RESUMEN
Brain-penetrant neurotensin NTS1 receptor agonists produce antipsychotic drug-like effects in animal models, including inhibition of conditioned avoidance responding and reversal of psychostimulant-induced hyperactivity and stereotypy. Allosteric interactions between NTS1 receptors and dopamine D2 receptors may account for some of these antipsychotic effects. In order to determine the role that dopamine receptors may play in the behavioral effects produced by activation of NTS1 receptors, a drug discrimination approach was used in rats to evaluate the potential mediation of NTS1 receptor agonist stimulus effects by dopamine D1 and D2 receptors. Rats were trained to discriminate either the NTS1 receptor agonist PD149163, the D1 receptor agonist SKF81297, or the D2 receptor agonist quinpirole from vehicle in a two choice drug discrimination task. Full stimulus generalization occurred from PD149163 to the typical antipsychotic drug and D2 receptor-preferring antagonist haloperidol. However, stimulus generalization did not occur from SKF81297 or quinpirole to PD149163. The discriminative cue for SKF91297 and quinpirole was fully blocked the D1 receptor antagonist SCH23390 and the D2/3 receptor antagonist raclopride, respectively. Cross generalization did not occur between SKF91297 and quinpirole. Based on these findings, the stimulus effects of PD149163 may be mediated, in part, through D2 receptor antagonism, but this may only be evident when PD149163 is used as the training drug.
Asunto(s)
Discriminación en Psicología/efectos de los fármacos , Neurotensina/análogos & derivados , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Neurotensina/agonistas , Regulación Alostérica , Animales , Conducta Animal/efectos de los fármacos , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Generalización de la Respuesta/efectos de los fármacos , Generalización del Estimulo/efectos de los fármacos , Ligandos , Masculino , Neurotensina/farmacología , Ratas Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Esquema de RefuerzoRESUMEN
People diagnosed with depression also tend to have a co-morbid nicotine addiction. Thus, there is interest in whether medications used to treat depression alter the effects of nicotine. This study assessed whether the antidepressant drugs citalopram, imipramine, and reboxetine, with differing specificity for the serotonin and norepinephrine transporter, altered responding controlled by the conditional stimulus (CS) effects of nicotine. Rats received intermixed 20-min nicotine (0.4 mg base/kg, SC) and saline sessions. On nicotine sessions, rats had intermittent access to sucrose; no sucrose was available on saline sessions. After discrimination performance stabilized and a nicotine generalization curve (0.025-0.4 mg/kg) was established, the antidepressant drugs were assessed. In these tests, rats were pretreated with citalopram (1-17 mg/kg), imipramine (1-17 mg/kg), or reboxetine (1-30 mg/kg) before the training dose of nicotine and placement in a chamber for a 4-min extinction test. At the higher doses, all three antidepressant drugs blocked responding evoked by the nicotine CS and decreased nicotine-induced hyperactivity. When these higher doses of citalopram, imipramine, and reboxetine were tested alone (no nicotine), they decreased chamber activity and/or dipper entries. Nevertheless, all three drugs produced partial or complete blockade of the CS effects of nicotine at doses that produced no effect on dipper entries or chamber entries. This finding suggests that both neurotransmitters play a role in the CS effects of nicotine and that modifications in these systems by antidepressants may be clinically relevant.
