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

Pesquisas com drogas de abuso têm mostrado consistentemente que a apresentação de estímulos ambientais associados ao uso destas substâncias pode induzir comportamentos de busca e autoadministração das mesmas. Existe a hipótese de que o controle que estímulos ambientais adquirem sobre comportamentos de autoadministração e busca por drogas de abuso poderia ser influenciado tanto pela forma de administração da droga, autoadministração (administração ativa) ou heteroadministração (administração passiva), quanto pela contingência (operante ou respondente) em que a droga foi associada com tais estímulos. Foram formados trios compostos por um sujeito de cada grupo (CONT, ACOP e VEÍC) e realizados dois experimentos. Inicialmente os sujeitos de cada trio foram acoplados por meio de caixas experimentais separadas e expostos a tentativas discretas de apresentação dos estímulos luminosos, S1 e S2, simultaneamente. Como consequência do girar a roda operante na presença de S1 por um integrante do grupo CONT, este recebia uma infusão endovenosa de morfina (0,75 mg/kg), e simultaneamente os animais acoplados no trio recebiam uma infusão de morfina na mesma dose (grupo ACOP) ou de veículo (grupo VEÍC). Posteriormente, os sujeitos de todos os grupos foram treinados a pressionar uma barra por infusões endovenosas de morfina, sem contingência discriminativa programada alguma. Para esta fase, no experimento 1, S2 esteve presente durante as sessões experimentais, porém no experimento 2, nenhum S foi apresentado. Finalmente, os estímulos S1 e S2 foram apresentados em tentativas discretas, em condições de extinção. Os resultados mostram que, durante a extinção, o desempenho dos animais do grupo CONT, mas não os dos grupos ACOP e VEÍC, foi condizente com o treino recebido inicialmente (com 80% ou mais de respostas na barra em presença de S1), indicando que foi estabelecido controle discriminativo sobre a autoadministração de morfina no treino sob a contingência operante, mas não sob a respondente. Estes resultados sugerem que comportamentos de autoadministração e busca por drogas de abuso são influenciados tanto pela forma de administração da droga, quanto pelo tipo de contingência em que uma droga é associada com estímulos ambientais / Drug abuse research has consistently shown that presentation of a drug associated with environmental stimuli can induce drug-seeking and drug-administration behaviors. It has been hypothesized that stimuli control over drug-seeking and self-administration behaviors could be influenced by drug administrations nature, self-administration (active administration) or hetero-administration (passive administration), and also influenced by the drug-stimuli association contingency (operant or respondent). Animals were exposed to right jugular vein catheterization procedure. Groups Contingent (C), Yoked (Y) and Toked Saline (YS) were formed randomly after recovery. Yoked triads were formed with one subject from each group and two experiments were executed. Initially a discriminative training (light stimuli S1 and S2 discrete trials) was presented to triads. Each time C S group member turned an instrumental wheel in presence of S1, simultaneously, an intravenous morphine infusion (0.75 mg/kg) were administrated to that subject and yoked Y group member, as well as an intravenous saline infusion was administrated to yoked YS group member, in every triad. Afterward all subjects were individually trained to lever-press for an intravenous morphine infusion with no discrimination contingency programed. In this phase, S2 was presented through sessions in Experiment 1, while in Experiment 2 no S were presented. After achieving response stability, subjects were exposed to extinction sessions. Stimuli S1 and S2 discrete trials were presented but no consequences were programed for bar-press responses. Results show that only C groups performance was consistent with the previously received discriminative training (80% or more of bar-press responses in S1 presence) during extinction sessions, indicating that an operant training, but not a respondent training, successfully established morphine self-administration discriminative control. These results suggest that self-administration behaviors are in fact influenced by drugs administration nature and also by the drug-stimuli association contingency

