RESUMO
Clinical studies have shown differential efficacy of several antidepressants in children and adolescents compared to adults, yet few animal studies have sought to characterize this phenomenon. We compared effects of fluoxetine and imipramine in two common behavioral assays that hold high predictive validity for antidepressant activity, tail suspension and forced swim test, using juvenile (5 weeks) and adult (12 weeks) mice from 3 strains. C57BL/6J-Tyr(c-Brd) (C57), hybrid C57BL/6J-Tyr(c-Brd)x129S5/SvEvBrd (F2), and Balb/cAnNTac (Balb/C) mice were tested in forced swim test and tail suspension after i.p. dosing with either fluoxetine or imipramine. Brain tissues were analyzed to evaluate levels of VMAT2, a possible modulator of age-dependent sensitivity to antidepressants. Imipramine had more consistent antidepressant effect across age groups and strains. Imipramine increased struggle in mice of both ages. Fluoxetine did not have an effect on immobility in Balb/C of both ages in tail suspension. Fluoxetine also did not increase forced swim struggle behavior in juvenile mice of all strains, but was effective in increasing struggle in adults. Juvenile mice had higher immobility and lower struggle than adults in forced swim, and juveniles also had higher immobility in tail suspension test for Balb/C and C57. In addition, VMAT2 levels were increased in juveniles. These results confirm that standard antidepressants produce effects in both juveniles and adults but age-related differences were evident in both tests. Further examination of these effects is needed to determine whether it may be related to age-dependent difference in the clinical response to antidepressants of these classes.
Assuntos
Envelhecimento/fisiologia , Antidepressivos Tricíclicos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Fluoxetina/farmacologia , Elevação dos Membros Posteriores , Imipramina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Polimorfismo Genético , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Natação , Triptofano Hidroxilase/genética , Proteínas Vesiculares de Transporte de Monoamina/metabolismoRESUMO
Studies of the biobehavioral actions of psychostimulants commonly focus on locomotion and less commonly on feeding, and only rarely are these measures considered in conjunction within the same animal. The present study compared the impact of (+)-amphetamine and three amphetamine analogs, PAL-287, PAL-313, and PAL-353, on eating and locomotion assessed concurrently using an automated activity/feeding chamber during a daily 45 min session. Each analog is a potent releaser of norepinephrine and of dopamine, but exerts differential serotonin-releasing activity (PAL-287>PAL-313>amphetamine>PAL-353). Rats were tested with each of five doses of drug (0, 2, 4, 8, or 16 micromol/kg, i.p.), given in equimolar concentrations and in random dose order. PAL-353, an analog with minimal serotonin-releasing capacity, markedly stimulated forward locomotion at 2, 4, 8 and 16 micromol/kg, as did amphetamine, whereas PAL-287 and PAL-313 did not. In contrast to the locomotor findings, all four amphetamine-like drugs exerted similar effects on the suppression of food intake. These results suggest that the capacity of an amphetamine analog (i.e. amphetamine and PAL-353) to stimulate serotonin release can diminish its psychostimulant action on locomotion, but does not reliably augment drug-induced hypophagia.
Assuntos
Anfetamina/química , Anfetamina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Animais , Comportamento Alimentar/fisiologia , Masculino , Atividade Motora/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
Variations in dietary constituents such as carbohydrate are known to alter psychostimulant function in brain. Relatively few studies have examined the reinforcing effects of psychostimulants in subjects maintained on high-fat diets. The present experiment compared the rate of acquisition of an operant response for intravenous (i.v.) cocaine infusions (0.2 mg/kg) in rats fed either a chow-pellet diet or a 35.9% (by weight) high-fat diet for 45 days prior to cocaine self-administration testing. Rats maintained on a high-fat diet for 45 days exhibited diminished acquisition of cocaine self-administration, and this effect was not a function of dietary-induced obesity. The results suggest that prolonged exposure to a high-fat diet diminishes the efficacy of cocaine reinforcement.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/prevenção & controle , Gorduras na Dieta/uso terapêutico , Animais , Condicionamento Operante/efeitos dos fármacos , Dieta , Masculino , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Autoadministração , Abuso de Substâncias por Via Intravenosa/psicologia , Aumento de Peso/efeitos dos fármacosRESUMO
Psychostimulants including amphetamine and cocaine induce locomotion and stereotypy and suppress eating. Although the capacity of cocaine to alter locomotion is usually viewed as related to dopamine neurotransmission, recent studies suggest that norepinephrine, acting through alpha1-adrenergic receptors (alpha1-ARs) can facilitate cocaine-stimulated locomotion. Of the three alpha1-AR subtypes (alpha(1A), alpha(1B), and alpha(1D)) identified to date, inactivation of the alpha(1B)-AR subtype diminishes cocaine-stimulated locomotion, whereas the impact of inactivation of the alpha(1A)-AR subtype on either eating or locomotion is unknown. In the present study, we assessed the relative impact of ICV administration of the alpha(1B)-AR antagonist 5-methylurapidil (5-MU) on cocaine-stimulated hyperlocomotion and hypophagia, using a concurrent method [Wellman, P.J., Ho, D.H., Davis, K.W., 2005. Concurrent measures of feeding and locomotion in rats. Physiology of Behavior 84 (5), 769-774.]