Asunto(s)
Antidepresivos/farmacología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Animales , Antidepresivos/administración & dosificación , Antidepresivos/uso terapéutico , Conducta Animal/efectos de los fármacos , Citalopram/administración & dosificación , Citalopram/farmacología , Citalopram/uso terapéutico , Aprendizaje Discriminativo , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Generalización de la Respuesta/efectos de los fármacos , Imipramina/administración & dosificación , Imipramina/farmacología , Imipramina/uso terapéutico , Masculino , Morfolinas/administración & dosificación , Morfolinas/farmacología , Morfolinas/uso terapéutico , Nicotina/administración & dosificación , Nicotina/efectos adversos , Nicotina/antagonistas & inhibidores , Agonistas Nicotínicos/administración & dosificación , Agonistas Nicotínicos/efectos adversos , Agonistas Nicotínicos/química , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Reboxetina , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Tabaquismo/tratamiento farmacológicoRESUMEN
Gender differences in the discriminative stimulus properties of drugs of abuse have sometimes been reported, although we have previously found no differences in subjective or discriminative responses in human subjects acquiring an alcohol discrimination. The aim of the present work was to determine if there were gender differences in the effects of lorazepam, a benzodiazepine-receptor agonist which substituted for the alcohol stimulus in trained social drinkers. Volunteers who had already acquired an alcohol (0.2g/kg) placebo discrimination were administered (double-blind) either placebo (nine females, nine males) or lorazepam 2mg (six females, six males). They then sampled a series of five drinks and rated each one for likeness to the training stimulus (the generalization response). In addition they completed rating scales for subjective effects and the Digit Symbol Substitution Test (DSST). Lorazepam substituted for the alcohol stimulus equally in both sexes and increased associated scores for lightheadedness. Females however, showed a much greater DSST performance impairment following lorazepam, compared with males. This effect was independent of body weight differences and sedation. These results are discussed in the light of current knowledge of gender differences in response to drugs of abuse and suggest that the stimulus and cognitive effects of benzodiazepine-receptor agonists are modulated by different brain mechanisms.
Asunto(s)
Consumo de Bebidas Alcohólicas/psicología , Ansiolíticos/farmacología , Aprendizaje Discriminativo/efectos de los fármacos , Lorazepam/farmacología , Adolescente , Adulto , Atención/efectos de los fármacos , Método Doble Ciego , Femenino , Generalización de la Respuesta/efectos de los fármacos , Humanos , Masculino , Factores Sexuales , Encuestas y CuestionariosRESUMEN
Morphine is an effective training drug in drug discrimination procedures. In subsequent generalization tests in which other opioids are administered, mu opioid agonists selectively substitute for the training drug. Given the relative selectivity of morphine for the mu receptor, such substitution patterns suggest that the mu opioid receptor is mediating the discriminative control of this compound. The present study assessed this selective mediation by examining the ability of the delta opioid agonist SNC80 to substitute for (and the delta opioid antagonist naltrindole to antagonize) morphine stimulus effects in rats trained to discriminate morphine from its vehicle in the conditioned taste aversion baseline of drug discrimination learning. Although morphine and methadone produced dose-related substitution for morphine (10 mg/kg), there was no evidence of substitution for morphine by SNC80 at any dose tested. Further, although naloxone (3.2 mg/kg) completely blocked the discriminative effects of morphine, naltrindole (3.2-10 mg/kg) did not significantly affect the morphine stimulus. These data suggest that the discriminative control established to morphine is mediated by its activity at the mu, but not the delta, receptor.
Asunto(s)
Discriminación en Psicología/efectos de los fármacos , Morfina/farmacología , Narcóticos/farmacología , Receptores Opioides delta/efectos de los fármacos , Receptores Opioides mu/efectos de los fármacos , Animales , Benzamidas/farmacología , Aprendizaje Discriminativo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Generalización de la Respuesta/efectos de los fármacos , Metadona/farmacología , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Piperazinas/farmacología , Ratas , Ratas Long-Evans , Receptores Opioides delta/antagonistas & inhibidoresRESUMEN
Rats trained to discriminate the mu agonists fentanyl or morphine from their respective vehicles generalize to the partial mu agonist nalorphine incompletely and inconsistently. Any number of factors may influence the generalization patterns obtained, one of which being the specific dose of the full opioid agonist used during training, a factor reported to influence generalization with other partial opioid agonists. To assess if training dose influences stimulus generalization to nalorphine and to support its role in the aforementioned variability across studies, in the present experiments rats were trained to discriminate either a low (5.6 mg/kg) or a high (10 mg/kg) dose of morphine from distilled water within the taste aversion baseline of drug discrimination learning. Subjects were then given a range of doses of morphine, nalorphine, methadone, or naloxone to assess the degree of substitution (if any) of these compounds for the training dose of morphine. For all subjects, morphine fully substituted for itself, and the opioid antagonist naloxone failed to substitute for the morphine cue. Rats generalized the morphine cue to nalorphine in subjects trained at the lower dose but not in subjects trained at the higher dose. Rats generalized the morphine cue to methadone in the latter group (the high dose group), indicating that the failure to generalize to nalorphine in this group was not a general inability of an opioid agonist to substitute for morphine. Naloxone blocked morphine stimulus control in all subjects and nalorphine control in the low-dose group for which nalorphine substituted for morphine, suggesting that morphine control (and the nalorphine substitution) was based on opioid activity. These results indicate that the substitution patterns of nalorphine in morphine-trained subjects are a function in part of the dose of morphine used in training and support the position that nalorphine is a partial opioid agonist with intermediate efficacy.
