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Le modèle de sensibilisation comportementale permet d'étudier les changements neuronaux induits par les drogues. Chez les rongeurs, l'activité locomotrice augmente au fur et à mesure des injections et se maintient à long terme. En parallèle à cette sensibilisation, on observe une sensibilisation neurochimique des transmissions noradrénergique (NA) et sérotoninergique (5-HT) jusqu'à un mois après la dernière injection. Cette sensibilisation neurochimique, qui se traduit par des libérations de NA et de 5-HT potentialisées mesurées au niveau du cortex préfrontal, est commune à toutes les drogues et fortement corrélée à la sensibilisation comportementale. Le but de ce travail était d'identifier les mécanismes qui maintiennent à long terme cette hyper-réactivité. Nous avons tout d'abord montré que la réponse locomotrice potentialisée à l'amphétamine se maintient durant le premier mois de sevrage, et décroit de 60% entre 2 et 4 mois. Toutefois les souris restent plus vulnérables à la drogue et ce, même après de longs sevrages. Nous avons également démontré que l'hyper-réactivité des systèmes se maintient à long terme notamment grâce à une désensibilisation fonctionnelle persistante des récepteurs ?2A- adrénergiques et 5-HT1A, responsables du rétrocontrôle inhibiteur des transmissions NA et 5-HT. On observe une diminution de l'expression des protéines G?i couplées à ces récepteurs, dans le locus coeruleus et dans le raphé dorsal, respectivement. La même altération des rétrocontrôles ayant été mesurée chez les animaux sensibilisés au MDMA, les résultats suggèrent que les récepteurs ?2A-adrénergiques et 5-HT1A pourraient être des cibles indirectes des psychostimulants. / The behavioral sensitization model allows the study of the neuronal changes induced by drugs of abuse. In rodents, the locomotor activity increases progressively with the injections of drug, and stays long-lastingly potentiated. Concurrent with this sensitization, a neurochemical sensitization of noradrenergic and serotonergic transmissions is developed until one month after the last injection. This sensitization, quantified through potentiated noradrenergic and serotonergic releases in the prefrontal cortex, was shown to be common to almost all drugs of abuse and highly correlated to behavioral sensitization. The aim of this study was to identify the mechanisms sustaining this hyper-reactivity. We first showed that the potentiated response persists after the first month of withdrawal, and decreases to 40% of the response after 2 to 4 months of withdrawal. However, all mice remain more vulnerable to the drug, even after long (4 months) withdrawals. We also showed that the systems? hyper-reactivity is sustained in the long term by a functional and persistent desensitization of the ?2A-adrenergic and 5-HT1A receptors, responsible for the inhibitory feed-back of noradrenergic and serotonergic transmissions. We observed a decreased expression of G?i proteins coupled receptors in the locus coeruleus and the dorsal raphe.The same feed-back dysfunctions were found in animals sensitized to MDMA, which suggests that ?2A-adrenergic and 5-HT1A receptors are indirect targets of psychostimulant drugs

O enriquecimento ambiental (EA) reverte a sensibilização comportamental (SC) ao etanol em camundongos e diminui os níveis de BDNF no córtex pré-frontal (CPF). O objetivo deste trabalho foi estudar os efeitos do EA sobre parâmetros comportamentais, resposta de corticosterona ao estresse, expressão de microRNAS e a participação da via BDNF-TrkB no CPF frente à SC ao etanol. Camundongos mantidos em EA foram submetidos a testes comportamentais (ansiedade, depressão, anedonia e comportamentos repetitivos). Também foram tratados repetidamente com etanol e expostos ao EA para a avaliação da corticosterona plasmática e da expressão de microRNAs no CPF. A via BDNF-TrkB foi inibida no CPF de camundongos que desenvolveram a SC ao etanol. O EA diminuiu a atividade locomotora e exploratória, a ativação do eixo HPA após estresse agudo, aumentou o peso do baço e diminuiu a expressão de miR-132 e let-7d. Os resultados sugerem o envolvimento de microRNAs na reversão da SC ao etanol; contudo, a via BDNF-TrkB no CPF não parece estar diretamente envolvida neste processo. / The environmental enrichment (EE) reverts the ethanol-induced behavioral sensitization (EIBS) in mice and decreases BDNF levels in the prefrontal cortex (PFC). The aim of this work was to evaluate the effects of EE on behavioral parameters, on the corticosterone response to stress and on microRNA expression and to assess the involvement of the BDNF-TrkB pathway in the PFC on the EIBS. Mice kept in EE were submitted to behavioral tests (anxiety, depression, anhedonia and repetitive behaviors). Mice were also treated repeatedly with ethanol and exposed to EE for the assessment of plasma corticosterone levels and microRNA expression in the PFC. The BDNF-TrkB pathway was blocked in the PFC of mice that developed EIBS. EE decreased locomotion, exploratory activity and HPA axis activation after acute stress, increased spleen weight and decreased miR-132 and let-7d expression. The results suggest the involvement of microRNAs in the reversal of EIBS promoted by EE; however, the BDNF-TrkB pathway in the PFC does not seem to be directly involved in this process.

