RESUMO
The involvement of cholecystokinin (CCK) in the mechanisms of stress and/or anxiety was assessed by in vivo microdialysis in rats subjected to a social stress paradigm. During the initial 30 min period of each conditioning session, a male Sprague Dawley rat (intruder) was placed in a protective cage inside the cage of a male Tryon Maze Dull rat (resident), allowing unrestricted visual, olfactory, and auditory contacts but precluding close physical contact between them. During the following 15 min period, both the protective cage and the resident were removed (nondefeated intruders) or only the protective cage was removed allowing the resident to attack the intruder (defeated rats). This procedure was repeated once daily for 4 d. On the fifth day, a guide cannula was implanted into the prefrontal cortex of intruders. During a single 30 min test session, performed 4 d later, intruders were subjected to only the 30 min protected confrontation to the resident. Anxiety-like behavior (immobility, ultrasonic vocalizations, and defensive postures), associated with an increase (approximately +100% above baseline) in cortical outflow of CCK-like material (CCKLM), were observed in defeated intruders. Pretreatment with diazepam (5 mg/kg, i.p.), but not buspirone (0.5-2 mg/kg, i.p.), prevented both the anxiety-related behavior and CCKLM overflow. The selective CCK-B receptor antagonist CI-988 (2 mg/kg, i.p.) reduced the anxiety-like behavior without affecting the increase in CCKLM outflow. These data indicate that anticipation of social defeat induces a marked activation of cortical CCKergic neurons associated with anxiety-related behaviors in rats.
Assuntos
Ansiedade/metabolismo , Colecistocinina/metabolismo , Dominação-Subordinação , Espaço Extracelular/metabolismo , Córtex Pré-Frontal/metabolismo , Agressão/fisiologia , Animais , Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Modelos Animais de Doenças , Eletrodos Implantados , Masculino , Microdiálise , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Ratos Sprague-Dawley , Estresse Fisiológico/metabolismo , TerritorialidadeRESUMO
In animals, as in humans, benzodiazepines affect memory, inducing almost exclusively an anterograde amnesia. The characteristics of this amnesic-like effect are reviewed in terms of alterations in acquisition, consolidation, recall and/or forgetting processes. Explanations alternative to a true amnesia, i.e., state-dependent learning, cognitive deficits, attenuation of the emotional weight of the conditioning events are examined. Finally, the interference of these putative amnesic effects with experimental procedures devoted to the study of the anxiolytic activities of benzodiazepines are considered.
Assuntos
Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Memória/efeitos dos fármacos , Animais , Benzodiazepinas , Cognição/efeitos dos fármacos , Eletroencefalografia , Aprendizagem/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Ratos , Sono REM/efeitos dos fármacosRESUMO
Numerous pharmacological data indirectly support the idea that interactions between cholecystokinin (CCK) and opioids participate in the development of tolerance to morphine. Biochemical investigations were performed with the aim of directly assessing the status of such interactions in morphine treated rats. Tolerance to the alkaloid after s.c. implantation of morphine pellets for three days was not associated with any change in the levels of both CCK like-material (CCKLM) and proCCK mRNA in the frontal cortex. However, microdialysis in the freely moving rat showed that this morphine treatment produced a significant increase (+40%) of the cortical spontaneous CCKLM outflow, which could be completely prevented by intracortical infusion of naloxone (10 microM). The opioid receptors responsible for morphine-induced cortical CCKLM overflow appeared to be of the delta type because intracortical infusion of selective delta-opioid receptor antagonists such as naltriben (10 microM) and 7-benzylidenenaltrexone (10 microM) also prevented the effect of morphine, whereas CTOP (10 microM), a selective mu-opioid receptor antagonist, and nor-binaltorphimine (10 microM), a selective K-opioid receptor antagonist, were inactive. These data indicate that morphine tolerance is associated with delta-opioid receptor mediated activation of cortical CCKergic systems in rats.