Pesquisas com drogas de abuso têm mostrado consistentemente que a apresentação de estímulos ambientais associados ao uso destas substâncias pode induzir comportamentos de busca e autoadministração das mesmas. Existe a hipótese de que o controle que estímulos ambientais adquirem sobre comportamentos de autoadministração e busca por drogas de abuso poderia ser influenciado tanto pela forma de administração da droga, autoadministração (administração ativa) ou heteroadministração (administração passiva), quanto pela contingência (operante ou respondente) em que a droga foi associada com tais estímulos. Foram formados trios compostos por um sujeito de cada grupo (CONT, ACOP e VEÍC) e realizados dois experimentos. Inicialmente os sujeitos de cada trio foram acoplados por meio de caixas experimentais separadas e expostos a tentativas discretas de apresentação dos estímulos luminosos, S1 e S2, simultaneamente. Como consequência do girar a roda operante na presença de S1 por um integrante do grupo CONT, este recebia uma infusão endovenosa de morfina (0,75 mg/kg), e simultaneamente os animais acoplados no trio recebiam uma infusão de morfina na mesma dose (grupo ACOP) ou de veículo (grupo VEÍC). Posteriormente, os sujeitos de todos os grupos foram treinados a pressionar uma barra por infusões endovenosas de morfina, sem contingência discriminativa programada alguma. Para esta fase, no experimento 1, S2 esteve presente durante as sessões experimentais, porém no experimento 2, nenhum S foi apresentado. Finalmente, os estímulos S1 e S2 foram apresentados em tentativas discretas, em condições de extinção. Os resultados mostram que, durante a extinção, o desempenho dos animais do grupo CONT, mas não os dos grupos ACOP e VEÍC, foi condizente com o treino recebido inicialmente (com 80% ou mais de respostas na barra em presença de S1), indicando que foi estabelecido controle discriminativo sobre a autoadministração de morfina no treino sob a contingência operante, mas não sob a respondente. Estes resultados sugerem que comportamentos de autoadministração e busca por drogas de abuso são influenciados tanto pela forma de administração da droga, quanto pelo tipo de contingência em que uma droga é associada com estímulos ambientais / Drug abuse research has consistently shown that presentation of a drug associated with environmental stimuli can induce drug-seeking and drug-administration behaviors. It has been hypothesized that stimuli control over drug-seeking and self-administration behaviors could be influenced by drug administrations nature, self-administration (active administration) or hetero-administration (passive administration), and also influenced by the drug-stimuli association contingency (operant or respondent). Animals were exposed to right jugular vein catheterization procedure. Groups Contingent (C), Yoked (Y) and Toked Saline (YS) were formed randomly after recovery. Yoked triads were formed with one subject from each group and two experiments were executed. Initially a discriminative training (light stimuli S1 and S2 discrete trials) was presented to triads. Each time C S group member turned an instrumental wheel in presence of S1, simultaneously, an intravenous morphine infusion (0.75 mg/kg) were administrated to that subject and yoked Y group member, as well as an intravenous saline infusion was administrated to yoked YS group member, in every triad. Afterward all subjects were individually trained to lever-press for an intravenous morphine infusion with no discrimination contingency programed. In this phase, S2 was presented through sessions in Experiment 1, while in Experiment 2 no S were presented. After achieving response stability, subjects were exposed to extinction sessions. Stimuli S1 and S2 discrete trials were presented but no consequences were programed for bar-press responses. Results show that only C groups performance was consistent with the previously received discriminative training (80% or more of bar-press responses in S1 presence) during extinction sessions, indicating that an operant training, but not a respondent training, successfully established morphine self-administration discriminative control. These results suggest that self-administration behaviors are in fact influenced by drugs administration nature and also by the drug-stimuli association contingency