Asunto(s)
Aprendizaje Discriminativo/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Morfina/farmacología , Nalorfina/farmacología , Antagonistas de Narcóticos/farmacología , Narcóticos/farmacología , Animales , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Femenino , Generalización de la Respuesta/efectos de los fármacos , Metadona/administración & dosificación , Metadona/farmacología , Morfina/administración & dosificación , Nalorfina/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Narcóticos/administración & dosificación , Ratas , Ratas Long-EvansRESUMEN
RATIONALE: Studies of the discriminative stimulus effects of drug mixtures provide an approach to polydrug abuse and studies on single drugs with multiple effects. OBJECTIVE: This study was designed to investigate whether the use of the AND-OR procedure increases the specificity of drug mixture discriminations. METHODS: Rats were trained to discriminate a mixture of amphetamine (0.4 mg/kg) plus pentobarbitone (10 mg/kg) from saline (AND-discrimination, n = 8) or to discriminate the same mixture from its component drugs alone (AND-OR discrimination, n = 9). The studies used two-lever operant procedures with a tandem variable interval 1-min fixed ratio 10 schedule of food reinforcement. RESULTS: Under AND-discrimination conditions, there was partial generalization to nicotine and midazolam when each drug was administered singly, and there was no generalization to cocaine, caffeine or ethanol. With the AND-OR discrimination, there was no generalization to any of the preceding drugs administered singly. In "single substitution" tests, nicotine or midazolam was co-administered with the training doses of pentobarbitone and amphetamine, respectively; there was full generalization in the AND-discrimination and partial generalization under AND-OR conditions. Cocaine co-administered with pentobarbitone generalized fully under both procedures, but the dose of cocaine needed was much larger in the AND-OR than in the AND-discrimination. In "dual substitution" tests, mixtures of two novel substances were tested. Mixtures of either nicotine plus midazolam or caffeine plus ethanol produced very marked generalization under AND-discrimination conditions, but were without significant effect in the AND-OR procedure. Throughout the studies, in every instance where comparisons were made, generalization was greater or occurred at lower doses under AND- than under the AND-OR discrimination. CONCLUSIONS: The study yielded extensive evidence supporting the hypothesis that the AND-OR discrimination procedure increases the specificity of discriminations based on drug mixtures.
Asunto(s)
Discriminación en Psicología/efectos de los fármacos , Generalización de la Respuesta/efectos de los fármacos , Animales , Ansiolíticos/farmacología , Cafeína/farmacología , Depresores del Sistema Nervioso Central/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Cocaína/farmacología , Dextroanfetamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Etanol/farmacología , Masculino , Midazolam/farmacología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , RatasRESUMEN
The effects of the opioid antagonist, naltrexone, on operant responding for oral ethanol reward delivered on a fixed-ratio schedule, and on the discriminative stimulus properties of intraperitoneally injected ethanol, was examined in two separate experiments. The ages, food/water motivational conditions, and naltrexone doses for the two experiments were similar to allow a direct comparison of naltrexone effects on the two measures. Male food-deprived C57BL/6 mice responded for ethanol during either preprandial (low thirst, high hunger motivation) or postprandial (high thirst, low hunger motivation tests). The reinforcing value of ethanol relative to water was greater during the preprandial tests; however, the amounts of ethanol consumed was greater during the postprandial tests, with some mice becoming unconscious during the 15-min test session. Naltrexone produced dose-responsive reductions in responding for ethanol under either testing condition. During postprandial tests, naltrexone reduced responding for ethanol reward at a dose (1.25 mg/kg) that had little effect on responding for water reward, suggesting some selectivity for ethanol reward. In addition, doses of naltrexone that reduced responding for ethanol rewards did not alter the discrimination of ethanol (g/kg) in an operant discrimination task, but did reduce the total number of responses made during these tests. Thus, under similar motivational and dosing conditions, the opiate antagonist attenuated the reinforcing, but not the discriminative properties of ethanol, suggesting that the latter is mediated by either different or additional neural mechanisms in C57BL/6 mice.
