Thesis--Auburn University, 2009. / Abstract. Vita. Includes bibliographical references.

Animal models have previously been used to study tolerance and sensitization using two different procedures that are difficult to compare. Tolerance has been studied by administering a drug to a subject that is engaged in an operant behavior, and sensitization by administering a drug to a subject that is not engaged in an operant behavior. Previous research has shown that sensitization can occur when d-amphetamine is administered to rats emitting an operant behavior for a food presentation. The first goal of the experiment was to show operant sensitization using dose response curves. The second goal of the present experiment was to determine if operant sensitization is context specific. These goals were addressed by administering d-amphetamine to rats engaged in an operant behavior in two stimulus contexts and creating dose-response curves. Sensitization occurred but was not found to be context-specific, with the dose-response curves not being significantly different between the two contexts. It is not clear whether this result was due to the drug administration procedure or the counterbalancing assignments used. Further research is needed to determine whether operant sensitization is context specific.

Yes / Background: Asenapine is a new pharmacological agent for the acute treatment of schizophrenia and bipolar disorder. It has relatively higher affinity for serotonergic and α2-adrenergic than dopaminergic D2 receptors. We evaluated the effects of asenapine, risperidone, and olanzapine on acute and subchronic psychotomimetic-induced disruption of cued reversal learning in rats. Methods: After operant training, rats were treated acutely with D-amphetamine (0.75 mg/kg intraperitoneally [i.p.]) or phencyclidine (PCP; 1.5 mg/kg i.p.) or sub-chronically with PCP (2 mg/kg i.p. for 7 days). We assessed the effects of acute coadministration of asenapine, risperidone, or olanzapine on acute D-amphetamine– and PCP-induced deficits and the effects of long-term coadministration of these agents (for 28 additional days) on the deficits induced by subchronic PCP. Results: Deficits in reversal learning induced by acute D-amphetamine were attenuated by risperidone (0.2 mg/kg i.p.). Acute PCP-induced impairment of reversal learning was attenuated by acute asenapine (0.025 mg/kg subcutaneously [s.c.]), risperidone (0.2 mg/kg i.p.), and olanzapine (1.0 mg/kg i.p.). Subchronic PCP administration induced an enduring deficit that was attenuated by acute asenapine (0.075 mg/kg s.c.) and by olanzapine (1.5 mg/kg i.p.). Asenapine (0.075 mg/kg s.c.), risperidone (0.2 mg/kg i.p.), and olanzapine (1.0 mg/kg i.p.) all showed sustained efficacy with chronic (29 d) treatment to improve subchronic PCP-induced impairments. Conclusion: These data suggest that asenapine may have beneficial effects in the treatment of cognitive symptoms in schizophrenia. However, this remains to be validated by further clinical evaluation. / This research was supported by Schering-Plough Corporation, now Merck & Co., Inc. and Pfizer Inc.

Psychomotor stimulant abuse is a significant public health problem. While many individuals experiment with stimulants, there is marked variability in individuals' behavioral and subjective response to these drugs and these differences may be associated with their risk for abuse. One characteristic shown to be associated with drug abuse is sensation seeking, defined as the seeking of novel sensations and experiences and the willingness to take risks for the sake of such experiences. While observational studies have shown that individuals with elevated sensation seeking are more likely to report stimulant use and abuse, less clear is whether subjective and behavioral response to acute stimulant administration may vary as a function of sensation seeking status. We recently completed an outpatient laboratory study in which 37 healthy adults received repeated opportunities to sample and choose between d-amphetamine (d-AMPH; 5, 10, 20 mg/70kg) or placebo. That study provided an opportunity to examine associations between sensation seeking and d-AMPH choice and subjective response under rigorous double-blind experimental conditions. The Zuckerman Sensation Seeking Scale V was administered at intake, providing a Total sensation seeking score as well as four subscales (i.e., Experience Seeking, Disinhibition, Thrill and Adventure Seeking, Boredom Susceptibility). We hypothesized that elevated sensation seeking at intake would be associated with increased preference for d-AMPH over placebo in subsequent choice sessions, as well as greater positive d-AMPH subjective effects. Among males, increased baseline sensation seeking was associated with increased d-AMPH choice and positive subjective effects at the 5 and 10 mg/70 kg doses. Among females we found no significant associations between sensation seeking and d-AMPH choice or subjective effects. Finally, when the association between sensation seeking and other baseline characteristics was examined, there was a significant positive association with lifetime drug use as well as impulsivity. Taken together, our data suggest that elevated sensation seeking in males may be associated with increased sensitivity to d-AMPH reinforcement and positive subjective effects, suggesting increased vulnerability for stimulant use and abuse.