Assuntos
Colecistocinina/metabolismo , Morfina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Receptores Opioides delta/metabolismo , Analgésicos Opioides/farmacologia , Animais , Interações Medicamentosas , Tolerância a Medicamentos , Masculino , Antagonistas de Entorpecentes/farmacologia , Córtex Pré-Frontal/metabolismo , Precursores de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Opioides delta/antagonistas & inibidoresRESUMO
The present study provides evidence that, in mice subjected to the forced swimming test, the anti-immobility effect of the tricyclic antidepressants, desipramine and imipramine (16-32 mg/kg) was antagonized by the acute co-administration of a benzodiazepine, diazepam (0.25-2 mg/kg) and lorazepam (0.125 mg/kg). This effect cannot be accounted for by variations in plasma and/or brain levels of each compound since brain and plasma concentrations of desipramine and plasma levels of diazepam and desmethyldiazepam, measured immediately after the swimming test, were not significantly modified by the co-administration. Diazepam (2 mg/kg) also counteracted the reduction of time spent immobile induced by the MAO inhibitors, toloxatone (256 mg/kg) and selegiline (4 mg/kg) and the 5-HT1A receptor agonist, 8-OH-DPAT (1 mg/kg), but not by the psychostimulant, caffeine (32 mg/kg). The sedative neuroleptic, thioridazine (4 mg/kg) was also found to reverse the anti-immobility effect of desipramine whereas the non-benzodiazepine anxiolytics, alpidem (8 mg/kg) and buspirone (0.5 mg/kg) did not. These results indicate that the observed interactions were unlikely to be accounted for by a reduction of the stressful aspect of the situation whereas the participation of some motor or sedative component could not be totally ruled out.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/antagonistas & inibidores , Atividade Motora/efeitos dos fármacos , Análise de Variância , Animais , Ansiolíticos/farmacocinética , Antidepressivos/farmacocinética , Benzodiazepinas , Encéfalo/metabolismo , Cafeína/farmacologia , Cromatografia Líquida de Alta Pressão , Masculino , Camundongos , Fatores de TempoRESUMO
In chronically implanted awake rats, microinjections of chlordiazepoxide (5 x 10(-7) M) into the dorsal raphé significantly attenuated the inhibition of lever-pressing for food elicited by a signal of punishment. This effect is abolished by prior application of 5,7-dihydroxytryptamine into the dorsal raphé (3 weeks after the infusion of the neurotoxin, dorsal raphé tryptophan hydroxylase activity was reduced to 25% of control values). Furthermore, the disinhibitory effect of intra raphé chlordiazepoxide can be mimicked or potentiated by intra raphé dorsalis application of serotonin (10(-7) or 10(-8) M, respectively). Further evidence for a crucial interaction between benzodiazepines and serotoninergic processes are provided by in vitro experiments showing that chlordiazepoxide or diazepam (10(-5) M) are able to facilitate the K+-evoked [3H]serotonin release from rat midbrain slices. Finally, a high density of [3H]flunitrazepam binding sites was found in the dorsal (and the median) raphé nucleus, the Kd and Bmax values being not altered by prior infusion of 5,7-dihydroxytryptamine. These in vitro data suggest possible means by which intra raphé (and perhaps peripherally administered) benzodiazepines may affect the activity of serotoninergic neurons and thereby produce their effects on experimental anxiety.