Asunto(s)
Condicionamiento Operante/efectos de los fármacos , Aprendizaje Discriminativo/efectos de los fármacos , Etanol/farmacología , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Recompensa , Animales , Relación Dosis-Respuesta a Droga , Privación de Alimentos , Generalización de la Respuesta/efectos de los fármacos , Habituación Psicofisiológica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Esquema de RefuerzoRESUMEN
Heteroreceptor posttetanic changes in excitatory postsynaptic currents (EPSC) and inward currents evoked by the local iontophoretic application of acetylcholine (ACh) on the dorsal surface of PLa3 and PRa3 Helix lucorum neurons were studied. The following changes in the currents were revealed over the course of 1-1.5 h after tetanization. The rhythmical ACh application (0.5-1.0 cps, 10-40 s) evokes potentiation of the orthodromic EPSC. The tetanic orthodromic stimulation of one of the nerves (n. intestinalis, n. pallialis dexter, or n. pallialis sinister; 1-5 cps, 1-2 min) causes the potentiation of the ACh current and also heterosynaptic depression of the EPSC. It is concluded that activation of subsynaptic and nonsynaptic neurotransmitter chemoreceptors evokes the development of generalized posttetanic changes in neuronal responses.
Asunto(s)
Acetilcolina/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Generalización de la Respuesta/efectos de los fármacos , Caracoles Helix/efectos de los fármacos , Neuronas/efectos de los fármacos , Membranas Sinápticas/efectos de los fármacos , Animales , Estimulación Eléctrica/métodos , Potenciales Postsinápticos Excitadores/fisiología , Generalización de la Respuesta/fisiología , Caracoles Helix/fisiología , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Microelectrodos , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Receptores Colinérgicos/efectos de los fármacos , Receptores Colinérgicos/fisiología , Procesamiento de Señales Asistido por Computador/instrumentación , Membranas Sinápticas/fisiologíaRESUMEN
Pigeons trained to discriminate methamphetamine from saline after a history of training to discriminate pentobarbital from saline responded on the drug key after both pentobarbital and methamphetamine, but the association of these drugs by reinforcing their discriminative stimulus responses on the same key did not influence their effects on either punished or unpunished responding. Similarly, pigeons trained to discriminate morphine from saline after a history of discrimination of buspirone from saline, responded on the drug key after both buspirone and morphine, but the association of their discriminative stimulus responses did not influence their effects on either punished or unpunished responding. Whether the effects of these drugs as discriminative stimuli, or their effects on punished and unpunished responding were studied first in the session did not influence the effects of these drugs. Low doses of methamphetamine or pentobarbital did not produce responding on the drug key in birds trained to discriminate higher doses of both drugs, but combinations of these doses did produce responding on the drug key. However, these combinations of low doses of methamphetamine with pentobarbital did not increase the rate-increasing effects of pentobarbital on punished responding.