. Rats were infused ICV with one of 3 doses of 5-MU (0, 3, or 30 nmol) and then injected (i.p.) with 0, 2.5, 5.0, 10.0, or 20.0 mg/kg cocaine HCl on each of five tests. Rats always received the same 5-MU dose, but a different cocaine dose on each trial. Feeding and locomotion were assessed concurrently during a 45-min postinjection period. Significant suppression of eating was noted at 2.5 mg/kg cocaine, a dose that does not alter forward locomotion in the rat. Administration of 5-MU did not alter locomotion in rats treated with saline, but did significantly increase baseline food intake. Neither cocaine-induced hypophagia nor hyperlocomotion was altered by ICV administration of 5-MU. These results suggest that the capacity of alpha1-AR agonists (e.g. phenylpropanolamine) to suppress eating may be related to activation of the alpha(1A)-AR subtype, whereas cocaine does not act through the alpha(1A)-AR subtype to suppress eating nor does this subtype modulate cocaine-induced hyperlocomotion.
Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Piperazinas/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1 , Anfetamina/farmacologia , Animais , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Masculino , Norepinefrina/metabolismo , Fenilpropanolamina/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
The physiological mechanism through which food restriction (FR) enhances the biobehavioral actions of psychostimulants is unknown but may involve the gut peptide ghrelin. Plasma levels of ghrelin are increased by FR and reduced by eating. Moreover, systemically administered ghrelin crosses into the brain and is known to augment the locomotor-stimulating effects of cocaine [COC: Wellman et al., 2005]. This study sought to determine whether pretreatment with ghrelin (5 nmol) would enhance the rewarding properties of COC (0.0, 0.312, 0.625, or 1.25 mg/kg i.p.) as measured by conditioned place preference (CPP). Adult male Sprague-Dawley rats were given free access to both sides of a CPP chamber to determine initial side preference. The rats were then confined for 30 min to either their preferred side or non-preferred side on 8 consecutive days. When rats were confined to the least preferred side, each was injected with 0.5 ml (i.p.) of either ghrelin (5 nmol) or saline 1 h before the conditioning trial and then injected (i.p.) with one of the COC doses immediately prior to the conditioning trial. On alternate days, rats were injected with vehicle one hour before and again immediately before the conditioning trial. Place preference scores were computed as the differences in time (min) spent on the least preferred side of the chamber for the pre-test and the postconditioning test, covaried by the initial degree of preference (% time spent on the black side during the pre-test). These analyses indicated a significant interaction between ghrelin pretreatment and COC dose on changes in preference scores. Significantly higher place preference scores were noted for rats treated with either 0.312 or 0.625 mg/kg COC doses, but only when these COC doses were preceded by administration of 5 nmol ghrelin. In contrast, saline pretreated rats exhibited significant CPP at the 1.25 mg/kg COC dose, but the ghrelin pretreated group did not. These results provide partial support for the contention that ghrelin pretreatment can augment the rewarding effects of sub-threshold doses of COC in a CPP procedure. Moreover, these findings are consistent with the view that ghrelin may play a role in the capacity of FR to augment psychostimulant action.
Assuntos
Cocaína/farmacologia , Condicionamento Operante , Hormônios Peptídicos/farmacologia , Reforço Psicológico , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Interações Medicamentosas , Grelina , Injeções Intraperitoneais , Masculino , Hormônios Peptídicos/administração & dosagem , Ratos , Ratos Sprague-DawleyRESUMO
Learning models of associative and nonassociative drug tolerance predict that the development of contextual tolerance to drug effects is disrupted when the drug is delivered at short interdose intervals (IDIs). The authors examined the impact of 1 long IDI and 2 short IDIs in the development of contextual nicotine tolerance. Associative tolerance was investigated by giving rats (Rattus norvegicus) 10 subcutaneous injections of nicotine at either long (72-hr) IDIs or short (6-hr and 4.5-hr) IDIs. The delivery of nicotine was either explicitly paired or explicitly unpaired with a distinctive context. A 3rd group of rats was exposed to the experimental procedures but received only saline. Associative tolerance to nicotine's analgesic effects was defined as a shift to the right of the dose-response curve (DRC) of rats in the explicitly paired condition with respect to the DRC of rats in the explicitly unpaired condition. Analgesia was assessed with the tail-flick and hot-plate devices. In the tail-flick assessment, associative tolerance was evident in the 72-hr and the 6-hr IDI conditions only. In the hot-plate assessment, associative tolerance was present in the 72-hr IDI condition only. The findings suggest that contextual tolerance to nicotine's analgesic effects are positively related to IDI length and are more readily demonstrated with the tail-flick method than with the hot-plate method. Overall, the results supported the thesis that nicotine tolerances that develop to different IDIs are qualitatively different and may be mediated by different psychological and physiological mechanisms.