Abnormality of dopamine D2 receptor (D2R) function, often observed as D2R supersensitivity (D2RSS), is a commonality of schizophrenia and related psychiatric disorders in humans. Moreover, virtually all psychotherapeutic agents for schizophrenia target D2R in brain. Permanent D2RSS as a feature of a new animal model of schizophrenia was first reported in 1991, and then behaviorally and biochemically characterized over the next 15–20 years. In this model of schizophrenia characterized by production of D2RSS in ontogeny, there are demonstrated alterations of signaling processes, as well as functional links between the biologic template of the animal model and ability of pharmacotherapeutics to modulate or reverse biologic and behavioral modalities toward normality. Another such animal model, featuring knockout of trace amine-associated receptor 1 (TAAR1), demonstrates D2RSS with an increase in the proportion of D2R in the high-affinity state. Currently, TAAR1 agonists are being explored as a therapeutic option for schizophrenia. There is likewise an overlay of D2RSS with substance use disorder. The aspect of adenosine A2A-D2heteroreceptor complexes in substance use disorder is highlighted, and the association of adenosine A2Areceptor antagonists in discriminative and rewarding effects of psychostimulants is outlined. In summary, these new animal models of schizophrenia have face, construct, and predictive validity, and distinct advantages over earlier models. While the review summarizes elements of D2RSS in schizophrenia per se, and its interplay with substance use disorder, a major focus is on presumed new molecular targets attending D2RSS in schizophrenia and related clinical entities.

Estrogens seem to play a role in the locomotor activating effects of cocaine. Japanese quail provide a good model for hormonal manipulation as alterations of their photoperiod controls hormone levels. The current study aims to examine the role of early life photoperiod manipulation in cocaine-induced behavioral sensitization in quail. It was expected that if quail were raised on a short photoperiod, they would have a reduction in gonadal hormones and this reduction in hormones would affect the acquisition of cocaine-induced behavioral sensitization. Quail were raised on an 8L:16D or a 16L:8D light cycle. Following 2 days of habituation, quail were administered saline, 5 mg/kg, or 10 mg/kg cocaine for 10 days. Restricted photoperiods in early life were correlated to lower gonadal hormone levels in females and males. Male quail raised on the short-light cycle developed a sensitized response to 10 mg/kg cocaine. Female quail raised on the short- or long-photoperiod developed behavioral sensitization to 5 mg/kg cocaine. Furthermore, early life reduction in estradiol in females modulated the amount of activity on day 10 of cocaine treatment. The current research extends previous research by finding a possible early life gonadal hormone control of behavioral sensitization in the quail.