Asunto(s)
Aprendizaje Discriminativo/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Animales , Buspirona/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Columbidae , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Generalización de la Respuesta/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Masculino , Metanfetamina/farmacología , Morfina/farmacología , Narcóticos/farmacología , Pentobarbital/farmacología , Refuerzo en Psicología , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
Pigeons were trained in a 3-choice assay to discriminate among injections of 5.6 mg/kg U-50,488H, 5.6 mg/kg morphine, and vehicle solution. In dose-response tests, subjects rarely responded on the U-50,488H-appropriate key when morphine was administered or on the morphine-appropriate key when they received U-50,488H. A high dose of naltrexone (1.0 mg/kg) completely blocked the morphine cue but failed to block completely the U-50,488H cue. In generalization tests, d-amphetamine primarily engendered saline-appropriate responding. Ethylketazocine produced mixed results, in that moderate doses produced responding on both the morphine- and U-50,488H-appropriate keys, but 3.2 mg/kg engendered primarily morphine-appropriate responding. These results demonstrate the feasibility, but not necessarily the value, of 3-choice discrimination procedures involving mu and kappa agonists and vehicle.
Asunto(s)
3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Analgésicos no Narcóticos/farmacología , Discriminación en Psicología/efectos de los fármacos , Morfina/farmacología , Narcóticos/farmacología , Animales , Columbidae , Dextroanfetamina/farmacología , Aprendizaje Discriminativo/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Etilcetociclazocina/farmacología , Generalización de la Respuesta/efectos de los fármacos , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacologíaRESUMEN
The objective of this study was to examine if (R)-methanandamide, a metabolically stable chiral analog of the endogenous ligand anandamide, is a cannabimimetic with a lower efficacy than delta9-THC. Employing a two-lever choice drug discrimination procedure, rats were trained to discriminate between 1.8, 3.0, or 5.6 mg/kg delta9-tetrahydrocannabinol (delta9-THC) and vehicle. Different training doses were used in order to create assays with different efficacy demands. Generalization tests with 18 mg/kg (R)-methanandamide yielded around 90% delta9-THC responses in the two lower delta9-THC training dose conditions. However, only around 60% delta9-THC responses occurred in the 5.6 mg/kg delta9-THC training dose condition in tests with 18 mg/kg (R)-methanandamide; a higher dose (30 mg/kg) produced even fewer delta9-THC-appropriate responses in this group. Morphine did not substitute for delta9-THC. In conclusion, the data with delta9-THC and (R)-methanandamide indicate that cannabinoid agonists can have varying degrees of intrinsic activity at a receptor site, or may produce their behavioral actions through multiple mechanisms, or both.
Asunto(s)
Ácidos Araquidónicos/farmacología , Discriminación en Psicología/efectos de los fármacos , Dronabinol/farmacología , Generalización de la Respuesta/efectos de los fármacos , Alucinógenos/farmacología , Animales , Ácidos Araquidónicos/administración & dosificación , Aprendizaje Discriminativo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Dronabinol/administración & dosificación , Alucinógenos/administración & dosificación , Masculino , Morfina/farmacología , Narcóticos/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Rats were pre-tested in several individual difference screens--novelty-induced activity, novelty-induced place preference, novel-object interaction, and amphetamine-induced activity. Rats that were more sensitive to the locomotor effects of amphetamine were more active in an inescapable novel environment and displayed a greater preference for a novel environment. All animals were then trained to discriminate amphetamine (1 mg/kg) from saline in a two-bar discrimination procedure using food-maintained responding. After acquisition of the discrimination (mean = 37 trials), two amphetamine generalization tests (0.0625, 0.125, 0.25, 0.5, 1.0 and 2.0 mg/kg) were conducted. In the second generalization test, rats that were more sensitive to the activating effect of amphetamine were also more sensitive to the discriminative stimulus effects of amphetamine (i.e. lower median effective dose). Moreover, high responders in the novelty-induced activity and novelty-induced place preference screens were more sensitive than low responders to the bar-press suppressant effects of amphetamine in the first generalization test. The relationships are discussed in terms of identifying processes common to the screens (e.g. stress and reward).
