RESUMO
Psilocybin has received attention as a treatment for depression, stress disorders and drug and alcohol addiction. To help determine the mechanisms underlying its therapeutic effects, here we examined acute effects of a range of behaviourally relevant psilocybin doses (0.1-3 mg/kg SC) on regional expression of Fos, the protein product of the immediate early gene, c-fos in brain areas involved in stress, reward and motivation in male rats. We also determined the cellular phenotypes activated by psilocybin, in a co-labeling analysis with NeuN, a marker of mature neurons, or Olig1, a marker of oligodendrocytes. In adult male Sprague-Dawley rats, psilocybin increased Fos expression dose dependently in several brain regions, including the frontal cortex, nucleus accumbens, central and basolateral amygdala and locus coeruleus. These effects were most marked in the central amygdala. Double labeling experiments showed that Fos was expressed in both neurons and oligodendrocytes. These results extend previous research by determining Fos expression in multiple brain areas at a wider psilocybin dose range, and the cellular phenotypes expressing Fos. The data also highlight the amygdala, especially the central nucleus, a key brain region involved in emotional processing and learning and interconnected with other brain areas involved in stress, reward and addiction, as a potentially important locus for the therapeutic effects of psilocybin. Overall, the present findings suggest that the central amygdala may be an important site through which the initial brain activation induced by psilocybin is translated into neuroplastic changes, locally and in other regions that underlie its extended therapeutic effects.
Assuntos
Encéfalo , Psilocibina , Ratos , Masculino , Animais , Psilocibina/farmacologia , Psilocibina/metabolismo , Ratos Sprague-Dawley , Encéfalo/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Locus Cerúleo/metabolismo , Tonsila do Cerebelo/metabolismoRESUMO
Serotonin modulates many motivated behaviours via multiple receptor subtypes. Agonists at 5-HT2C receptors have potential for treating behavioural problems associated with obesity and drug use. In this work we examined the impact of the 5-HT2C receptor agonist lorcaserin on several motivated behaviours related to feeding, reward and waiting impulsivity, and on neuronal activation in key brain areas mediating those behaviours. In male C57BL/6J mice effects of lorcaserin (0.2, 1 and 5 mg/kg) were examined on feeding, and on operant responding for a palatable reward. Feeding was reduced only at 5 mg/kg, whereas operant responding was reduced at 1 mg/kg. At a much lower dose range lorcaserin 0.05-0.2 mg/kg also reduced impulsive behaviour measured as premature responding in the 5-choice serial reaction time (5-CSRT) test, without affecting attention or ability to perform the task. Lorcaserin induced Fos expression in brain regions related to feeding (paraventricular nucleus and arcuate nucleus), reward (ventral tegmental area), and impulsivity (medial prefrontal cortex, VTA) although these effects did not show the same differential sensitivity to lorcaserin as the behavioural measures. These results indicate a broad profile of action of 5-HT2C receptor stimulation on brain circuitry and on motivated behaviours, but with clear evidence of differential sensitivity across behavioural domains. This is exemplified by the fact that impulsive behaviour was reduced at a much lower dose range than was feeding behaviour. Along with previous work, and some clinical observations, this work supports the idea that 5-HT2C agonists may be useful for behavioural problems associated with impulsivity.
Assuntos
Receptor 5-HT2C de Serotonina , Serotonina , Animais , Masculino , Camundongos , Comportamento Impulsivo , Camundongos Endogâmicos C57BL , Recompensa , Serotonina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/farmacologiaRESUMO
Noradrenaline and alpha-2 receptors are implicated in the neuroadaptive changes in alcohol dependence leading to increased alcohol seeking. Preclinical methods often used to induce dependence, such as alcohol vapor, require long exposure periods. Another method, gavage with alcohol, induces dependence in a shorter time frame (4-6 d), but its effects on relapse are less well understood. We examined the role of alpha-2 receptors in alcohol self-administration (ASA) and relapse in male and female rats made alcohol dependent by gavage. The influence of these variables on the inhibitory effects of the alpha-2 agonist guanfacine on ASA, and on reinstatement induced by the alpha-2 antagonist yohimbine were determined. We also extended this analysis to relapse induced by the kappa opioid receptor agonist U50,488. Male and female Sprague Dawley rats, trained to self-administer alcohol were treated with intragastric vehicle or alcohol (12 g/kg/d for 5 d). In Exp. 1 we examined the effects of alcohol gavage on reinstatement induced by yohimbine (0.625-1.25 mg/kg) and U50,488 (1.25-2.5 mg/kg). In Exp. 2 we determined the effects of a longer period of alcohol gavage on guanfacine (0.25-0.75 mg/kg)-induced reductions in ASA and on yohimbine (0.625-2.5 mg/kg)-induced reinstatement. Our key findings are that alcohol dependence induced by gavage produces sex-specific effects on reinstatement. Non-dependent females had greater reinstatement than males, but dependence reduced reinstatement in females. In males, dependence modestly enhanced yohimbine-induced reinstatement, while U50-induced reinstatement was absent irrespective of dependence condition. Alcohol dependence did not modify the inhibitory effects of guanfacine on ASA in males or females.