Assuntos
Nível de Alerta/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Clordiazepóxido/farmacologia , Núcleos da Rafe/efeitos dos fármacos , Receptores de Droga/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , 5,7-Di-Hidroxitriptamina/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Flunitrazepam/metabolismo , Gânglios Espinais/efeitos dos fármacos , Masculino , Metergolina/farmacologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Receptores de GABA-A , Serotonina/metabolismo , Serotonina/farmacologia , Triptofano Hidroxilase/metabolismoRESUMO
Two subtypes of cannabinoid receptors have been identified to date, the CB1 receptor, essentially located in the CNS, but also in peripheral tissues, and the CB2 receptor, found only at the periphery. The identification of delta9-tetrahydrocannabinol (delta9-THC) as the major active component of marijuana (Cannabis sativa), the recent emergence of potent synthetic ligands and the identification of anandamide and sn-2 arachidonylglycerol as putative endogenous ligands for cannabinoid receptors in the brain, have contributed to advancing cannabinoid pharmacology and approaching the neurobiological mechanisms involved in physiological and behavioral effects of cannabinoids. Most of the agonists exhibit nonselective affinity for CB1/CB2 receptors, and delta9-THC and anandamide probably act as partial agonists. Some recently synthesized molecules are highly selective for CB2 receptors, whereas selective agonists for the CB1 receptors are not yet available. A small number of antagonists exist that display a high selectivity for either CB1 or CB2 receptors. Cannabinomimetics produce complex pharmacological and behavioral effects that probably involve numerous neuronal substrates. Interactions with dopamine, acetylcholine, opiate, and GABAergic systems have been demonstrated in several brain structures. In animals, cannabinoid agonists such as delta9-THC, WIN 55,212-2, and CP 55,940 produce a characteristic combination of four symptoms, hypothermia, analgesia, hypoactivity, and catalepsy. They are reversed by the selective CB1 receptor antagonist, SR 141716, providing good evidence for the involvement of CB1-related mechanisms. Anandamide exhibits several differences, compared with other agonists. In particular, hypothermia, analgesia, and catalepsy induced by this endogenous ligand are not reversed by SR 141716. Cannabinoid-related processes seem also involved in cognition, memory, anxiety, control of appetite, emesis, inflammatory, and immune responses. Agonists may induce biphasic effects, for example, hyperactivity at low doses and severe motor deficits at larger doses. Intriguingly, although cannabis is widely used as recreational drug in humans, only a few studies revealed an appetitive potential of cannabimimetics in animals, and evidence for aversive effects of delta9-THC, WIN 55,212-2, and CP 55,940 is more readily obtained in a variety of tests. The selective blockade of CB1 receptors by SR 141716 impaired the perception of the appetitive value of positive reinforcers (food, cocaine, morphine) and reduced the motivation for sucrose, beer and alcohol consumption, indicating that positive incentive and/or motivational processes could be under a permissive control of CB1-related mechanisms. There is little evidence that cannabinoid systems are activated under basal conditions. However, by using SR 141716 as a tool, a tonic involvement of a CB1-mediated cannabinoid link has been demonstrated, notably in animals suffering from chronic pain, faced with anxiogenic stimuli or highly motivational reinforcers. Some effects of SR 141716 also suggest that CB1-related mechanisms exert a tonic control on cognitive processes. Extensive basic research is still needed to elucidate the roles of cannabinoid systems, both in the brain and at the periphery, in normal physiology and in diseases. Additional compounds, such as selective CB1 receptor agonists, ligands that do not cross the blood brain barrier, drugs interfering with synthesis, degradation or uptake of endogenous ligand(s) of CB receptors, are especially needed to understand when and how cannabinoid systems are activated. In turn, new therapeutic strategies would likely to emerge.
Assuntos
Comportamento Animal/efeitos dos fármacos , Canabinoides/farmacologia , Animais , Sistema Nervoso Central/efeitos dos fármacos , HumanosRESUMO
In rats trained in an operant fixed-interval-30-s schedule of food reward (FI-30s), acute exposure to contingent footshock resulted in a response suppression that was released by diazepam (DZP; 4 mg/kg ip) but not by buspirone (0.25 or 0.50 mg/kg ip). Compared with baseline, hippocampal and cortical extracellular levels of serotonin (5-HText) did not change, regardless of operant period (punished or nonpunished) and drug. In contrast, in the striatum, an increase of 5-HText levels (535%) occurred during the punished period, counteracted by DZP. This effect was observed only in rats that were low responders during both nonpunished and punished periods, that is, those that exerted an efficacious control over responding. Uncontrollable shocks or exposure to an unfamiliar open field did not modify striatal 5-HText. Together, these results suggest that an acute activation of 5-HT neurons afferent to the striatum allows the rats to efficiently block responses that are negatively reinforced.
