RESUMEN
Group II metabotropic glutamate receptors (mGluRs) have been implicated in regulating the psychopharmacologic effects of cocaine and other drugs of abuse. The present study investigated the interactions between the group II mGluR agonist LY379268 [(-)-2-oxa-4-aminobicyclo [3.1.0] hexane-4,6-dicarboxylate] and cocaine in squirrel monkeys whose operant behavior was maintained under a second order schedule of i.v. cocaine self-administration with or without presentations of a cocaine-paired visual stimulus, extinguished and subsequently reinstated by priming injections of cocaine with or without presentations of a cocaine-paired stimulus, and controlled by cocaine trained as a discriminative stimulus. Antagonism studies with the group II mGluR antagonist LY341495 [2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl) propanoic acid] investigated the extent to which the cocaine-modulating effects of LY379268 could be reversed by blocking group II mGluRs. Quantitative observational studies investigated the effects of LY379268 and LY341495 on species-typical behaviors, balance, and muscle resistance. Pretreatment with LY379268 reduced cocaine self-administration and cocaine-induced reinstatement of drug seeking in a dose-dependent, LY341495-reversible manner. Significant effects of LY379268 were observed both in the presence and absence of the cocaine-paired stimulus. LY379268 did not alter the discriminative stimulus effects of cocaine, nor did it markedly affect observed behavior, with the exception of an increase in visual scanning. Emesis frequently was observed after the highest dose of LY379268 (1.0 mg/kg). The results suggest that LY379268, by stimulating group II mGluRs, can attenuate the reinforcing and priming effects of cocaine at doses that do not alter its perceptibility or markedly suppress other behaviors.
Asunto(s)
Aminoácidos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Trastornos Relacionados con Cocaína/psicología , Cocaína/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Agonistas de Aminoácidos Excitadores/uso terapéutico , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Animales , Condicionamiento Operante/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Actividad Motora/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Receptores de Glutamato Metabotrópico/agonistas , Saimiri , Prevención Secundaria , Autoadministración , Estimulación Química , Abuso de Sustancias por Vía Intravenosa/tratamiento farmacológico , Abuso de Sustancias por Vía Intravenosa/psicologíaAsunto(s)
Trastornos Relacionados con Cocaína/fisiopatología , Trastornos Relacionados con Cocaína/psicología , Animales , Trastornos Relacionados con Cocaína/prevención & control , Señales (Psicología) , Modelos Animales de Enfermedad , Haplorrinos , Primates , Receptores de Amina Biogénica/fisiología , Recurrencia , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicologíaRESUMEN
The use of noninvasive measures of hypothalamic-pituitary-adrenal (HPA) axis function is of growing interest among preclinical and clinical investigators. This report describes a method for the repeated assessment of salivary free cortisol in awake, unrestrained squirrel monkeys (Saimiri sciureus) based on a saliva sampling technique previously developed for rhesus monkeys. Individually housed adult male squirrel monkeys were trained to chew on dental rope attached to a pole, from which saliva was extracted by centrifugation and analyzed for cortisol by radioimmunoassay (RIA). Eight of nine monkeys readily acquired the task, reliably providing adequate saliva samples for the assay. Salivary free cortisol levels were examined in these subjects under basal conditions and in response to two types of neuroendocrine challenge. Levels of salivary free cortisol showed relatively low intra- and interindividual variability, with mean individual morning levels ranging between 17.1 and 37.9 microg/dl. Squirrel monkeys demonstrated a consistent daily rhythm in salivary free cortisol ranging from a high of 27.4 +/- 5.2 microg/dl (mean +/- SEM) at 12 P.M. to a low of 7.5 +/- 1.6 microg/dl at 6 P.M. Intravenous (IV) challenges with 1 microg/kg ACTH, or 10 and 50 microg/kg CRF resulted in significant increases in salivary free cortisol. The described sampling technique provides a reliable and sensitive means for repeated measurement of HPA activity in unrestrained, awake squirrel monkeys. In addition, our findings illustrate several features of HPA system rhythmicity and reactivity using salivary cortisol instead of blood plasma or serum.
