Exposure to chronic stress increases the locomotor response to cocaine and the basal levels of corticosterone in adolescent rats

Repeated exposure to stress results in augmentation in the locomotor response to psychostimulant drugs. We investigated the locomotor response to a novel environment or cocaine [ 10 mg/kg, intraperitoneally (i.p.)] and basal corticosterone levels in male adolescent rats exposed to chronic restraint or variable stress. Animals in the chronic restraint group were restrained for 1 hour daily. The chronic variable stress protocol consisted of exposure to different stressors twice a day in random order. Chronic restraint and variable stress regimens began simultaneously on postnatal day (P) 25 and were applied for 10 days. During this period the control group was left undisturbed except for cleaning the cages. Three days after the last exposure to stress, cocaine- and novelty-induced locomotion were recorded in an activity cage. Plasma corticosterone levels were determined in a subset of stress and control animals. Exposure to both chronic restraint and variable stress increased cocaine- induced locomotion and basal corticosterone plasma levels, while no change was observed in the response to a novel environment. Moreover, rats exposed to variable stress displayed the greatest locomotor response following a challenge dose with cocaine when compared to control and chronic restraint stress groups. This observation indicates that the stress regimen is relevant to the degree of stress-induced sensitization to cocaine.

Social defeat stress in rats: escalation of cocaine and speedball binge self-administration, but not heroin

Exposure to intermittent episodes of social defeat stress can increase drug seeking and leads to intense drug taking in rats.This study investigated the consequences of repeated, intermittent social defeat stress on patterns of drug self-administration in rats with access to heroin, cocaine, or a heroin-cocaine combination (speedball).Male Long-Evans rats were either handled (controls) or subjected to 25-min social defeat stress episodes on days 1, 4, 7, and 10 during confrontations with an aggressive resident. Ten days following the last defeat, rats were assessed for locomotor cross-sensitization in response to heroin or cocaine. Animals were then prepared with intrajugular catheters for drug self-administration. Separate groups of controls and defeated rats were examined for self-administration of heroin (experiment 1), a heroin-cocaine combination (experiment 2), or cocaine (experiment 3). Drug self-administration patterns were evaluated using fixed or progressive ratio schedules of reinforcement during limited access sessions or a 24-h unlimited access binge.Rats with a history of intermittent social defeat stress showed sensitized locomotor behavior when challenged with heroin or cocaine relative to controls. During the 24-h binge session, defeated rats escalated cocaine-taking behavior (ca. 110 mg/kg vs. 66 mg/kg in controls), persisted in self-administering cocaine or the heroin-cocaine mixture for more hours, and showed a tendency for increased heroin-cocaine intake, but no effects on heroin taking.A history of social defeat stress seems to preferentially promote escalated intake of cocaine but not heroin, unless a heroin-cocaine combination is available.

Exposição repetida à cafeína aumenta a atividade locomotora induzida pelo femproporex em ratos adolescentes e adultos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Ontogênese, estresse e dependência de substâncias psicoativas

O estudo da dependência de substâncias psicoativas apresentou grandes avanços conceituais nas últimas décadas. A evolução dos conceitos foi paralela às evidências científicas que têm revelado os aspectos comportamentais e os mecanismos neurais envolvidos nesse fenômeno. Contudo, um grande desafio que permanece na pesquisa sobre a dependência de substâncias psicoativas é a identificação de quais fatores são responsáveis pela transição do uso controlado para o uso compulsivo. Está demonstrado que muitas variáveis interagem para influenciar a probabilidade de que qualquer indivíduo inicie o uso abusivo de substâncias psicoativas ou se torne dependente. Nos últimos anos, o estresse tem sido destacado como um fator importante na iniciação, manutenção e recaída da utilização de substâncias psicoativas. Neste trabalho analisamos os conceitos e teorias da farmacodependência e as principais evidências comportamentais pré-clínicas que demonstram a relação entre estresse e a vulnerabilidade ao abuso e dependência de psicoestimulantes.

The reinstatement of amphetamine-induced place preference is long-lasting and related to decreased expression of AMPA receptors in the nucleus accumbens

A great deal of effort has been devoted to elucidating the psychopharmacology underlying addiction and relapse. Long-term neuroadaptations in glutamate transmission seem to be of great relevance for relapse to stimulant abuse. In this study, we investigated amphetamine-induced conditioned place preference during adolescence and the reinstatement of the conditioned behavior following a priming injection of the drug 1 day (adolescence), 30 days (early adulthood) and 60 days (adulthood) after the extinction test. The nucleus accumbens was dissected immediately after the reinstatement test to examine alterations in GluR1 and NR1 subunits of glutamatergic receptors. Our results showed that a priming injection of amphetamine was able to reinstate the CPP 1 and 30 days after extinction. However, it failed to reinstate the conditioned response after 60 days. GluR1 levels were decreased on days 1 and 30 but not on day 60 while NR1 levels were unaltered in the reinstatement test. Using a relapse model we found that reinstatement of amphetamine-induced conditioning place preference during adolescence is long lasting and persists through early adulthood. Decreased levels of GluR1 in the nucleus accumbens might be related to the reinstatement of amphetamine-induced conditioning place preference. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.