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.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Hoodia gordonii à uma planta da famÃlia das apocinÃceas. OriginÃria do sudeste da Ãfrica, onde tem sido historicamente usada para suprimir o apetite durante longas jornadas de caÃa, sendo utilizada em diversos paÃses com o objetivo de emagrecer. No Brasil foi retirada do mercado devido à falta de estudos que comprovem sua eficÃcia e seguranÃa para o uso. O objetivo deste trabalho foi avaliar as alteraÃÃes comportamentais, neuroquÃmicas e glicolipÃdicas em ratos tratados com Hoodia gordonii. Para a realizaÃÃo deste estudo H. gordonii foi administrada por via oral nas doses de 25 e 50 mg/Kg durante oito dias consecutivos em ratos Wistar machos (160-200g), D-anfetamina 2 mg/Kg foi administrada intraperitonealmente de forma aguda e usada como padrÃo positivo. Os testes aconteceram 60 minutos apÃs o ultimo dia de tratamento com a Hoodia e 30 minutos apÃs o tratamento com D-anfetamina. Foram avaliados a variaÃÃo de peso dos animais durante o tratamento, bem como o consumo de Ãgua e comida. Para os testes comportamentais foram feitos os testes de labirinto em cruz elevado, campo aberto e placa perfurada. Para os estudos neuroquÃmicos foi feito HPLC com detecÃÃo eletroquÃmica. Para os testes glicolipÃdicos foi feita dosagem de Glicose, HDL, LDL, TG, colesterol total, ALT e AST. Os resultados mostraram que H. gordonii à capaz de reduzir o ganho de massa corpÃrea, bem como reduzir o consumo de comida e Ãgua. Os resultados dos testes comportamentais mostraram que ela à capaz de reduzir os parÃmetros observados no teste do labirinto em cruz e placa perfurada sem mostrar alteraÃÃo significante no campo aberto. Os resultados dos experimentos neuroquÃmicos evidenciaram um aumento do conteÃdo de noradrenalina e dopamina em corpo estriado de ratos, detectados eletroquimicamente pelo HPLC. Nos testes bioquÃmicos foi visto que ela tem a capacidade de reduzir os nÃveis de glicose, bem como a concentraÃÃo de triglicerÃdeos e colesterol total em soro de ratos, sem mostrar alteraÃÃo significante da ALT e AST. Foi possÃvel concluir que H. gordonii à capaz de reduzir a ingestÃo de alimentos e que este efeito pode estar de alguma forma ligado à neurotransmissÃo noradrenÃrgica e dopaminÃrgica, possuindo tambÃm atividade ansiogÃnica evidenciada pelos estudos comportamentais. / Hoodia gordonii is a plant of the family apocinaceae. Originally from southeastern Africa, where it has historically been used to suppress appetite during long hunting trips, being used in several countries in order to lose weight. In Brazil was withdrawn from the market due to lack of studies proving its efficacy and safety for use. The aim of this study was to evaluate the behavioral changes and neurochemical glicolipÃdicas in rats treated with Hoodia gordonii. For this study H. gordonii was administered orally at doses of 25 and 50 mg/kg for eight consecutive days in male Wistar rats (160-200g), D-amphetamine 2 mg/kg was intraperitoneally administered acutely and used as a positive standard. The tests took place 60 minutes after the last day of treatment with the Hoodia and 30 minutes after treatment with D-amphetamine. We evaluated the weight change of the animals during treatment, as well as the consumption of water and food. For behavioral tests were performed tests elevated plus-maze, open field and hole board. For neurochemical studies was done HPLC with electrochemical detection. For testing was done glycolipid glucose, HDL, LDL and TG, total cholesterol, ALT and AST. The results showed that H. gordonii is capable of reducing body mass gain and reduce the consumption of food and water. The results of behavioral tests showed that it is able to reduce the parameters observed in the plus-maze test and hole board showing no significant change in the open field. The results of experiments showed an increase in the neurochemical content of noradrenaline and dopamine in the striatum of rats electrochemically detected by HPLC. In biochemical tests it was seen that it has the ability to lower blood glucose levels as well as the concentration of triglycerides and total cholesterol in serum from mice, showing no significant change in ALT and AST. It was concluded that H. gordonii is able to reduce food intake, and this effect may be somehow linked to the dopaminergic and noradrenergic neurotransmission, having also anxiogenic activity evidenced by behavioral studies.

Progressive-ratio schedules are useful for studying the reinforcing effects of drugs. Earlier human laboratory studies showed that d-amphetamine significantly increased break points relative to placebo. However, the magnitude of the increase was modest, which may be attributable to rather high levels of placebo responding. We used novel response requirements in a modified progressive-ratio procedure and hypothesized that the altered range of response requirements would decrease responding for placebo and increase responding for d-amphetamine. Eight participants completed the study. The participants first sampled oral doses of d-amphetamine (0, 8, 16, and 24mg). In subsequent sessions, the participants were offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure with response requirements ranging from 400 to 1800 mouse clicks. A battery of participant-rated drug-effect questionnaires, a performance measure, and cardiovascular measures were included to more fully characterize the effects of d-amphetamine. Placebo maintained low levels of responding. The intermediate dose of d-amphetamine increased responding significantly above placebo levels. d-Amphetamine produced prototypical subject-rated effects that were an orderly function of dose. These data suggest that the modified response requirements resulted in lower levels of placebo taking and a larger separation between the number of placebo and d-amphetamine capsules earned. Behavioural Pharmacology.