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Dextroanfetamina/farmacología , Discriminación en Psicología/efectos de los fármacos , Ambiente , Individualidad , Actividad Motora/efectos de los fármacos , Animales , Aprendizaje por Asociación/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Generalización de la Respuesta/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Estimulación QuímicaRESUMEN
Two groups of N/Nih male rats were trained to discriminate saline vehicle from either 2.0 mg/kg (n = 10) or 10.0 mg/kg (n = 10) cocaine in a food-motivated, two-lever operant paradigm. The rats trained at the low-dose cocaine took a significantly longer training period to reach criterion performance than did the high-dose cocaine group. In addition, the ED50 value for the 2.0 mg/kg cocaine-trained animals (0.465 mg/kg) was significantly lower than the ED50 value (2.105 mg/kg) for those animals trained at the 10.0 mg/kg dose of cocaine. This correlation of ED50 values for stimulus generalization decreasing with reduction in training dose was in contrast to the time-course of the two groups when tested from 15 to 240 min post-injection; this experimentation indicated that there was a non-significant difference in half-life for the 2.0 mg/kg (t1/2: 97.1 min) vs. that of the 10.0 mg/kg cocaine-trained group (t1/2: 83.4 min). Generalization tests with other purportedly dopaminergically-active drugs of abuse including 0.05-0.8 mg/kg d-amphetamine, 0.125-1.5 mg/kg methamphetamine and 0.125-1.0 mg/kg methcathinone indicated that the highest doses of each produced generalization and, with the exception of methcathinone, the ED50 values were significantly lower in the low-cocaine trained group. The stimulus properties of cocaine, as they generalize to amphetamine, methamphetamine and methcathinone, can be explained by effects upon central dopaminergic neurons and may be qualitatively different in low-and high-dose trained rats.
Asunto(s)
Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Aprendizaje Discriminativo/efectos de los fármacos , Dopaminérgicos/farmacología , Generalización de la Respuesta/efectos de los fármacos , Psicotrópicos/farmacología , Anfetamina/farmacología , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Masculino , Metanfetamina/farmacología , Propiofenonas/farmacología , RatasRESUMEN
This report summarizes a recent series of experiments dealing with the effect of peripheral (i.p.) administration of SP on the learning of avoidance and habituation tasks. In summary, the results from these studies show that peripheral post-training SP administration in rats enhances memory in a dose- and time-dependent way. The effect of substance P on retention was observed across tasks with different response requirements and in the absence of explicit punishment. The memory-enhancing effects are long-lasting, until 21 days post-training, and are mediated, at least in part, via interactions with the endogenous opioid system. The mnemotropic effects of peripherally administered SP are sensitive to the functional integrity of the vagus, suggesting that the vagus nerve may be one pathway by which systemic SP influences memory storage processes in the brain. Furthermore, the data indicated that these effects seemed to be encoded by different SP sequences, the N-terminal SP1-7, but not the C-terminal hepta- and hexapeptide sequences being responsible for the memory-promoting effects. Taken together, these studies strongly suggest that SP may be considered to have memory-promoting effects.
Asunto(s)
Memoria/efectos de los fármacos , Sustancia P/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Electrochoque , Generalización de la Respuesta/efectos de los fármacos , Inyecciones Intraperitoneales , Ratas , Estimulación Química , Sustancia P/administración & dosificación , Factores de Tiempo , VagotomíaRESUMEN
Male hamsters that have been repeatedly defeated by larger, aggressive males subsequently flee from, rather than attack, nonaggressive male intruders that are introduced into their home cages. We have referred to this generalization of flight in response to nonaggressive intruders as "conditioned defeat" (CD). In an attempt to reverse CD pharmacologically, diazepam (DZP) was administered to hamsters at two different time points relative to CD acquisition and subsequent response generalization tests, which involved the exposure of subjects to nonaggressive intruders (NAIs). In Experiment 1, subjects were given a single injection of one of 4 doses of DZP (0, 2, 6, or 20 mg/kg) immediately following CD acquisition. Twenty-four hours later, contrary to expectations, subjects that had received the 6 mg/kg dose displayed elevated flight responses in the presence of an NAI. Flight responding declined over days except in subjects that received the highest dose. In the second experiment, hamsters were administered a single injection of either 0, 2, or 6 mg/kg DZP just prior to a response generalization test occurring 24 h following CD training. Flight responses to the NAIs were again exaggerated in subjects that were given the 6 mg/kg dose, an effect that persisted several days without further drug administration. The present findings suggest the possibility that benzodiazepines can potentiate fear responses under certain stressful conditions.
