This investigation was an analysis of the effects of methylphenidate (MPH; trade name: Ritalin) on drug reward using the conditioned place preference (CPP) behavioral paradigm in a rodent model and underlying mechanisms of this effect. Animals were conditioned in adolescence from postnatal day (P)33-39) or P44-49 with saline, 1 or 5 mg/kg MPH. Rats administered 5 mg/kg but not 1 mg/kg MPH, resulted in a significant preference that was more robust in younger male adolescent rats. The 5 mg/kg dose of MPH also resulted in a significant decrease of the dopamine transporter in both the nucleus accumbens and striatum, revealing dopamine clearance is decreased by MPH in brain areas that mediate reward. Finally, MPH-induced CPP was blocked by the dopamine D1 but not D2 antagonist, demonstrating the importance of the D1 receptor in the rewarding effects of MPH. These results demonstrate that dopamine mediates the rewarding effects of MPH in adolescence.

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Recent clinical and preclinical reports have identified traumatic brain injury (TBI) as an important risk factor affecting the development of substance use disorders (SUDs). Notably, these studies show that factors like age at the time of injury and TBI severity may increase the risk of substance abuse behavior post-TBI. Furthermore, radiological assessments in clinical TBI populations have observed neuropathology in select brain regions that form key neurocircuits that mediate drug reward and drug-seeking behavior. Therefore, the effects of TBI on the function of these brain structures may influence the risk of substance abuse behavior following brain injury. In order to test the effect of experimental TBI on substance abuse behavior, we utilized two premiere preclinical models: 1) the controlled cortical impact (CCI) model of experimental TBI and 2) a biased, three-phase, cocaine conditioned place preference (CPP) assay. Furthermore, we characterized the effect of experimental TBI on / Pathology

The amphetamine derivative, 3,4-methylenedioxymethamphetamine (MDMA), is a popular drug often taken by young adults at dance clubs or rave parties. Laser light shows, fast-paced electronic music, and hot crowded dance floors are characteristic of these events, and Ecstasy users report that the acute effects of the drug are potentiated by these stimulatory conditions. However, it remains largely unknown how environmental stimuli impact the neurochemical and physiological effects of MDMA. The aim of the first study presented in this dissertation was to investigate how auditory stimuli (music, white noise, and no additional sound) influence MDMA conditioned place preference (CPP), self-administration, and nucleus accumbens (NAcc) dopamine (DA) and serotonin (5-HT) responses. Findings revealed a significant CPP for animals exposed to white noise during MDMA conditioning trials. After self-administration of MDMA (1.5 mg/kg), NAcc DA and 5-HT were highest in rats exposed to music during the test session. The second study aimed to investigate the effects of ambient temperature (23°or 32°C) on long-term MDMA self-administration and neurochemical responses. Results indicated no difference in self-administration or locomotor activity rates for the high versus room temperature groups across sessions. However, MDMA (3.0 mg/kg) administered in high ambient temperature resulted in significantly greater NAcc serotonin release compared to when taken at room temperature, but no differences in dopamine response was determined between the two conditions. Overall, these results indicate that auditory and thermal stimuli can effect MDMA-induced behavioral and neurochemical responses. The last aim tested a novel apparatus and method for use in animal models of drug reinforcement. By combining traditional CPP and self-administration procedures, this approach provided more informative data and circumvented some inherent drawbacks of each method alone. In addition to confirming the ability to produce drug conditioned place preferences after short- and long-term experiments, the long-term version of the procedure revealed a significant positive relationship between lever response rate and CPP magnitude. Therefore, this experimental design can be used to identify subgroups of rats that may vary in sensitivity to drug motivational effects. Further study of these populations may be useful in the development of behavioral and pharmacological therapies for drug addiction. / text