Although sensation-seeking status is associated with age of initiation and amount of drug use among adolescents, and sensitivity to the behavioral and reinforcing effects of drugs among young adults, it is unclear whether sensation-seeking status among adolescents is predictive of sensitivity to the pharmacological effects of drugs (i.e. abuse potential) as adults. This study examined the acute behavioral effects of oral diazepam and d-amphetamine in young adults, ages 18-21 years, who had consistently scored in the highest or lowest third of their grade-based cohort on a modified Sensation Seeking Scale that was completed annually between ages 10 and 14 years. Healthy participants completed 16 7.5-h test days, with test days separated by a minimum of 48 h. Each day, assessments consisting of computer task performance, verbal report of drug effects, and cardiovascular measures were completed 0, 50, 110, 170, 230, and 290 min after drug administration. Placebo and three active doses of diazepam and d-amphetamine (2.5, 5.0 and 10.0 mg/70 kg) were tested under double-blind conditions according to a randomized-block design. Typical stimulant and sedative effects were obtained with d-amphetamine and diazepam, respectively. Drug effects varied as a function of sensation-seeking status, with magnitude of effects on cardiovascular function, task performance, and report of positive drug effects being greater among high sensation seekers, and report of negative drug effects being greater among low sensation seekers. Adolescents who report high levels of sensation seeking on a consistent basis are more sensitive to pharmacological effects of stimulant and sedative drugs that are associated with abuse potential as young adults.

To determine whether behavioral sensitization produced by prolonged D-amphetamine administration affects susceptibility of nigrostriatal dopaminergic neurons to the neurotoxic actions of 6-hydroxydopamine (6-OHDA), rats were treated daily from the 23 rd day after birth for 11 consecutive days with D-amphetamine (1.0 mg/kg s.c.) or saline. On the last day of treatment, one group primed with D-amphetamine and one control group of rats were tested to confirm behavioral sensitization development. The remaining animals were additionally treated on the 34 th day (one day after the last D-amphetamine injection) with 6-OHDA HBr (300 μg in 10 μl i.c.v., salt form, half in each lateral ventricle) or its vehicle. Four weeks later the levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-metoxytyramine (3-MT), as well as 5-hydroxytrypatmine (5-HT) and its metabolite 5-hydroxyindoleacteic acid (5-HIAA) were assayed in the striatum, by HPLC/ED. In rats with behavioral sensitization, 6-OHDA reduced endogenous dopamine and its metabolites content to a comparable degree in comparison to controls. This finding indicates that presumed up-regulation of the dopamine transporter in the behaviorially sensitized rats did not increase the neurotoxicity of a high dose of 6-OHDA.

No / Rationale Phencyclidine (PCP), a glutamate/N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to induce a range of symptoms similar to those of patients with schizophrenia, while d-amphetamine induces predominantly positive symptoms. Previous studies in our laboratory have shown that PCP can selectively impair the performance of an operant reversal-learning task in the rat. Furthermore, we found that the novel antipsychotic ziprasidone, but not the classical antipsychotic haloperidol, could prevent the PCP-induced deficit. Objectives The aim of the present study was to validate the model further using the atypical antipsychotic clozapine and then to investigate the effects of lamotrigine, a broad-spectrum anticonvulsant that is known to reduce glutamate release in vitro and is able to prevent ketamine-induced psychotic symptoms in healthy human volunteers. A further aim was to compare effects of PCP and d-amphetamine in the test and investigate the effects of the typical antipsychotic haloperidol against the latter. Methods Female hooded-Lister rats were food deprived and trained to respond for food in a reversal-learning paradigm. Results PCP at 1.5 mg/kg and 2.0 mg/kg and d-amphetamine at 0.5 mg/kg significantly and selectively impaired performance in the reversal phase of the task. The cognitive deficit induced by 1.5 mg/kg PCP was attenuated by prior administration of lamotrigine (20 mg/kg and 30 mg/kg) or clozapine (5 mg/kg), but not haloperidol (0.05 mg/kg). In direct contrast, haloperidol (0.05 mg/kg), but not lamotrigine (25 mg/kg) or clozapine (5 mg/kg), prevented a similar cognitive impairment produced by d-amphetamine (0.5 mg/kg). Conclusions Our findings provide further data to support the use of PCP-induced disruption of reversal learning in rodents to investigate novel antipsychotic drugs. The results also provide evidence for different mechanisms of PCP and d-amphetamine-induced disruption of performance in the test, and their different sensitivities to typical and atypical antipsychotic drugs.