Assuntos
Alcoolismo , Receptores Opioides kappa , Adrenérgicos , Animais , Etanol , Feminino , Guanfacina , Masculino , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Recidiva , Autoadministração , IoimbinaRESUMO
The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) modulates fundamental motivational processes, and the neurochemical and behavioural effects of drugs of abuse. Recently, attention has focused on the role of 5-HT acting via 5-HT2A and 5-HT2C receptor sub-types in this regard. We examined the impact of manipulating 5-HT2A and 5-HT2C receptor mediated function on several aspects of alcohol self-administration and alcohol-seeking behaviour in male and female rats. Specifically, experiments investigated the effect of the 5-HT2A inverse agonist/antagonist pimavanserin, and the 5-HT2C receptor agonist lorcaserin on these behaviours. In male and female rats trained to respond for alcohol reinforcement on fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement pimavanserin (0.3, 1 and 3 mg/kg) had no consistent effect on responding. Lorcaserin (0.25, 0.5 and 1 mg/kg) reduced these behaviours in both sexes. Following extinction of responding for alcohol, alcohol-seeking was reinstated by cues previously paired with alcohol. Pimavanserin (1 mg/kg) and lorcaserin (0.5 mg/kg) significantly reduced this reinstatement. In a two-bottle 24 h intermittent access procedure pimavanserin had no significant effects, but lorcaserin reduced alcohol consumption in both sexes at 1, 4 and 24 h after access to alcohol was allowed. Finally, as determined using in vivo microdialysis, alcohol increased, and lorcaserin (0.5 mg/kg) reduced, extracellular levels of DA in the NAc in male rats. In rats treated with lorcaserin prior to alcohol injection the net effect was that DA levels were not changed compared to those measured in control rats. These results suggest that blocking 5-HT2A receptor activity has a very limited action to reduce alcohol-seeking. Activating 5-HT2C receptors had a broader behavioural profile to reduce alcohol self-administration, alcohol drinking and alcohol seeking. These effects may partly result from a blunting of the effect of alcohol on mesolimbic DA release.
Assuntos
Agonistas do Receptor 5-HT2 de Serotonina , Serotonina , Animais , Benzazepinas , Relação Dose-Resposta a Droga , Feminino , Masculino , Piperidinas , Ratos , Receptor 5-HT2C de Serotonina , Autoadministração , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Ureia/análogos & derivadosRESUMO
Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood-brain barrier penetration hinder their application. Targeted nanoparticle delivery systems are being tapped for their ability to improve the delivery of therapeutics into the brain non-invasively. We have developed a family of mannosylated glycoliposome delivery systems for targeted drug delivery applications. Herein, we demonstrate via in vivo distribution studies the potential of these glycoliposomes to improve the utility of CNS active therapeutics using dynantin, a potent and selective dynorphin peptide analogue antagonist of the kappa opioid receptor (KOR). Glycoliposomal entrapment protected dynantin against known rapid metabolic degradation and ultimately improved brain levels of the peptide by approximately 3-3.5-fold. Moreover, we linked this improved brain delivery with improved KOR antagonist activity by way of an approximately 30-40% positive modulation of striatal dopamine levels 20 min after intranasal administration. Overall, the results clearly highlight the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the CNS.