Este estudo visa o desenvolvimento de microemulsões que, após captação de água do tecido subcutâneo, transformar-se-ão em gel nanoestruturado de fase hexagonal para liberação sustentada de naltrexona e tratamento do alcoolismo. A microemulsão selecionada, composta por monooleína, tricaprilina, propilenoglicol e água (ME-MO) resultou na liberação in vitro de 31 % de naltrexona em 96 h. Após sua administração subcutânea, foi observada formação do gel em 48 h, o qual persistiu por mais de 30 dias in vivo, promovendo liberação prolongada do marcador fluorescente Alexa flúor. A eficácia da formulação foi avaliada em modelo de preferência condicionada por lugar induzida por etanol; ME-MO com 5 e 10% de naltrexona foi comparada à solução de naltrexona diária. Não observou-se diferença significativa entre a solução de naltrexona e ME-MO 5%, enquanto que ME-MO 10% diferiu destas, e antagonizou a preferência condicionada por lugar. Esses resultados demonstram o potencial de ME-MO como uma plataforma para liberação prolongada de fármacos no tratamento de dependência química. / This study focuses on the development of microemulsions that after in vivo water uptake of the subcutaneous tissue will turn into liquid-crystalline gels for sustained release of naltrexone, used in the treatment of alcoholism. Three microemulsions based on monoolein and tricapryline (ME-MO), vitamin E TPGS and propylene glycol, TPGS and Span were selected. The latter resulted is faster drug release (65% in 96 h). Based on the ability of the gel formed to withstand dilution, ME-MO was selected for in vivo studies. After subcutaneous administration, hexagonal phase formation was observed in 48 h and its persistence for more than 30 days in those animals. The efficacy of the formulation was assessed using conditioned preference place model. The animals were divided into four groups: Saline (control); Naltrexone solution (1 mg / kg) daily for 8 days (30 min before ethanol administration), and ME-MO with 5% or 10% naltrexone (single administration). The results suggest that ME-MO 10% antagonized the preference induced by ethanol.

This investigation was an analysis of the interaction of adolescent exposure to methylphenidate (MPH; trade name: Ritalin) on nicotine sensitization and conditioned place preference (CPP) in a rodent model and underlying mechanisms of this effect. Animals were treated IP with 1 mg/kg MPH or saline using a ―school day‖ regimen of five days on, two days off, from postnatal day (P) 28-50. During the final two weeks of MPH treatment, animals were either behaviorally sensitized to nicotine (0.5 mg/kg free base) or saline for 10 days, or conditioned to nicotine or saline using the CPP behavioral paradigm. In addition, three days after behavioral sensitization was complete, animals were analyzed for stress behavior using the forced swim stress behavioral test. In addition, 24 hours after post-test conditioning animals were analyzed for the effect of a clinically relevant dose of pre-exposed MPH (1mg/kg) and nicotine treatment on the expression of BDNF in the nucleus accumbens and dorsal hippocampus. Behavioral results revealed that adolescent pre-exposure to MPH blunted nicotine behavioral sensitization in both male and female rats during the first week of testing. However, MPH enhanced nicotine CPP in both adolescent male and female rats. Interesting, animals administered MPH demonstrated a significantly decreased latency to immobility in the forced swim stress behavioral test. In addition, pre-exposure to a 1 mg/kg dose of MPH appears to have sensitized the BDNF response to nicotine in females as compared to all other groups.