Adolescent cannabis use has grown because of increased availability and higher societal acceptance. This increase in cannabis use is problematic as adolescents who experiment with cannabis are more likely to abuse cannabis and experiment with other illicit drugs such as cocaine. The reason for the greater susceptibility to drugs use is unclear and may be the result of altered drug sensitivity after cannabis exposure. Thus, the present investigation used the behavioral sensitization paradigm to examine the behavioral response of early adolescent rats to the cannabinoid agonist CP 55,940 (CP) or cocaine after repeated cannabinoid administration. It was hypothesized that: (1) CP would cause a sensitized response in both male and female adolescent rats, (2) female rats would have a greater behavioral response than male rats, (3) pretreatment with CP would induce cross-sensitization to cocaine, (4) pretreatment with cocaine would cause behavioral sensitization and conditioned activity in male and female adolescent rats. In the first experiment, 137 male and female Sprague-Dawley rats were given CP (4, 13.2, or 40 µg/kg, IP) or vehicle (50% DMSO/H2O) once daily for 5 consecutive days on postnatal day (PD) 30- PD 34. Distance traveled and stereotyped movement was assessed for 1 h after each drug injection. After a 48 h abstinence period (i.e., on PD 36), rats were given CP (4 or 13.2 µg/kg, IP) and distance traveled and stereotyped movement was monitored for 2 h. In the second experiment, 146 male and female rats were tested with the same protocol as in Experiment 1 except that rats were given CP (13.2 or 4 µg/kg), cocaine (20 mg/kg), or vehicle (saline or 50% DMSO/H2O) for five days and then tested with saline or cocaine (10 mg/kg) after 48 h. In the first experiment, no dose of CP altered distance traveled scores or stereotyped movement over the five pre-exposure days nor did CP cause behavioral sensitization on the test day. In the second experiment, pretreatment with cocaine led to enhanced distance traveled scores and stereotyped movement when challenged with cocaine (behavioral sensitization) or saline (conditioned activity) on test day. In contrast, CP-pretreated rats did not show greater activity when injected with cocaine or saline on test day. These data show that cannabinoids do not act like psychostimulant drugs, since CP did not cause the same changes in drug sensitivity as cocaine. The cocaine sensitization observed in adolescent rats indicates that this age group is particularly vulnerable to the rewarding effects of cocaine, and suggests that early cocaine exposure can augment drug seeking behavior. The failure to detect cannabinoid-induced sensitization, conditioned activity, or cocaine cross-sensitization during adolescence suggests that CP, when given at a consistent dose, does not increase the addictive properties of cannabinoids or cocaine. The results also indicate that cannabinoid use does not alter drug responsivity or lead to greater drug seeking and abuse in the adolescent population.

Made available in DSpace on 2016-06-02T19:22:03Z (GMT). No. of bitstreams: 1 2282.pdf: 1838286 bytes, checksum: 7d4dd1d44a59556a7f728e6a88087367 (MD5) Previous issue date: 2009-03-05 / Universidade Federal de Minas Gerais / We investigated the interaction between ontogeny, stress and environment where the drug is administered on the behavioral sensitization to cocaine and related neuroadaptations. This study was divided in two parts. In the first one we evaluated the behavioral sensitization to cocaine and alterations of glutamate receptors and tyrosine hydroxylase enzyme following repeated cocaine administrations or stress exposure on adolescent rats. These alterations were evaluated from adolescence to adulthood. The results showed that cocaine administration during adolescence produced long-term behavioral sensitization to cocaine until adulthood and increased of GluR1 glutamate receptor subunit in the medial prefrontal cortex. The stress-induced behavioral sensitization was evident during adolescence but did not reach adulthood. In the second part, we evaluated the environmental modulation of behavioral sensitization to cocaine and alterations of CREB and upstream kinases activation in adult rats. The results showed that the expression of cocaine-induced behavioral sensitization was specific to the environment paired with previous cocaine administration. Moreover, the number of neurons with CREB activation in the nucleus accumbens was increased in sensitized animals and specific to the paired environment. Thus, our results add new findings on addiction related alterations in adolescent animals, its long-term effects and the environmental modulation of cocaine behavioral and neuronal sensitization. / Investigamos a influência da ontogênese, do estresse e do ambiente onde a substância psicoativa é administrada sobre a sensibilização comportamental à cocaína e o desenvolvimento de neuroadaptações. Para tanto, esse trabalho de tese foi dividido em duas partes. Na primeira, avaliamos os efeitos da administração repetida à cocaína ou exposição ao estresse em ratos adolescentes na sensibilização comportamental à cocaína e neuroadaptações dos receptores de glutamato e da enzima tirosina hidroxilase. Essas alterações foram avaliadas durante a adolescência e também acompanhadas até a idade adulta. Demonstramos nesses experimentos que a administração repetida de cocaína durante a adolescência provoca sensibilização comportamental que perdura até a idade adulta e causa aumento da proteína GluR1 dos receptores glutamatérgicos no córtex pré-frontal medial. A exposição ao estresse provoca sensibilização comportamental em adolescentes, mas esse efeito não permanece até a idade adulta. Na segunda parte da tese, avaliamos a influência do pareamento do ambiente onde a cocaína é administrada sobre a expressão da sensibilização comportamental a essa substância e alterações de CREB e enzimas cinases que ativam CREB em ratos adultos. Demonstramos que o pareamento do ambiente com as administrações de cocaína facilita a expressão da sensibilização comportamental. A sensibilização comportamental dependente do ambiente está relacionada ao aumento do número de neurônios com ativação de CREB no núcleo acumbens dos animais. Portanto, nosso estudo pretende contribuir para o entendimento de alterações relacionadas à dependência em animais adolescentes, seus efeitos duradouros e a influência do ambiente onde a substância é administrada.