Assuntos
Dinorfinas , Peptídeos , Receptores Opioides kappa/antagonistas & inibidores , Corpo Estriado/metabolismo , Dopamina , Dinorfinas/química , Dinorfinas/farmacocinética , Dinorfinas/farmacologia , Humanos , Lipossomos , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/farmacologiaRESUMO
BACKGROUND: Stress is associated with relapse to alcohol seeking during abstinence, but the processes underlying this relationship are poorly understood. Noradrenaline is a key transmitter in stress responses and in stress-induced drug seeking. The alpha-1 adrenoceptor antagonist prazosin has been investigated as a treatment for alcoholism and for chronic stress disorders that are frequently comorbid with alcoholism. In rats, we previously showed that prazosin blocks reinstatement of alcohol seeking induced by footshock and yohimbine stressors and reduces yohimbine-induced brain activation. The role of alpha-1 adrenoceptors in reinstatement induced by other stressors is not known. Our most recent work is on the role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking and have reported that the selective kappa opioid receptor agonist U50,488 induces reinstatement and neuronal activation in stress- and relapse-related brain regions. Here we determine the involvement of alpha-1 receptors in reinstatement and brain activation induced by U50,488. METHODS: We trained male Long-Evans rats to self-administer alcohol (12% w/v), extinguished alcohol-reinforced responding, and then determined the effects of prazosin (1 mg/kg) on U50,488 (2.5 mg/kg)-induced reinstatement and regional Fos expression. RESULTS: Prazosin blocked U50,488-induced reinstatement and decreased U50,488-induced Fos expression in the orbitofrontal cortex, nucleus accumbens core, ventral bed nucleus of the stria terminalis, central and basolateral amygdalar nuclei and ventral tegmental area. CONCLUSIONS: These findings suggest that prazosin may reduce U50,488-induced relapse by inhibiting activity in 1 or more of these brain areas.
Assuntos
(trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Alcoolismo/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Genes fos/efeitos dos fármacos , Prazosina/farmacologia , Receptores Opioides kappa/agonistas , Estresse Psicológico/tratamento farmacológico , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Long-EvansRESUMO
Alcohol dependence and stress are associated with relapse to alcohol during abstinence, but the underlying mechanisms are poorly understood. Kappa opioid receptors (KOR) are involved in alcohol reward and in the effects of stress. Previously, in non-dependent rats, we showed that KOR in the bed nucleus of the stria terminalis (BNST) mediate reinstatement of alcohol seeking induced by the selective KOR agonist U50,488. Here, we determine the effects of chronic, intermittent exposure to alcohol vapor on U50,488-induced reinstatement of alcohol seeking. We also study brain mechanisms involved using the neuronal activity marker Fos and phosphorylated p38 MAPK (p-p38), an intracellular messenger implicated in the effects of KOR stimulation. We trained male Long-Evans rats to self-administer alcohol (12% w/v) and exposed them to alcohol vapor (14â¯h vapor/10â¯h air) daily for 24â¯d or to the control condition, extinguished alcohol-reinforced responding and determined the dose response for U50,488-induced reinstatement. We then determined the effects of vapor exposure on U50,488-induced Fos and p-p38 expression. Vapor-exposed rats were more sensitive to U50,488-induced reinstatement. U50,488 increased Fos expression in brain areas involved in stress-induced relapse, and Fos activation in the ventral BNST was greater in vapor exposed rats. Vapor exposed rats had increased basal p-p38 expression in the dorsal BNST, LC and NTS. Our findings suggest that changes in the neuronal responses to KOR stimulation in the ventral BNST may be involved in the increased sensitivity to U50,488 accompanying dependence.
Assuntos
(trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/farmacologia , Administração por Inalação , Animais , Encéfalo/metabolismo , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Etanol/administração & dosagem , Extinção Psicológica/efeitos dos fármacos , Masculino , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Autoadministração , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Dependence on drugs has enduring effects on drug intake and relapse. The role of choice in enhanced susceptibility to drug use in drug dependence has been little studied. Here we determine the effects of alcohol dependence on the choice between alcohol and a non-drug reward, saccharin, using the discrete choice model in food-restricted male rats. We trained rats to self-administer alcohol (12% w/v) and saccharin (0.05, 0.1%), tested their choice of alcohol vs. saccharin, and determined the effects of deprivation and intertrial interval (ITI) duration on choice. We then determined the effects of alcohol dependence, induced by repeated intermittent exposure to alcohol vapor on choice of alcohol vs. saccharin (0.1%) in discrete choice trials as well as on the effects of adulteration of alcohol with quinine on choice. We trained another group of rats to self-administer intravenous (i.v.) nicotine (0.03 mg/kg/infusion) and oral saccharin (0.1%), determined their choice, and examined the roles of ITI duration and concurrent access on choice. Rats chose equivalent amounts of 0.05% saccharin and 12% alcohol, showed a stronger choice for 0.1% saccharin, and alcohol and saccharin choice were modestly decreased and increased, respectively, by deprivation. Alcohol dependence led to profound increases in the choice of alcohol over saccharin while adulteration of alcohol with quinine did not affect choice in non-dependent or dependent rats. Rats showed marked choice for 0.1% saccharin over i.v. nicotine. The strong effect that dependence had on alcohol choice is an important validation of the discrete choice procedure.