Multiple interactions between dopamine (DA), glutamate, and nitric oxide (NO) in mesolimbic and corticostriatal circuits suggest that NO may play a critical role in cocaine-induced behavioral and neural plasticity. Clinical and preclinical studies have revealed that females and adolescents display unique vulnerabilities to the behavioral and neurochemical effects of cocaine as a result of sex-dependent and ontogeny-dependent differences in dopaminergic systems. Thus, my research objectives were to investigate the contributions of the neuronal nitric oxide synthase (nNOS) gene, ontogeny, and gender on the rewarding and sensitizing effects of cocaine. I found that nNOS significantly influences the rewarding aspects of cocaine in adolescent mice and adult male mice (i.e., major deficits in several phases of cocaine conditioned place preference (CPP) were detected in nNOS knockout (KO) adolescent mice and nNOS KO adult male mice). However, the contribution of nNOS was sex-dependent as CPP phases were normal in KO adult females. In contrast to CPP, I found a major ontogeny-dependent contribution of nNOS to the sensitizing effects of cocaine. Namely, while nNOS is essential for the development of behavioral sensitization in adult males, this type of behavioral plasticity develops independently of nNOS during adolescence. The contribution of nNOS was once again sex-dependent as behavioral sensitization was normal in adult KO females. Together, this line of investigation has revealed that the NO-signaling pathway has a) a sex-dependent role in the neuroplasticity underlying cocaine CPP and b) a sex-dependent and ontogeny-dependent influence on cocaine-induced behavioral sensitization. Stereological and western blot analysis revealed that a sensitizing regimen of cocaine resulted in an increase in nNOS and tyrosine hydroxylase (TH) immunoreactivity in the dorsal striatum (dST) of adult, but not adolescent, wild-type (WT) male mice. In the absence of nNOS, dopaminergic neurons in the ventral tegmental area (VTA) were severely reduced and cocaine caused a downregulation of dST TH suggesting that nitrergic levels modulate TH. Thus, the finding that nNOS is essential for the development of sensitization in adulthood, but not adolescence, together with the fact that cocaine upregulated nNOS and TH in the dST in adult, but not adolescent mice, strongly suggest that the nitrergic system underlies behavioral sensitization through modulation of the dopaminergic system in adulthood. These findings suggest different approaches in the clinical treatment of drug craving and drug-seeking behavior in adolescent and adult patients.

Benzodiazepines are widely abused by anxious individuals. Consequently, this thesis modeled anxiety in a mouse model in order to investigate benzodiazepine motivation within this sub-population. Using the Tube test of Social Dominance and the Resident/Intruder Paradigm I investigated whether animals identified as dominant or submissive/defeated would differentially display a preference for 0.25 mg/kg midazolam in a conditioned place preference paradigm. Consistent with my hypotheses, benzodiazepine preference was mediated by negative reinforcement as submissive but not dominant mice displayed a preference for midazolam. Furthermore, different neural systems mediated benzodiazepine preference dependent on the stress status of the animal (acute vs. chronic stress) such that, acutely stressed animals experienced benzodiazepine preference through a dopamine-independent pathway whereas chronically stressed animals experienced benzodiazepine preference through a dopamine-dependent pathway. Within chronically stressed mice, blockade of either D1 or D2 receptors attenuated benzodiazepine preference.

Benzodiazepines are widely abused by anxious individuals. Consequently, this thesis modeled anxiety in a mouse model in order to investigate benzodiazepine motivation within this sub-population. Using the Tube test of Social Dominance and the Resident/Intruder Paradigm I investigated whether animals identified as dominant or submissive/defeated would differentially display a preference for 0.25 mg/kg midazolam in a conditioned place preference paradigm. Consistent with my hypotheses, benzodiazepine preference was mediated by negative reinforcement as submissive but not dominant mice displayed a preference for midazolam. Furthermore, different neural systems mediated benzodiazepine preference dependent on the stress status of the animal (acute vs. chronic stress) such that, acutely stressed animals experienced benzodiazepine preference through a dopamine-independent pathway whereas chronically stressed animals experienced benzodiazepine preference through a dopamine-dependent pathway. Within chronically stressed mice, blockade of either D1 or D2 receptors attenuated benzodiazepine preference.

The attribution of incentive salience to cues that become associated with drugs of abuse is a critical characteristic of individuals who may be vulnerable to drug addiction. Rodents with the propensity to sign track are thought to be vulnerable to drug abuse. The goal of the current work was to investigate whether sign trackers (STs) would acquire cocaine conditioned place preference (CPP) to a discrete cue using an avian species. In Experiment 1, sign and goal trackers (GTs) were first identified using a one third rank order split. Following identification, cocaine-CPP was conducted with a discrete cue in each end chamber. Contrary to previous research, results showed that GTs showed a CPP to the discrete cue but STs did not. Experiment 2 was conducted to determine whether sign and GTs had been misclassified with the rank order split. Experiment 2 compared the rank order method with a t-test method (absolute criterion). Misclassification of both sign and GTs occurred using the rank order split. The findings indicated that use of a more accurate method to identify sign and GTs may have led to different results for Experiment 1. The t-test method may be useful for models that require identification of STs.