Asunto(s)
Cebinae , Hidrocortisona/análisis , Saliva/química , Manejo de Especímenes/métodos , Vigilia/fisiología , Animales , Cebinae/fisiología , MasculinoRESUMEN
One of the major determinants of reinstatement to cocaine use among human addicts is acute reexposure to the drug, which often precipitates cocaine craving and relapse. We used an animal model of cocaine relapse to determine the role of the glutamatergic pathway from the medial prefrontal cortex (mPFC) to the nucleus accumbens in the reinstatement of cocaine-seeking behavior after a cocaine priming injection. Rats were trained to self-administer cocaine intravenously on a second order schedule. Responding was extinguished subsequently by substituting saline for cocaine. During subsequent reinstatement sessions, drug-seeking behavior was assessed after noncontingent priming injections. Results indicated that reinstatement induced by a systemic cocaine injection was blocked by intra-mPFC administration of the dopamine antagonist flupenthixol. Consistent with this finding, administration of cocaine directly into the mPFC reinstated cocaine-seeking behavior. Administration of cocaine into the nucleus accumbens also reinstated drug seeking, whereas microinjection of cocaine into the neostriatum or lateral septum did not. Reinstatement of cocaine seeking induced by intra-mPFC cocaine was blocked by administration of the AMPA receptor antagonist CNQX into the nucleus accumbens. Administration of the NMDA receptor antagonist AP-5 into the nucleus accumbens had variable effects on reinstatement induced by intra-mPFC cocaine in that AP-5 had no effect in some animals but augmented reinstatement in others. Subsequent experiments showed that intra-accumbal microinjection of AP-5 alone dose-dependently reinstated cocaine seeking. These data indicate that the glutamatergic pathway from the mPFC to the nucleus accumbens plays an important role in cocaine priming-induced reinstatement of drug seeking. Moreover, the present results demonstrate that AMPA and NMDA receptors in the nucleus accumbens have opposing roles in the reinstatement of cocaine-seeking behavior.
Asunto(s)
Trastornos Relacionados con Cocaína/etiología , Cocaína/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Núcleo Accumbens/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Receptores AMPA/antagonistas & inhibidores , Anestésicos Locales/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/administración & dosificación , Trastornos Relacionados con Cocaína/metabolismo , Condicionamiento Operante/efectos de los fármacos , Antagonistas de Dopamina/administración & dosificación , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Extinción Psicológica , Ácido Glutámico/metabolismo , Masculino , Microinyecciones , Neostriado/efectos de los fármacos , Núcleo Accumbens/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Recurrencia , Refuerzo en Psicología , Tabique del Cerebro/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
RATIONALE: The discriminative stimulus (DS) effects of chlordiazepoxide (CDP) differ from those of other typical benzodiazepine (BZ) agonists in that CDP does not always occasion full substitution for a BZ agonist DS. OBJECTIVES: The present study tested the hypothesis that the unusual DS effects of CDP may result from its relatively low intrinsic efficacy by examining the combinations of CDP and triazolam using isobolographic analysis in squirrel monkeys discriminating triazolam. METHODS AND RESULTS: Squirrel monkeys were previously trained to discriminate triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 (FR 10) schedule of food reinforcement. CDP occasioned partial substitution for triazolam and did not alter the DS effects of triazolam, whereas single doses of triazolam enhanced the DS effects of triazolam, and bretazenil antagonized the triazolam DS. The isobolographic analysis showed that CDP and triazolam combinations resulted in additive effects in animals in which CDP substituted for triazolam, whereas infra-additive effects were obtained in animals in which CDP did not substitute for triazolam. CONCLUSIONS: The partial substitution of CDP for triazolam and the infra-additive effects obtained in animals in which CDP did not substitute for triazolam suggest that CDP may have lower intrinsic efficacy than triazolam. However, the lack of overall effect of CDP pretreatment and the lack of shift in animals in which CDP substituted for triazolam suggest that other factors, such as differential activity at BZ receptor subtypes, may play a role in the effects of CDP.