Assuntos
Condicionamento Operante/fisiologia , Conflito Psicológico , Corpo Estriado/metabolismo , Espaço Extracelular/metabolismo , Hipocampo/metabolismo , Córtex Pré-Frontal/metabolismo , Serotonina/metabolismo , Animais , Comportamento Animal/fisiologia , Masculino , Ratos , Ratos WistarRESUMO
The effects of naloxone on diazepam-induced release of behavior in aversive situations were investigated in rats. Naloxone (0.5 and 1 mg/kg-1) suppressed diazepam-induced eating in an unfamiliar situation and reduced (1 mg/kg-1) spontaneous food intake. Naloxone (1 mg/kg-1) canceled the increased lever pressing produced by diazepam in a conflict procedure in which one electric shock was delivered at each seventh press. Naloxone (1 mg/kg-1) failed to reverse the enhanced responding for food induced by diazepam in the presence of a signal previously paired with electric foot shocks. In this situation, naloxone alone reinforced the behavioral suppression. These results suggest that transmission mediated by opiate peptides may be involved in only some 'disinhibitory' effects of benzodiazepines. In addition, such a peptidergic transmission may play a role in the control of stress-induced behavioral suppression.
Assuntos
Comportamento Animal/efeitos dos fármacos , Diazepam/farmacologia , Naloxona/farmacologia , Animais , Interações Medicamentosas , Eletrochoque , Meio Ambiente , Comportamento Alimentar/efeitos dos fármacos , Masculino , Ratos , Reforço PsicológicoRESUMO
The behavioral effects of the benzodiazepine (BZP)-receptor partial inverse agonists, beta-CCE and FG 7142, are reviewed and the claim that these compounds possess "anxiogenic" properties is examined. Results obtained from human studies and global observations in animals, as well as those from experiments on aggression in animals or from studies of pentylenetetrazole discrimination cannot be considered conclusive. Contradictory findings have been obtained in studies using animal testing procedures derived from BZP-sensitive models of anxiety and in newer experimental situations and these are discussed from various theoretical perspectives: (1) the ability of the models to measure increased anxiety; (2) the possible ability of the drugs to reveal latent anxiety which generalizes from a punished to an otherwise non-fearful component of a testing procedure ("spreading anxiety"); (3) anxiety produced by a pro- or pre-convulsant state. Finally, several hypotheses are considered to account for the behavioral effects of beta-CCE and FG 7142 without assuming anxiogenic properties. These include the possible existence of different forms of anxiety, rate dependency, and drug-induced motivational changes. It is concluded that available data are insufficient to strongly support the notion that FG 7142 and beta-CCE are the anxiogenic drugs "par excellence" they are often claimed to be.
Assuntos
Ansiedade , Depressores do Apetite/farmacologia , Carbolinas/farmacologia , Animais , Humanos , LigantesRESUMO
The present study investigated in rats whether variables which may affect the animals' tolerance for delay of reward could be critical for the benzodiazepine-induced release of punished behavior. Rats were subjected to conflict situations during which signalled FR4 non-punished periods (lights-off) alternated with punished periods of different durations signalled by lights-on stimuli. Lever presses during punished periods resulted in the delivery of both one food-pellet and one electric foot-shock (0.45 mA). The antipunishment effect of diazepam (2 mg/kg IP) clearly depended on the duration of the punished periods, release of punished behavior being observed only when punished periods exceeded 1 min. The duration of punished periods required for diazepam-induced release of responding was affected by factors which modified the contrast between rewards received in punished and non-punished periods. One of these factors was the FR schedule imposed during non-punished periods, since the anti-punishment effect of diazepam was observed during short-lasting (30-s and 1-min) punished periods separated by FR24 non-punished periods. A second factor was the ratio of the durations of punished and non-punished periods: diazepam released behavior during 2-min punished periods when the duration of the intercurrent non-punished periods was 1 min, but not when it was 4 min. The predictability of the duration of the punished periods also modulated the effect of diazepam since: with 1 min punished periods, diazepam released punished responding during the first exposures of the rats to the experimental session, but lost part or all its efficacy in animals extensively trained to the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Diazepam/farmacologia , Punição , Animais , Condicionamento Operante , Eletrochoque , Alimentos , Masculino , Ratos , Ratos Endogâmicos , RecompensaRESUMO
Cooper (1983, 1985) observed an inhibition of ambulation and fluid intake in rats following diazepam in the microgram dose range. The present study aimed at investigating the effects of microgram doses of this benzodiazepine on i) the threshold doses of either pentylenetetrazole, picrotoxin or bicuculline required to induce seizures in mice and ii) the suppression of lever pressing for food induced by the delivery of one electric footshock every ten presses in rats pretreated or not with isoniazid (64 mg/kg IP). Diazepam 4-32 micrograms/kg IP) neither reduced seizure threshold doses of either convulsant studied nor did this drug (16-128 micrograms/kg IP) reliably decrease the number of lever presses under the punishment schedule. The present study provides no further evidence for a dose-related biphasic effect of diazepam which could give new insight into the functioning of benzodiazepine-coupled brain processes.