Assuntos
Analgésicos/farmacologia , Nicotina/farmacologia , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Tolerância a Medicamentos , Masculino , Nicotina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Tempo de ReaçãoRESUMO
Studies of the effects of nicotine (NIC) on meal patterns in rats often employ chow pellet diets that contain little fat, whereas humans using NIC commonly consume diets relatively rich in fat. The aim of the present study was therefore to compare the impact of NIC administration and NIC cessation on meal pattern in adult male rats offered a standard powdered chow (CHOW: 10.9% fat by calories) diet or a palatable high-fat (HIFAT: 58.3% fat by calories) diet. Computerized meal pattern analyses were conducted for male rats treated for 14 days with injections of either saline or 1.4 mg/kg/day of NIC (as the free base given in 5 equal amounts) during the dark phase and continued for 10 days after NIC cessation. The suppression of daily caloric intake by NIC was larger in HIFAT-NIC rats than in CHOW-NIC rats (p < .01), such that NIC induced a greater suppression of body weight in HIFAT-NIC rats, relative to CHOW-NIC rats (p < 0.02). NIC administration reduced MS in both CHOW and HIFAT rats. CHOW fed rats showed a gradual increase in meal number in response to NIC, whereas HIFAT fed rats showed a significant initial suppression of meal number, which returned to control levels by day 4 of the 14 day NIC treatment period. In addition, NIC increased water intake more in HIFAT fed rats than in CHOW rats. Cessation of NIC resulted in transient increases in daily caloric intake in CHOW and in HIFAT rats. The present study demonstrates that NIC actions on food intake suppression, meal patterns, and weight reduction differ depending on whether the rats are fed low- or high-fat diets.
Assuntos
Ração Animal , Peso Corporal/efeitos dos fármacos , Gorduras na Dieta/administração & dosagem , Comportamento Alimentar/efeitos dos fármacos , Nicotina/farmacologia , Animais , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Psychostimulants including amphetamine and cocaine induce locomotion and stereotypy and suppress eating. Studies of the biobehavioral actions of psychostimulants commonly focus on locomotion and less commonly on feeding, and only rarely are these measures considered in conjunction within the same animal. Inasmuch as hyperactivity induced by a psychostimulant may compete with other motor behaviors, including eating, it would be important to concurrently assess changes in eating and locomotion after psychostimulant treatment. The present paper describes a modification of an automated activity chamber in which minute-by-minute recordings of food consumption are gathered in parallel with an assessment of locomotion. The present experiment illustrates the method by characterizing the temporal changes in locomotion and eating produced by administration of hypophagic doses of nicotine tartrate (0.28 mg/kg (as the base), IP) or cocaine hydrochloride (7.5 mg/kg, IP). At these doses, nicotine suppressed eating and locomotion, whereas cocaine suppressed eating, but facilitated forward locomotion. These outcomes support the viability of this apparatus and the concurrent method for the dissociation of feeding and locomotion.
Assuntos
Comportamento Alimentar/fisiologia , Atividade Motora/fisiologia , Animais , Cocaína/farmacologia , Dieta , Inibidores da Captação de Dopamina/farmacologia , Ingestão de Líquidos , Ingestão de Alimentos/fisiologia , Masculino , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Ratos , Ratos Sprague-Dawley , Comportamento Estereotipado/efeitos dos fármacosRESUMO
RATIONALE: Theories of drug tolerance differentiate between associative and behavioral (instrumental) drug tolerance. However, there is little research comparing these two forms of drug tolerance beyond alcohol and morphine. OBJECTIVE: We examined the time course development of associative and behavioral tolerance to the analgesic effects of nicotine. METHODS AND RESULTS: Associative tolerance was investigated by giving independent groups of rats one, five, 15, ten or 20 administrations of nicotine either explicitly paired or unpaired with a distinctive context. Associative tolerance, assessed in the tail flick, developed more rapidly and reached greater magnitude when nicotine and distinctive context were explicitly paired than when they were unpaired. This effect was evidenced after the fifth conditioning session and was maintained through the tenth, 15th, and 20th sessions. Contextual tolerance, assessed in the hot plate, was first evident after ten sessions. However, this effect disappeared safter 15 and 20 sessions. A second study examined the acquisition of behavioral tolerance to the disruptive effects of nicotine on the hot-plate response. Animals that practiced the test response while drugged developed greater tolerance than animals receiving as much nicotine and hot-plate practice but with these two conditions explicitly unpaired. This effect was evident in two different environments but did not generalize to the tail-flick test. CONCLUSIONS: The findings suggest that contextual tolerance to drug effects is test specific, with tail-flick responses depending on cue-associative tolerance processes and hot-plate responses requiring procedures that allow the animal to practice the test response while drugged.