Understanding Medication Self-Management Capacity among Older Adults Living in Low-Income Housing Communities ABSTRACT Background: Medication self-management capacity (MMC) is an individual’s cognitive and functional ability to self-administer a medication regimen as prescribed. Poor MMC is an issue in older adults often resulting in negative health outcomes and loss of independence. Therefore, understanding low-income older adults’ capacity to manage their medications may help identify individuals who are at risk for developing medication mismanagement and guide future intervention strategies based on an individual need to promote safe medication use and healthy aging in place in the community. Objectives: 1) To determine the cognitive and physical functional deficiencies in MMC among low-income older adults, 2) To identify variables that predict deficiencies in MMC in this population, 3) To determine the impact of using pharmaceutical aids/services on MMC, and 4) To examine the association between MMC and emergency room (ER) visits. Methods: This was a cross-sectional study of older adult residents living in low-income housing buildings served by the RHWP. At a study interview, information on demographics, medical history, and medication use was collected. MMC was evaluated using the Medication Management Instrument for Deficiencies in the Elderly (MedMaIDE) tool. Cognitive and functional status, health literacy and depression symptoms were assessed. ER visits were determined retrospectively over the last six months Descriptive analyses were performed to identify cognitive and physical functional deficiencies in MMC. Linear regression analysis was conducted to identify variables that predict MMC and assess the relationship between MMC and using pharmaceutical aid/service. Logistic regression analysis was used to examine the association between ER visits and MMC. Results: A total of 107 participants were included, and 89% were African-American with an average age of 68.54 years (±7.23). They had an average of 4.92 (±2.85) comorbidities and used approximately 8 (±4.12) medications on a regular basis. The mean total deficiency in medication management was 3 (±2.00) as assessed by MedMaIDE. Lacking medication knowledge was common among the participants: 69.16% could not name and 46% state the indication of all of their medications, and 38.32% did not how and when all of their medications should be taken. When controlling for ADLs and falls, the mean total deficiency score in MedMaIDE increased among those with an educational level equal to high school or less compared with participants who had a higher educational level than high school [β=1.32, 1.24, p= 0.0195, 0.0415, respectively], and participants who reported difficulty reading prescription medication labels or opening medication bottles compared with those who did not report any difficulties [β=1.18, 1.43, p= 0.0036, 0.0047, respectively]. About 20.56% of participants were receiving assistance with medications from someone, and 79.44% used at least one pharmaceutical aid/service. However, receiving assistance with medications and using pharmaceutical aid/service were not significantly associated with MMC [p= 0.5334, 0.0853, respectively]. The participants reported a total of 23 (21.5%) ER visits within six months. The adjusted model for age, educational level, number of comorbidities, and ADLs suggested that for every one-unit increase in the total deficiency score, the odds of ER visits increased by 1.23 (p=0.1809) times. Conclusion: Many older adults who lived in low-income housing had impaired capacity to manage their medications independently. They appeared to have inadequate medication knowledge, which affects their cognitive ability to manage medications. Low educational level and health literacy and reporting trouble reading labels or opening medication bottles were predictors to deficient MMC. Future studies are needed to confirm whether or not MMC predicts those who may not able to remain living independently safely or who may need additional support with medications to remain independent.

No description available.

La consommation répétée de drogues induit une plasticité cérébrale, qui pourrait sous-tendre le développement de la dépendance. La protéine phosphatase de type 1 (PP1) étant un acteur majeur de ces processus, nous nous sommes intéressés à sa régulation par la cocaïne. Nous avons montré qu’un traitement chronique par la cocaïne induit la répression du gène codant la sous-unitécatalytique β de PP1 (PP1Cβ), via l’hyperméthylation de sa région promotrice et le recrutement de la protéine de liaison à l’ADN méthylé, Mecp2. Cette répression, observée dans les principales structures du système de récompense du Rat, pourrait favoriser l’état phosphorylé des récepteurs NMDA et AMPA du glutamate et du facteur de transcription CREB, potentialisant ainsi les effets de la cocaïne. PP1 étant souvent considérée comme un régulateur négatif de la mémoire, sa répression pourrait également favoriser la ‘mémorisation’ du contexte et des habitudes liés à la drogue. L’expression de PP1Cβ a ensuite été analysée en réponse à des injections passives ou volontaires de cocaïne dans un test de conditionnement opérant, l’auto-administration intraveineuse. Étonnamment, une répression similaire de PP1Cβ est observée quel que soit le mode d’administration de la cocaïne. Son expression est par contre différente lorsque la cocaïne est remplacée par de la nourriture : elle est induite par le conditionnement opérant, sans être affectée par une distribution passive de nourriture. Le gène PP1Cβ participe donc sans doute aux neuroadaptations différentielles induites par les drogues et les récompenses naturelles, ouvrant ainsi de nouvelles perspectives dans la compréhension des effets à long terme des drogues. / Repeated intake of drugs of abuse is known to induce brain plasticity, which may underlie the development of drug addiction. Protein phosphatase type-1 (PP1) is one of the key proteins involved in brain plasticity mechanisms. We therefore studied its regulation in response to repeated cocaine intake by rats. The gene encoding the β catalytic subunit of PP1 (PP1Cβ) was found to be repressed by chronic cocaine treatment, through a mechanism involving DNA methylation of the PP1Cβ 5’-end followed by the recruitment of the methyl binding protein Mecp2. This repression was observed in the major brain structures of the reward system and probably favors the phosphorylation state of NMDA and AMPA glutamatergic receptors and of CREB transcriptionfactor, thus further increasing cocaine effects. PP1 is also known as a negative regulator of memory formation. Its repression by cocaine may therefore potentiate the ‘memorization’ of cocaine-related habits and context. PP1Cβ expression was next compared in response to passive vs voluntary cocaine injections in an operant intravenous cocaine self-administration paradigm. Surprisingly, a similar repression of PP1Cβ was found, independently on the cocaine administration mode. A completely different pattern of expression was observed when cocaine administration was replaced by food intake, as PP1Cβ expression was increased during food operant self-administration, but not in response to passive food delivery. Taken together, our data suggest that PP1Cβ participates to the differential neuroadaptations induced by drugs of abuse and natural rewards. They shed somenew light on the long-term mechanisms induced by drugs of abuse.