Assuntos
Condicionamento Operante/efeitos dos fármacos , Diazepam/administração & dosagem , Convulsões/induzido quimicamente , Animais , Bicuculina/farmacologia , Diazepam/farmacologia , Isoniazida/farmacologia , Camundongos , Pentilenotetrazol/farmacologia , Picrotoxina/farmacologia , PuniçãoRESUMO
Diazepam and muscimol, a direct GABA agonist, were compared on behavioral inhibition induced in rats by (1) novelty, (2) punishment, and (3) nonreward. (1) Muscimol (0.03--0.25 mg . kg-1 i.p. 30 min before testing, or i.v. immediately before testing) failed to enhance food intake consistently in a nonfamiliar situation and (0.125--0.5 mg . kg-1 i.p. or i.v.) to increase the ingestion of an unknown food (chocolate); (2) muscimol (0.125--0.5 mg . kg-1 i.p. or 0.25 i.v. 10 min before testing) was ineffective in reducing the inhibition of lever presses for food elicited by the delivery of an electric shock at every eighth press; (3) muscimol (0.125--0.5 mg . kg-1 i.p.) failed to attenuate the inhibitory effects on responding induced by the suppression of the reinforcement during extinction. Contrastingly, diazepam (2 mg . kg-1 i.p. 30 min before testing) was found to reduce each type of behavioral inhibition. These data lend no support to the hypotheses of GABA control of behavioral inhibition and of GABA involvement in the action of benzodiazepines on inhibition induced by novelty, punishment, or nonreward.
Assuntos
Comportamento Animal/efeitos dos fármacos , Diazepam/farmacologia , Muscimol/farmacologia , Oxazóis/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Meio Ambiente , Comportamento Alimentar/efeitos dos fármacos , Masculino , Punição , Ratos , RecompensaRESUMO
The stimulant effects of oxolinic acid were investigated in rats and mice. This drug, given orally, consistantly induced, in doses ranging from 16 to 256 mg.kg-1, locomotor stimulation and stereotyped behavior. These effects were antagonized by pimozide (1 mg.kg-1), alpha-methyltyrosine (64 mg.kg-1) or reserpine (4 mg.kg-1, 24 h before testing) pretreatment, suggesting a facilitatory role of oxolinic acid on catecholaminergic processes. Diazepam (4-16 mg.kg-1) reduced the stimulant effects induced by oxolinic acid but not those induced by amphetamine; oxolinic acid (8 mg.kg-1) markedly reduced the antipunishment effect elicited in rats by diazepam (2 mg.kg-1). Since benzodiazepines have been reported to enhance GABA functioning, these data suggest that oxolinic acid may impair GABA transmission. However, neither muscimol (0.5-1 mg.kg-1) or gamma-acetylenic-GABA (16-64 mg.kg-1) selectively reduced the stimulant effects elicited by oxolinic acid. Therefore, the possible facilitation exerted by this drug on catecholaminergic systems may not derive from the release of an inhibitory GABAergic control.