Assuntos
Analgésicos/farmacologia , Comportamento Animal/efeitos dos fármacos , Nicotina/farmacologia , Animais , Condicionamento Psicológico/efeitos dos fármacos , Tolerância a Medicamentos , Masculino , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacosRESUMO
RATIONALE: Following repeated injections with nicotine paired with a distinctive environment, some studies have reported that the distinctive context becomes a conditioned stimulus (CS) capable of eliciting conditioned corticosterone (CORT) release. Conversely, other studies have found that exposure to the CS results in conditioned attenuation of nicotine-induced CORT release. OBJECTIVE: The present study was designed to examine whether these sets of separate findings could be replicated in animals exposed to the same experimental procedures within the same study. METHODS: CORT assessments were conducted in a distinctive context after independent groups of animals were injected with either saline or nicotine (1 mg/kg, salt) after five or ten nicotine injections either explicitly paired or unpaired with a distinctive context. The design also included groups of nicotine-naïve rats exposed to the experimental procedures and assessed for CORT levels following either nicotine or saline injections during their first, and after their fifth and tenth context exposures. RESULTS: CORT levels were higher after nicotine than after saline, and higher in the paired than in the unpaired condition. Exposure to the context without nicotine produced conditioned CORT release and exposure to the context did not attenuate nicotine-induced CORT release. CONCLUSIONS: The results supported the notion that a CS associated with nicotine effects elicit a conditioned response (CR) in the form of CORT release. Future research will be needed to examine whether conditioned CORT release can explain the context-dependent attenuations of nicotine-induced CORT.
Assuntos
Corticosterona/sangue , Nicotina/farmacologia , Animais , Condicionamento Psicológico/fisiologia , Corticosterona/metabolismo , Injeções , Masculino , Nicotina/administração & dosagem , Psicofarmacologia/métodos , Ratos , Ratos Sprague-Dawley , Cloreto de Sódio/administração & dosagemRESUMO
The feeding-relevant pathway by which food deprivation (FD) augments cocaine action is unknown. Systemic administration of the 28 amino acid acylated peptide ghrelin (1-10 nmol) increases food intake in rats and circulating levels of rat ghrelin are up-regulated by FD. The present experiment examined the impact of ghrelin or vehicle pretreatment on the locomotion and stereotypy induced by systemic cocaine hydrochloride. Male Sprague-Dawley rats were pretreated at -60 min with 0 or 5 nmol rat ghrelin (IP) and then injected (IP) at time 0 with 0, 2.5, 5.0, or 10.0 mg/kg cocaine. Locomotor activity was monitored over a 45-min post-cocaine period. Rats received the same ghrelin dose, but a different cocaine dose (in random order) on each of the four drug trials, with each drug trial separated by at least 2 days. Administration of 5 nmol ghrelin-0 mg/kg cocaine slightly increased locomotion relative to that of 0 nmol ghrelin-0 mg/kg cocaine. Cocaine increased locomotion as a function of dose in the 0 nmol ghrelin group, but the effect of cocaine was even greater when preceded by 5 nmol ghrelin. These results indicate that acute injection of ghrelin, at a feeding-relevant dose, augments the acute effects of cocaine on locomotion in rats.
Assuntos
Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Hormônios Peptídicos/fisiologia , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Grelina , Masculino , Movimento/efeitos dos fármacos , Hormônios Peptídicos/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Regulação para CimaRESUMO
The microstructure of feeding in rats can be probed using a variety of protocols that employ videotape-based ratings, pellet feeders, and/or laboratory balances. A recent commercial product (BioDAQ, Research Diets, New Brunswick, NJ) uses a metal food hopper placed on a load cell to monitor daily food pellet consumption. In this system, movements of the hopper during eating and the cessation of hopper movements after eating are combined with momentary hopper weights for subsequent analyses of daily meal patterns. Our laboratory has devised an improved food cup for the BioDAQ system that is easily balanced, minimizes spillage, and is compatible with either powdered chow diets or nonpelleted soft diets (e.g., a high-fat diet). In the present paper, we describe the methods used to fabricate this food cup and present data illustrating its use in meal pattern analyses for rats fed either a ground laboratory chow or a 33% high-fat diet.