Assuntos
Alcoolismo , Depressores do Sistema Nervoso Central/administração & dosagem , Comportamento de Escolha , Etanol/administração & dosagem , Sacarina/administração & dosagem , Animais , Comportamento de Escolha/efeitos dos fármacos , Masculino , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Ratos Long-Evans , Ratos Sprague-Dawley , AutoadministraçãoRESUMO
κ-Opioid receptors (KORs) and their endogenous ligand dynorphin are involved in stress-induced alcohol seeking but the mechanisms involved are largely unknown. We previously showed that systemic injections of the KOR agonist U50,488, which induce stress-like aversive states, reinstate alcohol seeking after extinction of the alcohol-reinforced responding. Here, we used the neuronal activity marker Fos and site-specific injections of the KOR antagonist nor-BNI and U50,488 to study brain mechanisms of U50,488-induced reinstatement of alcohol seeking. We trained male Long-Evans rats to self-administer alcohol (12% w/v) for 23-30 days. After extinction of the alcohol-reinforced responding, we tested the effect of U50,488 (0, 1.25, 2.5, and 5 mg/kg) on reinstatement of alcohol seeking. Next, we correlated regional Fos expression with reinstatement induced by the most effective U50,488 dose (5 mg/kg). Based on the correlational Fos results, we determined the effect of bed nucleus of the stria terminalis (BNST) injections of nor-BNI (4 µg/side) on U50,488-induced reinstatement of alcohol seeking, and reinstatement induced by injections of U50,488 (0, 0.3, 1, and 3 µg/side) into the BNST. U50,488-induced reinstatement of alcohol seeking was associated with increased Fos expression in multiple brain areas, including the BNST, where it was significantly correlated with lever pressing. U50,488-induced reinstatement was blocked by BNST nor-BNI injections, and BNST U50,488 injections partially mimicked the drug's systemic effect on reinstatement. Our data indicate that the BNST is a critical site for U50,488-induced reinstatement of alcohol seeking and suggest that KOR/dynorphin mechanisms in this brain area play a key role in stress-induced alcohol seeking.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Comportamento de Procura de Droga/fisiologia , Etanol/administração & dosagem , Receptores Opioides kappa/fisiologia , Reforço Psicológico , Núcleos Septais/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Animais , Comportamento de Procura de Droga/efeitos dos fármacos , Masculino , Antagonistas de Entorpecentes/farmacologia , Ratos , Ratos Long-Evans , Receptores Opioides kappa/antagonistas & inibidores , Autoadministração , Núcleos Septais/efeitos dos fármacosRESUMO
UNLABELLED: The craving response to smoking-associated cues in humans or to intravenous nicotine-associated cues in adult rats progressively increases or incubates after withdrawal. Here, we further characterized incubation of nicotine craving in the rat model by determining whether this incubation is observed after adolescent-onset nicotine self-administration. We also used the neuronal activity marker Fos and the Daun02 chemogenetic inactivation procedure to identify cue-activated neuronal ensembles that mediate incubation of nicotine craving. We trained adolescent and adult male rats to self-administer nicotine (2 h/d for 12 d) and assessed cue-induced nicotine seeking in extinction tests (1 h) after 1, 7, 14, or 28 withdrawal days. In both adult and adolescent rats, nicotine seeking in the relapse tests followed an inverted U-shaped curve, with maximal responding on withdrawal day 14. Independent of the withdrawal day, nicotine seeking in the relapse tests was higher in adult than in adolescent rats. Analysis of Fos expression in different brain areas of adolescent and adult rats on withdrawal days 1 and 14 showed time-dependent increases in the number of Fos-positive neurons in central and basolateral amygdala, orbitofrontal cortex, ventral and dorsal medial prefrontal cortex, and nucleus accumbens core and shell. In adult Fos-lacZ transgenic rats, selective inactivation of nicotine-cue-activated Fos neurons in central amygdala, but not orbitofrontal cortex, decreased "incubated" nicotine seeking on withdrawal day 14. Our results demonstrate that incubation of nicotine craving occurs after adolescent-onset nicotine self-administration and that neuronal ensembles in central amygdala play a critical role in this incubation. SIGNIFICANCE STATEMENT: The craving response to smoking-associated cues in humans or to intravenous nicotine-associated cues in adult rats progressively increases or incubates after withdrawal. It is currently unknown whether incubation of craving also occurs after adolescent-onset nicotine self-administration. The brain areas that mediate such incubation are also unknown. Here, we used a rat model of incubation of drug craving, the neuronal activity marker Fos, and the Daun02 chemogenetic inactivation method to demonstrate that incubation of nicotine craving is also observed after adolescent-onset nicotine self-administration and that neuronal ensembles in the central nucleus of the amygdala play a critical role in this incubation in adult rats.