Indiana University-Purdue University Indianapolis (IUPUI) / Nicotine use among individuals with schizophrenia occurs at extremely high rates. The prevailing theory is that individuals with schizophrenia smoke as a form of self-medication to ameliorate sensory and cognitive deficits. However, these individuals also have enhanced rates of addiction to several drugs of abuse and may therefore smoke as a result of enhanced addiction liability. The experiments described herein explored these two hypotheses by assessing the effect that nicotine has on working memory, addiction vulnerability (locomotor sensitization and self-administration), and nicotinic acetylcholine receptor (nAChR) expression as well as the developmental expression of these characteristics in the neonatal ventral hippocampal (NVHL) neurodevelopmental animal model of schizophrenia. The results from these studies indicate that NVHLs had working memory impairments in both adolescence and adulthood, with nicotine having a negligible effect. Additionally, NVHLs displayed enhanced locomotor sensitization to nicotine which emerged in adulthood as well as an enhanced acquisition of nicotine self-administration, administering more nicotine overall. These behavioral differences cannot be attributed to nAChR expression as nicotine upregulated nAChR to a similar extent between NVHL and SHAM control animals. These data indicate that the enhanced rates of nicotine use among individuals with schizophrenia may occur as a result of an enhanced vulnerability to nicotine addiction.

BACKGROUND: Alcohol use disorders (AUDs) affect 15 million people nationwide, 4% of which are adolescents (ages 12-17) and adolescents who binge drink significantly increase their likelihood of suffering from an AUD in adulthood. Research shows that cues (i.e. flavors) paired with alcohol (EtOH) produce significant cue-induced alcohol craving and contribute to relapse in adolescent and adult populations. However, there is a lack of research focused on how cues that accompany EtOH drinking during adolescence, affect EtOH craving later in life. The current study sought to examine the sex- and developmental-dependent effects of adolescent exposure to flavor cues associated with EtOH on operant-lick behavior and cue-induced dopamine (DA) levels within the nucleus accumbens shell (AcbSh; reward structure) in adulthood. METHODS: Adolescent alcohol-preferring (P) rats were randomly assigned to one of 4 groups and received 24 hr. access to three bottles on their home cage: Paired: 0.1% blueberry flavor extract (BB) + 15% v/v EtOH and 2 water bottles; Unpaired: 0.1% BB, 15% v/v EtOH, and water; 15% EtOH alone, and 2 water bottles; BB alone and 2 water bottles. Home cage fluid consumption was measured for 2-weeks. On the third week bottles were removed and all animals underwent 9 days of operant training using an operant sipper paradigm. This consisted of two sipper spouts connected to the computer by a lickometer, which registered tongue contacts with the sipper tube (Paired: BB+EtOH or water; Unpaired BB or EtOH; EtOH alone: EtOH or water; BB alone: BB or water). When the fixed ratio (FR) requirement for number of licks/tongue contacts was met, a liquid delivery solenoid dispensed 0.05 ml of fluid into the sipper tube. Following the final operant session all rats remained in their home-cage for approximately 40 days until adulthood at which point they were returned to the operant chambers and tested for appetitive and consummatory behavior in response to the flavor cue (all rats: BB or water; NO EtOH). Two weeks after the final operant session all rats underwent microdialysis testing to examine cue-induced DA levels in the AcbSh. RESULTS: Data indicated that animals in the paired group exhibited a significantly greater level of licking at the BB sipper and a significantly greater level of DA release in response to the flavor cue compared to the other groups. CONCLUSIONS: Overall, the data suggest that cues paired with EtOH during adolescence may produce persistent changes to the behavioral and neurobiological mechanisms that contribute to an increased risk of developing an AUD later in life.