Cocaine-induced behavioral sensitization in adolescent rats endures until adulthood: Lack of association with GluR1 and NR1 glutamate receptor subunits and tyrosine hydroxylase

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Repeated administration of caffeine induces either sensitization or tolerance of locomotor stimulation depending on the environmental context

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Comparison of caffeine-induced locomotor activity between adolescent and adult rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

DAILY VARIATION IN PLASMA-CONCENTRATION OF FENCAMFAMINE AND STRIATAL DOPAMINE-RECEPTORS IN RATS

Fencamfamine (FCF) is a psychostimulant drug classified as an indirect dopamine agonist. In the present study we evaluated the daily variation in plasma FCF concentration and in striatal dopamine receptors. Adult male Wistar rats (250-300 g) maintained on a 12-h light/12-h dark cycle (lights on at 07:00 h) were used. Rats received FCF (10.0 mg/kg, ip) at 09:00, 15:00, 21:00 or 03:00 h and blood samples were collected 30 (N = 6) or 60 (N = 6) min after the injections. Plasma FCF was measured by gas chromatography using an electron capture detector. Two-way ANOVA showed significant differences in FCF concentration when blood samples were collected 30 min after the injection, and the highest value was obtained following injection 21:00 h. Moreover, at 15:00, 21:00 and 03:00h, plasma FCF levels were significantly lower 60 min after injection when compared to the 30-min interval. Two other groups of rats (N = 6) were decapitated at 09:00 or 21:00 h and the striata were dissected for the binding assays. The Bmax for [H-3]-spiroperidol binding to striatal membranes was higher at 21:00 h, without changes in affinity constant (Kd). In conclusion, plasma FCF levels and dopamine receptors undergo daily variation,a phenomenon that should be considered to explain the circadian time-dependent effects of FCF.

Repeated administration intensifies the reinforcing effect of fencamfamine in rats

1. In the present study, we evaluated the role of repeated administration on conditioning place preference (CPP) induced by fencamfamine (FCF) in male rats.2. Repeated FCF (3.5 mg/kg) or saline once or daily for ten consecutive days enhanced sniffing du ration and decreased locomotion and rearing duration.3. At the 3.5 mg/kg dose, FCF produced a significant place-preference effect.4. Repeated exposures to FCF intensified its reinforcing properties.5. These results suggest that repeated FCF administration sensitizes its rewarding effects, as with other addictive substances. GEN PHARMAC 29;2:265-261, 1997. (C) 1997 Elsevier B.V.

EFFECTS OF FENCAMFAMINE WITHDRAWAL IN RATS

1. The effects produced by discontinuation of long-term treatment with fencamfamine (FCF) were evaluated recording behavioral and body weight changes.2. 48 hr after withdrawal of FCF rats shelved a significant decrease in exploratory behavior when compared to saline-treated ones.3. Discontinuation of treatment with FCF resulted in a significant increase in body weight on days of drug withdrawal.4. These results suggest that FCF caused signs of withdrawal similar to other psychostimulant drugs.

Reinforcing properties of fencamfamine: Involvement of dopamine and opioid receptors

Fencamfamine (FCF) is a psychostimulant classified as an indirect dopamine agonist. The conditioning place preference (CPP) paradigm was used to investigate the reinforcing properties of FCF. After initial preferences had been determined, animals were conditioned with FCF (1.75, 3.5, or 7.0 mg/kg; IP). Only at the dose of 3.5 mg/kg FCF produced a significant place preference. Pretreatment with SCH23390 (0.05 mg/kg, SC) or naloxone (1.0 mg/kg SC) 10 min before FCF (3.5 mg/kg; IP) blocked both FCF-induced hyperactivity and CPP. Pretreatment with metoclopramide (10.0 mg/kg; IP) or pimozide (1.0 mg/kg, IP), respectively, 30 min or 4 h before FCF (3.5 mg/kg; IP), which blocked the FCF-induced locomotor activity, failed to influence place conditioning produced by FCF. In conclusion, the present study suggests that dopamine D 1 and opioid receptors are related to FCF reinforcing effect, while dopamine D 2 subtype receptor was ineffective in modifying FCF-induced CPP.

Modulação contexto-específica dos efeitos comportamentais e neuroquímicos decorrentes da cafeína

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Efeitos comportamentais e neuroquímicos agudos da cafeína em ratos adolescentes e adultos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Sensibilização comportamental ao etanol e neuroadaptações envolvendo a proteína (DELTA)FOSB: efeitos do tratamento com N-Acetilcisteína em camundongos

Pharmacological treatments currently used in ethanol addiction are inefficient, requiring new drugs for this purpose. The pro-drug N-Acetylcysteine (N-Ac) has shown efficacy in the treatment of addiction to cocaine and nicotine in preclinical research and clinical pilot studies. When administered, N-Ac is subsequently converted to cysteine, and cystine, which has an action on the central nervous system. However, there are few data about the possible application of N-Ac in the ethanol addiction. Behavioral sensitization is the gradual increase of the psychostimulant effects induced by repeated administration of drugs of abuse, including ethanol, and its development has been linked to important neuroadaptations in addiction. These neuroadaptations occur in neural circuits that mediate the reinforcing properties of these drugs and may involve several proteins. The ΔFosB protein accumulates in neurons after repeated activation and mediates long lasting changes in response to drugs of abuse. These changes are manifested mainly in the nucleus accumbens (Acb) and prefrontal cortex (PFC) neurons. The aim of the study was to evaluate the effects of N-Ac treatment in the development of ethanol behavioral sensitization and in alterations in the ΔFosB protein in mice. Swiss male mice were exposed to a standardized behavioral sensitization protocol to the experimental conditions of the laboratory and treated with N-Ac. At the end of behavioral sensitization procedure, animals were euthanized and their brains removed for ΔFosB quantification by Western blotting. Two experiments of behavioral sensitization were performed to the standardization of the protocol. The first, although effective in demonstrating the development of behavioral sensitization, was not effective in allowing the evaluation of the expression of the behavioral sensitization. The age of the animals and the conditions of luminosity and color of locomotion apparatus were changed and a new...