Assuntos
Núcleo Central da Amígdala/citologia , Fissura/fisiologia , Neurônios/fisiologia , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Fatores Etários , Animais , Animais Recém-Nascidos , Núcleo Central da Amígdala/metabolismo , Daunorrubicina/análogos & derivados , Daunorrubicina/metabolismo , Extinção Psicológica , Feminino , Neurônios/efeitos dos fármacos , Proteínas Oncogênicas v-fos/genética , Proteínas Oncogênicas v-fos/metabolismo , Fosfopiruvato Hidratase/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Autoadministração , Síndrome de Abstinência a Substâncias/fisiopatologia , Sacarose/administração & dosagem , Fatores de Tempo , beta-Galactosidase/metabolismoRESUMO
In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse.
Assuntos
Comportamento Aditivo/metabolismo , Encéfalo/metabolismo , Comportamento de Procura de Droga/fisiologia , Rede Nervosa/metabolismo , Estresse Psicológico/metabolismo , Animais , Comportamento Aditivo/patologia , Comportamento Aditivo/psicologia , Encéfalo/patologia , Condicionamento Psicológico/fisiologia , Glucocorticoides/biossíntese , Humanos , Drogas Ilícitas/metabolismo , Rede Nervosa/patologia , Autoadministração , Estresse Psicológico/patologia , Estresse Psicológico/psicologiaRESUMO
INTRODUCTION: Stress is related to heavy alcohol use and relapse in alcoholics. Using the reinstatement model, we have shown that corticotropin-releasing factor (CRF) underlies stress-induced relapse to alcohol seeking in laboratory rodents. Little is known about how other neurotransmitters interact with CRF in these effects. Dynorphin and its receptor (kappa opioid receptor, KOR) are involved in stress responses and in alcohol seeking. KOR and CRF receptors (CRF R) may interact in the production of stress-related behaviors but it is not known whether this interaction is involved in reinstatement of alcohol seeking. METHODS: Male Long Evans rats were trained to self-administer alcohol (12% w/v). After extinction of responding, we determined the effects of the KOR agonist, U50,488 (2.5, 5 mg/kg) on reinstatement of alcohol seeking, and their sensitivity to the selective KOR antagonist nor-binaltorphimine dihydrochloride (nor-BNI) (10 mg/kg) administered at different times before U50,488. We then examined the effects of nor-BNI on reinstatement induced by the stressor yohimbine (1.25 mg/kg) and on reinstatement induced by exposure to alcohol-associated cues. Finally, we determined whether CRF R1 blockade with antalarmin (10, 20 mg/kg) attenuates alcohol seeking induced by U50,488. RESULTS: U50,488 reinstated alcohol seeking. Prior treatment with nor-BNI 2, but not 24 h before administration of U50,488 or yohimbine blocked reinstatement induced by these drugs. Cue-induced reinstatement was blocked by nor-BNI administered 2 h prior to testing. Finally, U50,488-induced reinstatement was blocked by antalarmin. CONCLUSIONS: These data further support a role for KOR in reinstatement of alcohol seeking under nonstress and stressful conditions and that KOR and CRF R interact in these effects.