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.

In agreement with previous work, adult rats given selective lesions to dopamine (DA)-containing neurons as neonates exhibited a greater behavioral sensitization to repeated phencyclidine (PCP) treatment in comparison to sham-lesioned controls. Acute administration of olanzapine (1-5 mg/kg ip) or clozapine (15 mg/kg ip) decreased sensitized PCP-induced activity in both lesioned and control animals. Acute haloperidol (0.5 mg/kg ip) had no impact on PCP responsiveness in lesioned animals, but significantly antagonized PCP effects in sham-lesioned controls. Ketanserin, a selective 5-HT 2A/5-HT2C-receptor antagonist, significantly reduced PCP activation in both lesioned and control rats, suggesting that the efficacy of atypical antipsychotics against PCP-induced sensitized responses may be mediated by one of the 5-HT2-receptor subtypes. A 6-week chronic regimen of orally administered olanzapine, clozapine, or haloperidol failed to block the sensitization induced by repeated PCP exposure. However, a 10-month oral olanzapine treatment significantly blunted the behavioral sensitization to repeated PCP exposure in lesioned animals, even after withdrawal from chronic olanzapine for more than 3 weeks. A 10-month oral haloperidol treatment had no effect on the sensitization induced by repeated PCP dosing. The persistent effect of chronic olanzapine administration on PCP sensitization may be relevant to the chronic therapeutic efficacy of atypical antipsychotics treating schizophrenia - a clinical syndrome linked to enhanced sensitivity to N-methyl-D-aspartate (NMDA)-receptor antagonists.

This study analyzed repeated methylphenidate (MPH) administration and its effects on brain-derived neurotrophic factor (BDNF) in the dorsal striatum and nucleus accumbens of male and female adolescent rats. In Experiment 1, rats were administered intraperitoneal (ip) saline, 1, 3, or 5 mg/kg dose of MPH every second day from postnatal day (P)33–P49. Locomotor activity was analyzed for 10 min after each administration. Results revealed that the 1 mg/kg dose of MPH produced locomotor suppression, however, the 5 mg/kg dose of MPH produced locomotor sensitization and robust behavioral activation in females as compared to males. In Experiment 2, animals were administered ip saline or the 5 mg/kg dose of MPH using an identical regimen but a 30 min behavioral test was employed. Dorsal striatum and nucleus accumbens tissue was assayed for BDNF at P50. Females demonstrated sensitization to MPH and increased locomotor activation compared to males. Interestingly, females given MPH demonstrated a significant 42% decrease of striatal BDNF whereas males administered MPH demonstrated a significant 50.4% increase of striatal BDNF compared to controls. There were no effects on accumbal BDNF. This report demonstrates robust sex differences in the behavioral response, but sex-dependent changes in striatal BDNF in response to MPH in adolescence.