The basal ganglia are the key circuitry controlling movement and reward behavior. Both locomotion and reward-related behavior are also modified by dopaminergic input from the substantia nigra and the ventral tegmental area (VTA). If the basal ganglia are severed by lesion or in disease, such as in Parkinson’s disease, the affected individuals suffer from severe motor impairments and often of affective and reward-related symptoms. The subthalamic nucleus (STN) is a glutamatergic key area of the basal ganglia and a common target for deep brain stimulation in Parkinson’s disease to alleviate motor symptoms. The STN serves not only motoric, but also limbic and cognitive functions, which is often attributed to a tripartite anatomical subdivision. However, the functional output of both VTA and STN may rely more on intermingled subpopulations than on a strictly anatomical subdivision. In this doctoral thesis, the role of subpopulations within and associated with the basal ganglia is addressed from both a genetic and a behavioral angle. The identification of a genetically defined subpopulation within the STN, co-expressing Paired-like homeodomain transcription factor 2 (Pitx2) and Vesicular glutamate transport 2 (Vglut2), made it possible to conditionally reduce glutamatergic transmission from this subgroup of neurons and to investigate its influence on locomotion and motivational behavior, giving interesting insights into the mechanisms possibly underlying deep brain stimulation therapy and its side-effects. We address the strong influence of the Pitx2-Vglut2 subpopulation on movement, as well as the more subtle changes in reward-related behavior and the impact of the alterations on the reward-related dopaminergic circuitry. We also further elucidate the genetic composition of the STN by finding new markers for putative STN subpopulations, thereby opening up new possibilities to target those cells genetically and optogenetically. This will help in future to examine both STN development, function in the adult central nervous system and defects caused by specific deletion. Eventually identifying and characterizing subpopulations of the STN can contribute to the optimization of deep brain stimulation and help to reduce its side-effects, or even open up possibilities for genetic or optogenetic therapy approaches.

Rationale: Peak initiation of smoking occurs during adolescence and early onset of smoking is associated with a reduced probability of quitting and greater risk of relapse compared to later onset. Considering the epidemiological evidence, adolescents may exhibit a unique biological susceptibility to nicotine taking, in addition to the behavioural and psychosocial factors known to influence adolescent smoking. Objectives: The current series of experiments, using a rat model of adolescent nicotine taking, was designed to investigate age differences in the processes involved in the acquisition and maintenance of nicotine taking that might account for the elevated initiation rates of smoking during adolescence. Methods: We first investigated age differences in the neural response to acute nicotine administration using c-fos mRNA expression. We then examined age differences in the rewarding and aversive effects of nicotine in the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively. The direct reinforcing effects of nicotine were tested in adolescent and adult rats under a variety of reinforcement schedules in the operant intravenous self-administration paradigm; extinction and nicotine priming-induced reinstatement were also examined. Finally, age differences in nicotine withdrawal precipitated by mecamylamine were assessed. Results: Nicotine had greater activational effects on c-fos mRNA expression in reward-related neural substrates of adolescent compared to adult brain. Adolescent rats were also more sensitive to the rewarding effects of nicotine (CPP) yet less sensitive to its aversive effects (CTA) compared to adult rats. Nicotine was equally reinforcing in adolescents and adults self-administering under simple reinforcement schedules, but adults were more motivated to obtain nicotine under higher reinforcement schedules. Adults were more resistant to extinction, yet both age groups demonstrated similar priming-induced reinstatement of nicotine seeking. Under spontaneous acquisition conditions, adults were more sensitive to the reinforcing effects of a low nicotine infusion dose. The aversive effects of nicotine withdrawal were also more prominent in adults compared to adolescents. Conclusions: These findings have important implications since they demonstrate a unique susceptibility to the conditioned rewarding effects of nicotine that would promote acquisition of smoking behaviour during adolescence, whereas adults may be more vulnerable to processes involved in its maintenance.