Assuntos
Analgésicos Opioides/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/administração & dosagem , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inibidores , Estresse Fisiológico/efeitos dos fármacos , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Animais , Comportamento Aditivo , Comportamento Animal/efeitos dos fármacos , Sinais (Psicologia) , Masculino , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Long-Evans , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Autoadministração , Ioimbina/farmacologiaRESUMO
RATIONALE AND OBJECTIVES: Alcohol and nicotine are often taken together. In humans, intake of nicotine, via smoked tobacco, increases alcohol drinking, and alcohol increases smoking. Chronic nicotine treatment increases alcohol self-administration (SA) in laboratory animals; the reverse relationship is less clear. Most animal work modeling this has used passive administration, which lacks relevance to human co-abuse. Here, we describe a model based on sequential operant SA of alcohol and nicotine. METHODS: Animals are first trained on alcohol SA (0.19 ml of 12 % alcohol (w/v)/delivery) and then receive separate alcohol (8 %, w/v) and nicotine (15 µg/kg/infusion) SA sessions on the same day ("daily dual access"). Animals then receive access to alcohol and then to nicotine (or in the reverse order) in alternating 5-min periods in 2-h sessions ("alternating access"). We then determine if alternating access modifies the effects of naltrexone on responding for alcohol and nicotine. RESULTS: We found that with daily dual access, nicotine significantly increased alcohol SA when alcohol access occurred prior to nicotine access and that nicotine SA significantly decreased when the alcohol SA session preceded it. During alternating access, nicotine also significantly increased alcohol intake. Naltrexone (0.3 or 1 mg/kg) significantly reduced alcohol SA during these alternating access sessions in animals that also received nicotine SA, but had minimal effects on animals receiving alcohol SA alone. Naltrexone did not affect nicotine SA under any condition. CONCLUSIONS: This sequential access procedure effectively models the effects of nicotine on alcohol intake noted in humans.
Assuntos
Alcoolismo/complicações , Comportamento Aditivo/complicações , Etanol/administração & dosagem , Nicotina/administração & dosagem , Fumar , Animais , Condicionamento Operante/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Naltrexona/farmacologia , Ratos , Ratos Long-Evans , AutoadministraçãoRESUMO
RATIONALE: The correlation between stress and smoking is well established. The mechanisms that underlie this relationship are, however, unclear. Recent data suggest that the kappa-opioid system is involved in the mediation of negative affective states associated with stress thereby promoting drug addiction and relapse. Pharmacological treatments targeting the kappa-opioid system and this mechanism may prove to be useful therapeutics for nicotine addiction in the future. OBJECTIVES: We sought to determine whether there was a stress-specific role of the kappa-opioid system in nicotine seeking behavior. METHOD: Groups of male Long Evans rats were trained to self-administer nicotine intravenously; their operant responding for nicotine was extinguished prior to tests of reinstatement. Pretreatment with systemic injections of the kappa-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was given prior to tests of stress (systemic injections of yohimbine (YOH)) or cue-induced reinstatement of nicotine seeking. Systemic injections of the KOR agonist U50,488 were also given in a test for reinstatement of nicotine seeking. RESULTS: Nor-BNI pretreatment at 1h and 24h prior to testing was able to block YOH-induced, but not cue-induced reinstatement of nicotine seeking. U50,488 reinstated nicotine seeking behavior in a dose-dependent manner. CONCLUSIONS: These findings support the hypothesis that the kappa-opioid system is involved in relapse to nicotine seeking induced by stress, but not by conditioned cues. KOR antagonists such as nor-BNI may therefore be useful novel therapeutic agents for decreasing the risk of stress-induced drug relapse.
Assuntos
Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Receptores Opioides kappa/metabolismo , Estresse Psicológico/etiologia , Estresse Psicológico/prevenção & controle , Tabagismo/complicações , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2 , Analgésicos não Narcóticos/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Esquema de Medicação , Interações Medicamentosas , Extinção Psicológica/efeitos dos fármacos , Masculino , Naltrexona/administração & dosagem , Naltrexona/análogos & derivados , Ratos , Ratos Long-Evans , Autoadministração , Ioimbina/toxicidadeRESUMO
RATIONALE AND OBJECTIVES: Stress increases drug intake. This depends on the stressor, drug, and aspect of drug seeking assessed. The objectives of these experiments done in adolescent and adult male rats were to (1) examine social defeat effects on acquisition of nicotine self-administration (SA) and the reinforcing efficacy of nicotine and (2) determine the effects of acute exposure to intermittent footshock (FS) or yohimbine on the reinforcing efficacy of nicotine. METHODS: In experiment 1, rats received four defeat exposures prior to nicotine SA acquisition and progressive ratio (PR) SA sessions (30 µg/kg nicotine/infusion). Exposure to an olfactory cue previously paired with defeat was also tested on responding maintained by nicotine on the PR schedule. In experiments 2 and 3, the effects of FS (5 and 10 min) or yohimbine (0.625 and 1.25 mg/kg, i.p.) on PR responding for nicotine (15, 30, or 60 µg/kg/infusion) were assessed. Adolescents were aged PD34-36 and adults PD81-85 at the beginning of nicotine SA training. RESULTS: Defeat did not affect nicotine SA acquisition. Prior exposure to defeat or a defeat-paired olfactory cue did not affect PR responding for nicotine. FS modestly decreased PR responding in adolescents at the middle nicotine infusion dose. Yohimbine increased PR responding independent of nicotine infusion dose and age. CONCLUSIONS: Together with previous work with other drugs, our data indicate that the effects of stress on the reinforcing efficacy of nicotine are stressor- and drug-dependent. This suggests that there is heterogeneity among stressors on how they affect neuronal systems underlying drug intake.