Assuntos
Comportamento Animal/efeitos dos fármacos , Diazepam/farmacologia , Ácido Oxolínico/farmacologia , Animais , Barbital/farmacologia , Conflito Psicológico/efeitos dos fármacos , Diazepam/antagonistas & inibidores , Antagonistas de Dopamina , Humanos , Masculino , Atividade Motora/efeitos dos fármacos , Ácido Oxolínico/antagonistas & inibidores , Ratos , Comportamento Estereotipado/efeitos dos fármacos , Ácido gama-Aminobutírico/fisiologiaRESUMO
A new method involving the blockade of operant behaviour induced by the withdrawal of a conditioned signal for safety without presentation of a punishment signal has been developed for studying drugs with anxiolytic or anxiogenic properties. For this purpose, rats were trained under two alternating components of a multiple schedule of reinforcement FR8 (food)/FR1 (food) + RR 50% (shocks randomly delivered with 50 +/- 15% of the presses). The nonpunished and punished periods were signalled by one cue light above the right lever (safety signal) or the left lever (punishment signal), respectively. On the test session (safety signal withdrawal), the safety signal was turned off at the end of the first nonpunished period, but the punishment signal was not presented (every press was food rewarded and no shocks were delivered). During this period (4 min), rats exhibited a strong blockade of responding that lessened over time. This suppression seemed not to be caused by intervening events such as novelty, temporal conditioning, schedule of food delivery or ambiguity of the signal presented. The behavioural blockade induced by withdrawal of the safety signal was reduced by benzodiazepines: diazepam (0.5-4 mg/kg), chlordiazepoxide (4-8 mg/kg), nitrazepam (0.25-2 mg/kg), alprazolam (0.25-1 mg/kg), and partial agonists at benzodiazepine receptors: bretazenil (0.125-8 mg/kg) and ZK 91296 (32-64 mg/kg). Various 5-HT-related drugs also lessened the behavioural blockade:pCPA (3 x 150 mg/kg) and the 5-HT1A receptor agonists, buspirone (0.25-2 mg/kg), gepirone (0.25-1 mg/kg) but not 8-OH-DPAT. Compounds that may cause anxiety in humans further enhanced the blockade of lever pressing induced by the safety signal withdrawal at doses that did not modify baseline responding: d-amphetamine (0.125-0.5 mg/kg), caffeine (16 mg/kg) and picrotoxin (1 mg/kg). FG 7142 (8 mg/kg) and CGS 8216 (2-8 mg/kg) decreased responding during both components of the session. Therefore, the present paradigm seems sensitive to both "anxiolytic" and "anxiogenic" effects of drugs under identical procedural conditions.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Animais , Ansiedade/psicologia , Benzodiazepinas , Condicionamento Operante/efeitos dos fármacos , Antagonistas de Receptores de GABA-A , Masculino , Ratos , Ratos Endogâmicos , Receptores de GABA-A/farmacologia , Serotonina/fisiologiaRESUMO
The involvement of cannabinoid processes in positive reinforcement was studied using an unbiased, one-compartment, conditioned place preference (CPP) procedure in rats. This was achieved by examining the ability of the selective antagonist of the CB1 cannabinoid receptor subtype, SR 141716, to counteract the CPP supported by classical reinforcers. The acquisition of CPP induced by cocaine (2 mg/kg), morphine (4 mg/kg) and food (standard chow and sucrose pellets) was dose-dependently blocked by pre-pairing administration of SR 141716 (0.03-3 mg/kg). However, SR 141716 (up to 10 mg/kg) did not significantly counteract the expression of cocaine-induced CPP. On the other hand, the synthetic CB receptor agonist, WIN 55212-2 (0.3-1 mg/kg), established a robust place aversion (CPA), as already described with other agonists, and CPP was never observed, even at 100-fold lower doses. The aversive effect of WIN 55212-2 was reversed by SR 141716 (0.3-1 mg/kg), suggesting that it was accounted for by the stimulation of CB1 receptors. These findings indicate that, on their own, CB receptor agonists are unable to generate the processes necessary to induce a pleasurable state in animals, as assessed in place conditioning procedures. Nevertheless, a cannabinoid link may be involved in the neurobiological events, allowing the perception of the rewarding value of various kinds of reinforcers. However, a permanent endogenous cannabinoid tone seems unlikely to be necessary to ensure the organism a basal hedonic level since, given alone, SR 141716 supported neither CPP nor CPA.