Asunto(s)
Ansiolíticos/farmacología , Condicionamiento Clásico , Diazepam/farmacología , Dominación-Subordinación , Reacción de Fuga/efectos de los fármacos , Conducta Agonística/efectos de los fármacos , Animales , Cricetinae , Relación Dosis-Respuesta a Droga , Miedo/efectos de los fármacos , Generalización de la Respuesta/efectos de los fármacos , MasculinoRESUMEN
CGS 10746B is an imidazole-derivative related to the atypical antipsychotic clozapine which produces a decrease in dopamine release without altering dopamine metabolism or occupying D2 receptors. Rats were trained on an appetitively-motivated, two-choice, operant task to discriminate 20.0 mg/kg CGS 10746B from its vehicle. CGS 10746B was highly discriminable, producing rapid acquisition of the discrimination, and its effects were dose-responsive allowing generation of an ED50 value of 6.16 mg/kg. Substitution tests were conducted with other typical and atypical antipsychotic compounds: haloperidol, chlorpromazine, clozapine and SCH 23390. Additional tests examined generalization from the CGS 10746B stimulus properties to the calcium channel blocker isradipine, as well as to the anticholinergics atropine, scopolamine and methylscopolamine, as well as to the serotonergic agonist DOI. Clozapine and SCH 23390 were the only substances to substitute for the CGS 10746B stimulus cue. Results are discussed in terms of potential D1 receptor selectivity of CGS 10746B.
Asunto(s)
Antipsicóticos/farmacología , Discriminación en Psicología/efectos de los fármacos , Receptores de Dopamina D1/antagonistas & inhibidores , Tiazepinas/farmacología , Anfetaminas/farmacología , Animales , Colinérgicos/farmacología , Clozapina/farmacología , Señales (Psicología) , Aprendizaje Discriminativo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Generalización de la Respuesta/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Serotoninérgicos/farmacología , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
Neurophysiological and behavioural correlates of the long-term sensitization were investigated in Helix lucorum small. Application of 10% quinine solution on the snail's head initiated a long-term (for more than 24 hours) facilitation of defensive reactions. The behavioural effects correlated with the changes in evoked and spontaneous activity of L-PP11 neurons, i.e., facilitation of synaptic components in responses to testing stimulation, increase in membrane excitability and depolarization. Efficacy of sensitization depended on the duration of the experimental procedure. After daily training site-specific and modality-specific effects dominated (i.e., more expressed facilitation of responses to testing stimulation of the sensitized body site than that of the other sites or to testing stimulation of the same modality as sensitizing stimulation). After 3 days of training the effects of general sensitization were predominantly observed, i.e., facilitation of neuronal responses to stimulation of different modalities and body sites, depolarization of the membrane and increase in its excitability.