Assuntos
Envelhecimento/fisiologia , Comportamento de Procura de Droga/fisiologia , Nicotina/administração & dosagem , Agonistas Nicotínicos/farmacologia , Reforço Psicológico , Estresse Psicológico/fisiopatologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Sinais (Psicologia) , Dominação-Subordinação , Relação Dose-Resposta a Droga , Comportamento de Procura de Droga/efeitos dos fármacos , Eletrochoque , Masculino , Odorantes , Ratos Long-Evans , Esquema de Reforço , Autoadministração , Ioimbina/farmacologiaRESUMO
Stress is an important factor in the initiation and maintenance of smoking in adolescents. Women are more vulnerable to the development of addiction to smoking and have more difficulty quitting than men. Women also showe enhanced responses to stress. Despite these differences, no work has been done examining the effects of stress on the reinforcing efficacy of self-administered nicotine in adolescent rats, or if there are sex differences. Male and female adolescent Long Evans rats were trained to self-administer one of three different intravenous doses of nicotine (7.5, 15, 30 µg/kg/infusion) first on fixed ratio, and then on a progressive ratio (PR) schedule beginning on postnatal day 33. The effect of the pharmacological stressor yohimbine (0.3, 0.6 mg/kg, i.p.) on the reinforcing efficacy of nicotine was then determined using the PR schedule. Yohimbine stimulated nicotine intake and increased PR breakpoints and numbers of infusions received in both male and female adolescent rats. The infusion dose of nicotine was positively associated with yohimbine-induced increases in responding. Female rats showed significantly increased breakpoints at yohimbine doses and nicotine infusion doses at which males did not. The effects of the pharmacological stressor, yohimbine on the reinforcing efficacy of nicotine are therefore linked to sex and nicotine infusion dose. Female rats are more sensitive to stress-induced potentiation of nicotine self-administration.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Reforço Psicológico , Caracteres Sexuais , Ioimbina/farmacologia , Adolescente , Adulto , Fatores Etários , Análise de Variância , Animais , Condicionamento Operante , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Humanos , Infusões Intravenosas , Masculino , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Ratos , Esquema de Reforço , Recompensa , Autoadministração , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/fisiopatologia , Tabagismo/fisiopatologiaRESUMO
The pharmacological stressor yohimbine increases ongoing alcohol self-administration and reinstates alcohol seeking in rats. This effect is attenuated by systemic injections of a corticotropin-releasing factor (CRF) antagonist. The brain sites involved in CRF's role in yohimbine-induced alcohol taking and seeking are unknown. We report that injections of the CRF receptor antagonist d-Phe CRF into the median raphe nucleus (MRN) attenuated yohimbine-induced reinstatement of alcohol seeking but had no effect on yohimbine-induced increases in alcohol intake during ongoing self-administration. Results indicate an important role of MRN CRF receptors in yohimbine-induced reinstatement of alcohol seeking but not yohimbine-induced increases in alcohol intake.
Assuntos
Depressores do Sistema Nervoso Central/administração & dosagem , Hormônio Liberador da Corticotropina/fisiologia , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/administração & dosagem , Núcleos da Rafe/efeitos dos fármacos , Ioimbina/farmacologia , Animais , Hormônio Liberador da Corticotropina/análogos & derivados , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Hormônio Liberador da Corticotropina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , AutoadministraçãoRESUMO
RATIONALE AND OBJECTIVES: Relapse to alcohol use during abstinence or maladaptive eating habits during dieting is often provoked by stress. The anxiogenic drug yohimbine, which causes stress-like responses in humans and non-humans, reliably reinstates alcohol and food seeking in a rat relapse model. Yohimibine is a prototypical alpha-2 adrenoceptor antagonist, but results from studies on noradrenaline's role in yohimbine-induced reinstatement of drug and food seeking are inconclusive. Here, we further addressed this issue by studying the effect of the alpha-1 adrenoceptor antagonist prazosin and the alpha-2 adrenoceptor agonist guanfacine on yohimbine-induced reinstatement. METHODS: In exp. 1, we trained rats to self-administer alcohol (12% w/v, 1 h/day), and after extinction of alcohol-reinforced lever pressing, we tested prazosin's (0.5, 1.0, and 2.0 mg/kg, i.p.) or guanfacine's (0.125, 0.25, and 0.5 mg/kg, i.p.) effect on yohimbine (1.25 mg/kg, i.p.)-induced reinstatement; we also examined prazosin's effect on intermittent-footshock-stress-induced reinstatement. In exp. 2, we trained food-restricted rats to self-administer 45 mg food pellets and first examined prazosin's or guanfacine's effects on food-reinforced responding, and then, after extinction of lever presses, on yohimbine-induced reinstatement. RESULTS: Prazosin (0.5-2.0 mg/kg) blocked yohimbine-induced reinstatement of food and alcohol seeking, as well as footshock-induced reinstatement of alcohol seeking. Guanfacine attenuated yohimbine-induced reinstatement of alcohol seeking at the highest dose (0.5 mg/kg), but its effect on yohimbine-induced reinstatement of food seeking was not significant. Neither prazosin nor guanfacine affected high-rate food-reinforced responding. CONCLUSIONS: Results demonstrate an important role of postsynaptic alpha-1 adrenoceptors in stress-induced reinstatement of alcohol and food seeking.