Assuntos
Canabinoides/metabolismo , Condicionamento Operante/efeitos dos fármacos , Receptores de Droga/fisiologia , Animais , Benzoxazinas , Bloqueadores dos Canais de Cálcio/farmacologia , Canabinoides/antagonistas & inibidores , Cocaína/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , Morfina/farmacologia , Morfolinas/farmacologia , Atividade Motora/efeitos dos fármacos , Naftalenos/farmacologia , Entorpecentes/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Receptores de Canabinoides , Receptores de Droga/agonistas , Receptores de Droga/efeitos dos fármacos , RimonabantoRESUMO
Two behaviors related to nonreward (omission of water in an enclosure where the rats were habituated to drink) were studied. The time spent licking the bottles during water omission and the time spent drinking during a subsequent 5-min drinking session (water available) were recorded. The drinking session was performed 30 min after the water-omission session. Rats subjected to water omission showed an enhanced drinking time that varied with the length of the water omission session, with the motivational state of the animals, and with the previous number of water-omission sessions. Diazepam, chlordiazepoxide, lorazepam, and meprobamate (i.p., 30 min before water omission), increased the time spent licking the empty bottles, but failed to abolish subsequently enhanced drinking. However, some of our data suggested that minor tranquilizers weakly reduced the increased drinking induced by nonreward, despite their direct stimulation on water drinking. It is proposed that either minor tranquilizers are devoid of general antifrustration activity or nonreward-induced frustration and nonreward-induced drive enhancement may not be correlated.
Assuntos
Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Recompensa , Amobarbital/farmacologia , Animais , Benzodiazepinas , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Masculino , Meprobamato/farmacologia , Ratos , ÁguaRESUMO
This study investigated whether benzodiazepines reduce the capacity of animals to wait for food reward. Rats trained in a T-maze were allowed to choose between two magnitudes of reward: immediate, but small (two pellets) vs delayed, but large (eight pellets). The rats learned within ten sessions to select (80-100%) the arm leading to the largest reward. Separate groups of rats were then confined for 15, 30 or 60 s in the arm associated with the largest reward before gaining access to the spacially contiguous goal-box. The choice of the other arm was not followed by a period of waiting. Under these conditions, the frequency with which the small-reward arm was chosen increased linearly as a function of the duration of the waiting period. Diazepam (2-4 mg/kg IP) dose-dependently increased the number of times the small-reward arm was chosen during the sessions for which the waiting period was fixed at 15 or 30 s. Nitrazepam (2 mg/kg IP), chlordiazepoxide (16 mg/kg IP) and clobazam (16 mg/kg IP) had similar effects. The action of diazepam was counteracted by simultaneous administration of flumazepil (Ro 15-1788, 8 mg/kg PO). In the absence of confinement, these benzodiazepines, diazepam (4 mg/kg) excepted, did not modify selection of the large-reward arm. Conversely, the serotonin uptake blockers indalpine (2-4 mg/kg IP) and zimelidine (8-16 mg/kg IP) dose-dependently increased preference for the arm leading to the delayed (25 s) but large reward. These results suggest that benzodiazepines, perhaps by increasing impulsivity, render the animals less prone than controls to tolerate delayed access to reward.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Ansiolíticos/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Recompensa , Animais , Benzodiazepinonas/farmacologia , Diazepam/farmacologia , Flumazenil , Masculino , Piperidinas/farmacologia , Ratos , Ratos Endogâmicos , Antagonistas da Serotonina , Transmissão Sináptica/efeitos dos fármacos , Zimeldina/farmacologiaRESUMO
The effects of manipulating central serotonergic transmission were assessed on the anti-punishment effects of diazepam (2 mg/kg IP) in rats. In a paradigm involving the inhibition of pressing for food induced by the delivery of a signal previously associated with electric foot-shocks, lesioning serotonergic neurons of the dorsal raphé with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 1 microgram in 0.4 microliter) neither affected behavioral inhibition in control rats nor modified the ability of diazepam to release responding. Furthermore, suppression of pressing for food induced by a fixed ratio 7 schedule of shock presentation was reduced by bilateral infusion of 5,7-DHT (2 micrograms in 0.5 microliter) into the substantia nigra, but the ability of diazepam to increase punished responding was preserved. Finally, blockade of benzodiazepine-induced decrease in serotonin release by application of the benzodiazepine receptor antagonist Ro 15-1788 (10(-5)-10(-4)M in 0.2 microliter) into the dorsal raphé did not alter the releasing effect of diazepam on suppression of pressing for food caused by a signal of punishment. At these concentrations. Ro 15-1788 was devoid of any effect on behavioral inhibition in control rats. Taken together, these results indicate that the anti-punishment activity of benzodiazepines can be dissociated from the reduction in tryptaminergic transmission produced by these drugs.