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Generalización de la Respuesta/fisiología , Generalización del Estimulo/fisiología , Caracoles Helix/fisiología , Nociceptores/fisiología , Animales , Reacción de Fuga/efectos de los fármacos , Reacción de Fuga/fisiología , Generalización de la Respuesta/efectos de los fármacos , Generalización del Estimulo/efectos de los fármacos , Caracoles Helix/efectos de los fármacos , Relajantes Musculares Centrales/farmacología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Nociceptores/efectos de los fármacos , Quinina/farmacología , Factores de TiempoRESUMEN
When singly housed under laboratory conditions, male Syrian golden hamsters routinely attack novel conspecific intruders introduced into their home cages. As we report here, after being repeatedly defeated by a larger, more aggressive intruder, such normal territorial aggression on the part of the resident hamsters is replaced by defensive behavior and flight. We have found that such conditioned defeat (CD) can be reliably induced by a series of 5-min trials with an aggressive intruder whether these trials are spread over 4 days or are all given on the same day. A useful behavioral criterion for the appearance of CD during acquisition is the first occurrence of anticipatory flight (AF), i.e., the first time the resident flees from the next aggressive intruder before being attacked. CD shows generalization: Animals trained to the AF criterion (AF Group) subsequently show defensive behavior toward, and even flee from, intruders which show absolutely no sign of aggressiveness. Animals in the AF Group persisted in such defense behavior for two test sessions; animals given three additional defeat trials beyond the appearance of AF (AF + 3 Group) showed a greater magnitude and persistence of defense and flight. A comparison of CD-trained animals which met a non-aggressive intruder (NAI) every day for 5 days to similarly trained animals which met the intruder only on the fifth day after acquisition suggests that CD diminishes passively as a function of time and not as the consequence of repeated encounters with a nonaggressive stimulus animal. We also found that near ideal NAIs could be prepared by treating nonaggressive hamsters with high doses of diazepam: animals so treated locomote more or less continuously around the cage virtually ignoring the subject. An unexpected observation was that subjects in the AF Group tended to closely follow these diazepam-treated, rapidly locomoting NAIs around the cage. Following may be an example of the "risk assessment" activities directed toward a potential threat. The development of a rapid and reliable technique for inducing CD in hamsters sets the stage for further physiological and pharmacological work on this interesting phenomenon.
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Conducta Agonística , Nivel de Alerta , Condicionamiento Clásico , Dominación-Subordinación , Desamparo Adquirido , Territorialidad , Agresión/efectos de los fármacos , Conducta Agonística/efectos de los fármacos , Animales , Nivel de Alerta/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Cricetinae , Diazepam/farmacología , Reacción de Fuga/efectos de los fármacos , Miedo/efectos de los fármacos , Generalización de la Respuesta/efectos de los fármacos , Aseo Animal/efectos de los fármacos , Masculino , Mesocricetus , Actividad Motora/efectos de los fármacos , Comportamiento de Nidificación/efectos de los fármacos , Medio SocialRESUMEN
Pigeons were trained to discriminate 5.0 mg/kg morphine from saline. After morphine, subjects tracked the location of red response keys and after saline, the location of green keys. When stimulus generalization to other drugs was investigated dl-methadone produced morphine-like responding and this response generalization was primarily due to the l-isomer. Pretreatment with 1.0 mg/kg naloxone shifted the morphine generalization curve 10-fold to the right but only shifted the rate suppression curve 3-fold to the right. dl-Cyclazocine generated dose-related increases in responding on the red key location and in 3 of 5 birds, responses after 1.0 mg/kg were indistinguishable from those after morphine training doses. Meperidine did not produce responding on the red keys, nor did diazepam, cocaine, d-amphetamine, phencyclidine or pentobarbital. The discriminative stimulus effects of morphine are thus stereo-selective and pharmacologically specific. Generalization of responding to dl-cyclazocine but not to phencyclidine suggests that the morphine-like discriminative dl-cyclazocine cue was not due to interaction at sigma opiate receptors.
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Discriminación en Psicología/efectos de los fármacos , Morfina/farmacología , Desempeño Psicomotor/efectos de los fármacos , Animales , Cocaína/farmacología , Color , Columbidae , Señales (Psicología) , Ciclazocina/farmacología , Dextroanfetamina/farmacología , Diazepam/farmacología , Relación Dosis-Respuesta a Droga , Generalización de la Respuesta/efectos de los fármacos , Masculino , Meperidina/farmacología , Metadona/farmacología , Narcóticos/farmacología , Pentobarbital/farmacología , Fenciclidina/farmacologíaRESUMEN
Rats trained to discriminate intraperitoneal injections of 0.16 mg/kg LSD from saline injections were found to show stimulus generalization with 0.31-5 mg/kg of yohimbine. Partial generalization also occurred with clonidine and xylazine. Rats discriminating intraperitoneal injections of 5 mg/kg of yohimbine from saline generalized LSD at doses of 0.08-0.63 mg/kg. The data establish an equivalence between LSD and yohimbine as to discriminative effects in rats. This equivalence is consistent with LSD and yohimbine producing at least partly similar subjective effects in humans.