Assuntos
Etanol/administração & dosagem , Comportamento Alimentar/efeitos dos fármacos , Guanfacina/farmacologia , Prazosina/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Guanfacina/administração & dosagem , Masculino , Prazosina/administração & dosagem , Ratos , Ratos Long-Evans , Ratos Wistar , Prevenção Secundária , Autoadministração , Estresse Psicológico , Ioimbina/farmacologiaRESUMO
Adolescence is considered a period of enhanced vulnerability to the initiation of tobacco use. Biological differences in the sensitivity of adolescents and adults to the anxiogenic and anxiolytic effects of nicotine may contribute to this heightened vulnerability. Here, we investigated the age-dependency of the effects of acute nicotine on anxiety-related behaviour and neurotransmission. In Experiment 1, male adolescent (P33-37) and adult (P65-69) Long-Evans rats received nicotine (0, 0.4 or 0.8 mg/kg,s.c.) prior to testing using two measures of anxiety, the elevated plus maze (EPM) and light-dark (LD) transition box. In Experiment 2, in situ hybridization was used to assess, in different male adolescent and adult rats, CRF mRNA expression in the BNST, PVN and CeA in response to acute nicotine. In the EPM, adult rats displayed less anxious behaviour than adolescents. Nicotine (0.4, 0.8 mg/kg) increased open and closed arm entries in adolescent rats, suggesting increased general activity, but it did not affect behaviour in the LD box. CRF mRNA expression was elevated in PVN of adolescent rats, relative to adults. Nicotine, however, had no effect on CRF mRNA expression in the BNST, PVN or CeA. The present findings suggest that adolescents are more sensitive to the general activational, rather than anxiety-related, effects of nicotine, and that CRF mRNA expression in stress-related brain regions does not correlate with these effects. This work further characterizes the age-related differences in the anxiety-related effects of nicotine, and provides insight into potential factors influencing vulnerability to tobacco abuse.
Assuntos
Ansiedade/metabolismo , Ansiedade/psicologia , Hormônio Liberador da Corticotropina/biossíntese , Neurônios/metabolismo , Nicotina/farmacologia , Fatores Etários , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/induzido quimicamente , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Relação Dose-Resposta a Droga , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Long-Evans , Núcleos Septais/efeitos dos fármacos , Núcleos Septais/metabolismoRESUMO
Contexts associated with the availability of alcohol can induce craving in humans and alcohol seeking in rats. The opioid antagonist naltrexone attenuates context-induced reinstatement (renewal) of alcohol seeking and suppresses neuronal activation in the basolateral amygdaloid complex and dorsal hippocampus induced by such reinstatement. The objective of this study was to determine whether pharmacological blockade of opioid receptors in the basolateral amygdala or dorsal hippocampus would attenuate the context-induced reinstatement of alcohol seeking. Rats were trained to self-administer alcohol in one context (Context A), extinguished in a distinct context (Context B) and then tested for reinstatement of alcohol seeking in A and B contexts. Prior to the test session, rats were bilaterally microinjected with 0, 333 or 1000ng (total) naloxone methiodide into the basolateral amygdala or dorsal hippocampus. Naloxone methiodide in the amygdala, but not the hippocampus, dose dependently suppressed context-induced reinstatement. This suggests that opioid transmission in the basolateral amygdaloid complex is an important mediator of context-induced alcohol seeking.