Assuntos
5,7-Di-Hidroxitriptamina/farmacologia , Condicionamento Operante/efeitos dos fármacos , Diazepam/farmacologia , Di-Hidroxitriptaminas/farmacologia , Neurônios/efeitos dos fármacos , Punição , Serotonina/fisiologia , Animais , Benzodiazepinonas/farmacologia , Eletrochoque , Flumazenil , Injeções , Masculino , Neurônios/fisiologia , Núcleos da Rafe , Ratos , Ratos Endogâmicos , Esquema de Reforço , Substância NegraRESUMO
Numerous data support the hypothesis that dopamine (DA) plays a crucial role in reward-related processes and in incentive learning in animals and man. The possibility that various neuroleptics exhibiting a high affinity for the dopaminergic D2 (and D3) receptors could reinforce DA transmission was studied using the conditioned place preference paradigm (CPP) in rats. This was done by examining the ability of these compounds to potentiate the reinforcing properties of food in hungry rats subjected to a version of the CPP paradigm which consisted of repeated pairings of food with a single environmental cue, the floor texture of an open field. During the test session when food was no longer available in the open field, the increase in the time spent by drug-free rats on the food-paired texture was assumed to indicate the perceived rewarding value of the food. This time was significantly lengthened when the specific D2 (D3)-receptor antagonists sulpiride (4 mg/kg), amisulpride (0.5, 1 mg/kg) or pimozide (0.03, 0.06 mg/kg) were administered before the food conditioning sessions. Larger doses of these compounds as well as haloperidol, metoclopramide and the non-specific D1-D2 antagonist, chlorpromazine, regardless of the doses tested, did not exhibit this effect, but rather reduced the food-induced CPP, an action usually associated with neuroleptics. The positive effects of amisulpride was reversed by a D1 receptor antagonist, SCH 23390 (0.01 mg/kg). These results suggest that, as with amphetamine (0.5 mg/kg), some D2-specific neuroleptics enhance the incentive value of food in a narrow range of low doses, an effect proposed to reflect a "prohedonic" property.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Antipsicóticos/farmacologia , Condicionamento Operante/efeitos dos fármacos , Alimentos , Animais , Antagonistas dos Receptores de Dopamina D2 , Privação de Alimentos/fisiologia , Masculino , Ratos , Ratos Wistar , Receptores de Dopamina D1/antagonistas & inibidores , Reforço Psicológico , Recompensa , Sacarose/farmacologiaRESUMO
SR 141716, a selective central CB1 cannabinoid receptor antagonist, markedly and selectively reduces sucrose feeding and drinking as well as neuropeptide Y-induced sucrose drinking in rats. SR 141716 also decreases ethanol consumption in C57BL/6 mice. In contrast, blockade of CB1 receptors only marginally affects regular chow intake or water drinking. The active doses of SR 141716 (0.3-3 mg/kg) are in the range known to antagonize the characteristic effects induced by cannabinoid receptor agonists. These results suggest for the first time that endogenous cannabinoid systems may modulate the appetitive value of sucrose and ethanol, perhaps by affecting the activity of brain reward systems.