It has been well established that the stress-related neurochemical systems corticotropin-releasing factor (CRF), noradrenaline (NA), and dopamine (DA) mediate stress-induced reinstatement of drug seeking. The three series of experiments presented in this dissertation constitute a further exploration of the role these neurochemical circuits play in reinstatement by providing the first direct exploration of whether central CRF and catecholamine (NA and DA) systems interact to influence reinstatement of cocaine seeking. The primary objective of the first series of experiments was to determine whether NA and CRF systems interact to mediate reinstatement of cocaine seeking and, if so, to determine the direction of this interaction. Results showed that central administration of NA induced reinstatement and up-regulated the expression of c-fos mRNA, a marker of neuronal activation, in brain regions involved in footshock-induced reinstatement. Pretreatment with a CRF antagonist blocked NA-induced reinstatement. In contrast, pretreatment with the α2-adrenoceptor agonist, clonidine, failed to block CRF-induced reinstatement. Taken together, these findings suggest a functional interaction between NA and CRF systems in mediating stress-induced reinstatement of cocaine seeking, whereby activation of CRF receptors occurs subsequent to, and downstream of, the sites of action of NA. A second series of experiments examined the role of D1- and D2-like receptors in CRF-induced reinstatement. Pretreatment with the D1- or D2-like receptor antagonists, SCH23390 and raclopride, respectively, dose-dependently blocked CRF-induced reinstatement of cocaine seeking. Taken together with previous findings, these results suggest that CRF-induced reinstatement of cocaine seeking likely involves DAergic signaling via D1- and D2-like receptors, subsequent to activation of CRF receptors. The final series of experiments investigated the neuropharmacology of yohimbine-induced reinstatement, focusing on the roles of α2-adrenoceptors, D1- and D2-like receptors. These experiments were prompted by an unexpected finding in the first series of experiments, in which a CRF antagonist failed to interfere in yohimbine-induced reinstatement of cocaine seeking. Results showed that pretreatment with the α2-adrenoceptor agonist, clonidine, or raclopride, prior to tests for yohimbine-induced reinstatement failed to influence responding. In contrast, pretreatment with SCH23390 blocked yohimbine-induced reinstatement. Taken together, these findings suggest that yohimbine may act through system(s) other than NA to have its effects.

It has been well established that the stress-related neurochemical systems corticotropin-releasing factor (CRF), noradrenaline (NA), and dopamine (DA) mediate stress-induced reinstatement of drug seeking. The three series of experiments presented in this dissertation constitute a further exploration of the role these neurochemical circuits play in reinstatement by providing the first direct exploration of whether central CRF and catecholamine (NA and DA) systems interact to influence reinstatement of cocaine seeking. The primary objective of the first series of experiments was to determine whether NA and CRF systems interact to mediate reinstatement of cocaine seeking and, if so, to determine the direction of this interaction. Results showed that central administration of NA induced reinstatement and up-regulated the expression of c-fos mRNA, a marker of neuronal activation, in brain regions involved in footshock-induced reinstatement. Pretreatment with a CRF antagonist blocked NA-induced reinstatement. In contrast, pretreatment with the α2-adrenoceptor agonist, clonidine, failed to block CRF-induced reinstatement. Taken together, these findings suggest a functional interaction between NA and CRF systems in mediating stress-induced reinstatement of cocaine seeking, whereby activation of CRF receptors occurs subsequent to, and downstream of, the sites of action of NA. A second series of experiments examined the role of D1- and D2-like receptors in CRF-induced reinstatement. Pretreatment with the D1- or D2-like receptor antagonists, SCH23390 and raclopride, respectively, dose-dependently blocked CRF-induced reinstatement of cocaine seeking. Taken together with previous findings, these results suggest that CRF-induced reinstatement of cocaine seeking likely involves DAergic signaling via D1- and D2-like receptors, subsequent to activation of CRF receptors. The final series of experiments investigated the neuropharmacology of yohimbine-induced reinstatement, focusing on the roles of α2-adrenoceptors, D1- and D2-like receptors. These experiments were prompted by an unexpected finding in the first series of experiments, in which a CRF antagonist failed to interfere in yohimbine-induced reinstatement of cocaine seeking. Results showed that pretreatment with the α2-adrenoceptor agonist, clonidine, or raclopride, prior to tests for yohimbine-induced reinstatement failed to influence responding. In contrast, pretreatment with SCH23390 blocked yohimbine-induced reinstatement. Taken together, these findings suggest that yohimbine may act through system(s) other than NA to have its effects.

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.

