimuli associated with ethanol administration. / text

Mesolimbic dopamine plays an important role in ethanol reinforcement, and studies have shown that accumbal dopamine increases during operant ethanol self-administration. However, no one has ever studied this dopaminergic response during the acquisition of ethanol self-administration. Furthermore, some studies have shown that the dopamine signal does not correlate with the pharmacological effects of ethanol, but with the time during which the animal consumes the majority of the ethanol solution and when the sensory stimuli of ethanol are strongest. However, there is currently no direct evidence showing that the sensory stimuli of ethanol is indeed what causes the brief increase in accumbal dopamine during ethanol self-administration. The studies in this dissertation attempted to elucidate these issues. We designed and tested a placebo spout, which was to be used to study the relationship between accumbal dopamine and the sensory stimuli of ethanol during self-administration. Unfortunately, the placebo designs were either not feasible for performing microdialysis or did not show promising behavioral data. We also developed and tested a self-administration protocol in which the concentrations of ethanol (10%) were kept constant throughout the study. The new protocol was successful in initiating and maintaining ethanol self-administration, and the animals doubled their intake from day 1 to day 2 of ethanol consumption. Using this protocol, we trained male Long Evans rats to self-administer ethanol and measured accumbal dopamine during the first two days of ethanol self-administration through microdialysis. The behavioral and neurochemical data matched. A single exposure to ethanol was sufficient for the animals to double their ethanol consumption by day 2 and to cause an increase in accumbal dopamine during the first 5 minutes of ethanol self-administration. The dopamine response was observed during the time when the sensory stimuli of ethanol were strongest, but before ethanol reached peak concentrations in the brain. Overall, these results suggest that the dopamine response to ethanol self-administration may not be solely pharmacological and that a single exposure to ethanol is sufficient to learn the association between ethanol and its cues. These findings give us greater insight into mesolimbic dopamine's role in the early stages of ethanol reinforcement. / text

Introduction: Tobacco dependence is a chronic disorder that carries the risk of relapse at any time point during abstinence. It is a major health issue in the world and current pharmacotherapies have had limited efficacy. Therefore, development and validation of novel treatments are required. Objective: Investigate the novel neutral cannabinoid-1 receptor antagonist AM4113 on nicotine (main psychoactive ingredient in tobacco)-taking behaviour in animals. Methods: Using the nicotine intravenous- and food control- self administration paradigms, we tested the acute and chronic (10-days) effects of AM4113 on nicotine- and food-taking behaviour. Results: Acute AM4113 treatments (1-, 3-, 10-mg/kg) reduced nicotine self administration. Chronic AM4113 administration (10mg/kg) produced a sustained reduction of nicotine-taking behaviour during the course of the treatment. In the similar food control self administration experiments, AM4113 overall produced no effect. Conclusion: AM4113 can attenuate nicotine-taking behaviour and its effect is sustained under chronic treatment.

Introduction: Tobacco dependence is a chronic disorder that carries the risk of relapse at any time point during abstinence. It is a major health issue in the world and current pharmacotherapies have had limited efficacy. Therefore, development and validation of novel treatments are required. Objective: Investigate the novel neutral cannabinoid-1 receptor antagonist AM4113 on nicotine (main psychoactive ingredient in tobacco)-taking behaviour in animals. Methods: Using the nicotine intravenous- and food control- self administration paradigms, we tested the acute and chronic (10-days) effects of AM4113 on nicotine- and food-taking behaviour. Results: Acute AM4113 treatments (1-, 3-, 10-mg/kg) reduced nicotine self administration. Chronic AM4113 administration (10mg/kg) produced a sustained reduction of nicotine-taking behaviour during the course of the treatment. In the similar food control self administration experiments, AM4113 overall produced no effect. Conclusion: AM4113 can attenuate nicotine-taking behaviour and its effect is sustained under chronic treatment.

Propofol is a widely in use anesthetic drug. Propofol’s abuse liability has been supported by many case reports and a few animal studies. However, propofol’s reinforcing properties have not yet been investigated in-depth. In this study, multiple aspects of propofol’s abuse-related behaviour were investigated using the drug self-administration model in rats. METHODS: Rats were subjected to propofol self-administration under a fixed ratio 1 (FR1) schedule and different aspects of propofol self-administration behaviour including acquisition, maintenance of the behaviour under a higher ratio schedule, extinction and reinstatement were investigated. RESULTS: Rats acquired propofol self-administration under a FR1 schedule. The acquired behaviour was maintained under a FR2 schedule, showed a modest variation over a range of doses, and was extinguished upon substitution of vehicle for propofol, showing no reinstatement using a range of priming doses of propofol. CONCLUSION: Propofol has abuse potential showing modest reinforcing properties under our experimental conditions.

Propofol is a widely in use anesthetic drug. Propofol’s abuse liability has been supported by many case reports and a few animal studies. However, propofol’s reinforcing properties have not yet been investigated in-depth. In this study, multiple aspects of propofol’s abuse-related behaviour were investigated using the drug self-administration model in rats. METHODS: Rats were subjected to propofol self-administration under a fixed ratio 1 (FR1) schedule and different aspects of propofol self-administration behaviour including acquisition, maintenance of the behaviour under a higher ratio schedule, extinction and reinstatement were investigated. RESULTS: Rats acquired propofol self-administration under a FR1 schedule. The acquired behaviour was maintained under a FR2 schedule, showed a modest variation over a range of doses, and was extinguished upon substitution of vehicle for propofol, showing no reinstatement using a range of priming doses of propofol. CONCLUSION: Propofol has abuse potential showing modest reinforcing properties under our experimental conditions.

Translational research suggests that agonist replacement may be a viable treatment approach for managing methamphetamine dependence. This study sought to determine the effects of d-amphetamine maintenance on methamphetamine self-administration in stimulant using participants. A cognitive battery was used to determine the performance effects of methamphetamine alone and during d-amphetamine maintenance. During each maintenance condition, participants first sampled a dose of intranasal methamphetamine then had the opportunity to respond on a progressive ratio task to earn portions of the sampled dose. Subject-rated drug-effect and physiological measures were completed prior to and after sampling methamphetamine. Methamphetamine was self-administered as function of dose regardless of the maintenance condition. Methamphetamine produced prototypical subject-rated effects, some of which were attenuated by d-amphetamine maintenance. Methamphetamine was well tolerated during d-amphetamine maintenance and no adverse events occurred. The self-administration results are concordant with those of clinical trials that show d-amphetamine did not reduce methamphetamine use. Generally, there was no difference in cognitive performance after methamphetamine administration during both placebo and d-amphetamine maintenance. Overall d-amphetamine does not appear to be a viable treatment for preventing methamphetamine relapse, but translational literature suggests that other agonist medications or the combination of pharmacotherapy and behavioral therapies may be effective.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.