Extinguished alcohol-maintained responding has been shown to relapse in aresurgence preparation when food-reinforced responding is subsequently extinguished within the same context. However, drug and nondrug reinforcers are often specific to different contexts. Accordingly, the present experiments sought to determine whether loss of an alternative source of nondrug reinforcement in one context could produce relapse to drug seeking in a separate context. In one experiment, rats made topographically different responses for food or alcohol in alternating components of a multiple schedule. Both reinforcers were delivered during baseline, alcohol was withheld during the second phase of the experiment, and finally both reinforcers were withheld during the final phase. Extinguished alcohol-maintained responding increased upon discontinuation of food deliveries, but may have increased due to similarity between the final experimental phase and an initial training phase. In a second experiment, the training phase that complicated interpretation of the elevated responding observed in Experiment 1 was eliminated altogether. Alcohol seeking again relapsed upon discontinuation of food, suggesting that the training conditions were not the cause of the observed relapse in Experiment 1. Thus, loss of a nondrug reinforcer in one context can produce relapse to drug seeking in another. This procedure may provide a novel model of drug relapse in which loss of context-specific, alternative nondrug reinforcers precipitates relapse to drug seeking in a separate context.

Estudos reportando que a autoadministração repetida de drogas de abuso causa mudanças comportamentais, e na expressão de FosB, diferentes às causadas pela administração passiva repetida da mesma droga, em conjunto com estudos de discriminação de estímulos, têm sido chaves para compreender a dependência às drogas. Neste estudo se apresentam resultados de 3 experimentos que avaliaram diferenças gênicas e comportamentais entre a autoadministração de morfina e cocaína sob uma contingência operante, e a administração passiva destas drogas sob uma contingência Pavloviana, usando um modelo de administração de drogas acoplado e um protocolo de transferência operante-Pavloviana (PIT) seletiva em ratos. Os sujeitos foram distribuídos em três grupos: Administração por Contingência Operante (CO), Administração por Contingência Pavloviana (CP) e Controle (Ctr). No Experimento 1, cada sujeito do grupo CO foi exposto a sessões de autoadministração endovenosa de morfina. Depois, a expressão do gene FosB foi medida utilizando uma técnica imuno-histoquímicas em diferentes áreas do cérebro. No Experimento 2 os ratos foram expostos a um protocolo de PIT, treinando de forma inicial as contingências operante e Pavloviana separadamente, em associação a S1, utilizando infusões de morfina como reforçador. Em seguida foi treinado um encadeado de respostas (busca e administração) e finalmente, os sujeitos foram testados para avaliar o controle de estímulos que S1 adquiriu sobre as respostas de busca e administração. O Experimento 3 foi realizado utilizando os métodos dos primeiros dois experimentos, utilizando cocaína como reforçador. Em conjunto, os dados imunohistoquímicos e comportamentais sugerem que a maior expressão de FosB em subáreas envolvidas na dependência às drogas, em comparação entre os grupos CO e CP, está relacionada ao controle de estímulos estabelecido por S1 pelas diferentes contingências de aprendizagem. Ainda, os resultados apontam que estas áreas em que se encontrou uma expressão de FosB diferencial por diferentes contingências de administração de drogas coincidem com algumas das reportadas como envolvidas na PIT. Os resultados estão em concordância com estudos que reportam que a administração repetida de uma droga em contingências operantes ou pavlovianas alteram diferencialmente estruturas cerebrais envolvidas nos processos da dependência às drogas e apoiam a literatura que reporta que o estabelecimento de controle de estímulos que caracteriza a dependência se pode estabelecer por processos de aprendizagem na contingência operante e Pavloviana / Studies reporting that repeated drug self-administration produces behavioral changes, and in FosB expression, different from those produced by repeated passive administration of the same drug have been very important, together with stimulus control studies, have been the key to understand mechanisms underlying drug abuse. This study presents results from 3 experiments evaluating gene and behavioral differences between self-administration of morphine and cocaine under an operant contingency, and passive administration of these drugs under a Pavlovian contingency, using a yoked drug administration model and a selective Pavlovian to instrumental transfer (PIT) protocol in rats. Subjects were divided into three groups: Operant Contingency Administration (CO), Pavlovian Contingency Administration (CP) and Control (Ctr). In Experiment 1, each subject in the CO group was exposed to intravenous morphine self-administration sessions. Then, expression of FosB gene was measured using an immunohistochemical technique in different areas of the brain. In Experiment 2 rats were exposed to a PIT protocol, initially training the operant and Pavlovian contingencies separately in association with S1, using morphine infusions as a reinforcer. Then a chain of responses (seeking and taking) was trained and finally, subjects were tested to evaluate S1 stimulus control over search and administration responses. Experiment 3 was performed using the methods from the first two experiments, using cocaine as a reinforcer. Together, immunohistochemical and behavioral data interact and suggest that a higher expression on FosB expression in subareas involved in drug dependence, in comparison between CO and CP groups, is related to stimuli control established by S1 through the different learning contingencies. Moreover, results point out these same areas in which different FosB expression was found by different drug administration contingencies match some of those reported as being involved in PIT. Results are in agreement with studies reporting that repeated administration of a drug in operant or pavlovian contingencies differentially alter brain structures involved in drug dependence processes and support literature reporting the establishment of stimulus control characterizing addiction can be establish by learning processes in the operant and Pavlovian contingencies