Asunto(s)
Ansiolíticos/farmacología , Clordiazepóxido/farmacología , Discriminación en Psicología/efectos de los fármacos , Triazolam/farmacología , Animales , Discriminación en Psicología/fisiología , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Masculino , SaimiriRESUMEN
RATIONALE: Dopamine D1 ligands have been proposed as candidate medications for cocaine abuse. Previous studies have shown that the ability of D1 ligands to modulate the behavioral effects of cocaine may depend on agonist efficacy. OBJECTIVES: This study investigated the role of agonist efficacy in the ability of D1 ligands to modulate the reinforcing effects of cocaine in monkeys. METHODS: Squirrel monkeys trained to self-administer cocaine under a second-order schedule of reinforcement were treated daily with D1 agonists varying in efficacy from low to high (SKF 83959 < SKF 77434 < or = SKF 81297 < SKF 82958) and the D1 antagonist SCH 39166. RESULTS: D1 ligands, regardless of efficacy, produced dose-dependent reductions in responding maintained by a maximally effective dose of cocaine. Equivalent doses of each D1 ligand reduced responding for food under a similar second-order schedule, suggesting that the suppression was not specific to cocaine self-administration. When studied in combination with a range of cocaine doses, treatment with the agonists SKF 83959, SKF 77434, SKF 81297, and the antagonist SCH 39166 produced overall rightward and downward shifts in the dose-response function for cocaine self-administration. Treatment with the agonist SKF 82958, however, produced an overall suppression of responding, regardless of the dose of cocaine. CONCLUSIONS: In contrast to a high-efficacy agonist, low-efficacy D1 ligands modulated the reinforcing effects of cocaine in a manner consistent with at least a partial antagonism of cocaine self-administration. This delineation of the efficacy-dependent profile of effects for D1 ligands should guide research into their utility as cocaine pharmacotherapies.
Asunto(s)
Cocaína/administración & dosificación , Agonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/administración & dosificación , Ingestión de Alimentos/efectos de los fármacos , Receptores de Dopamina D1/agonistas , Animales , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/fisiología , Masculino , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptores de Dopamina D1/fisiología , Refuerzo en Psicología , Saimiri , AutoadministraciónRESUMEN
RATIONALE AND OBJECTIVES: Heroin previously was shown to engender partial cocaine-like discriminative stimulus (DS) effects in squirrel monkeys. The present study assessed the degree to which heroin modified the DS effects of cocaine and the cocaine-like DS effects of the selective dopamine transport blocker GBR 12909. METHODS AND RESULTS: In squirrel monkeys discriminating cocaine (0.3 mg/kg) from saline, cocaine and GBR 12909 dose-dependently engendered levels of responding on the cocaine-associated lever greater than or equal to 90% (full substitution). Heroin engendered full substitution for cocaine in two monkeys, partial substitution (75%) in a third monkey, and no substitution in the fourth monkey. When administered as a pretreatment, heroin shifted the dose-response function for cocaine to the left in the three monkeys for which heroin engendered cocaine-lever responding, but did not alter the DS effects of cocaine in the fourth monkey. Heroin pretreatment also shifted the dose-response function for the cocaine-like DS effects of GBR 12909 to the left in the former three monkeys, and did not alter the effects of GBR 12909 in the fourth monkey. Isobolographic analysis of the DS effects of cocaine-heroin and GBR 12909-heroin combinations in the former three monkeys revealed that the potencies of the combinations were not different from predicted values based on dose-additive effects. CONCLUSIONS: These findings show that heroin can enhance similarly the DS effects of cocaine and GBR 12909, suggesting that activation of dopaminergic systems underlies enhancement of the interoceptive effects of cocaine by heroin.
Asunto(s)
Cocaína/farmacología , Discriminación en Psicología/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Heroína/farmacología , Narcóticos/farmacología , Piperazinas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Masculino , SaimiriRESUMEN
Heroin has characteristic subjective effects that contribute importantly to its widespread abuse. Drug discrimination procedures in animals have proven to be useful models for investigating pharmacological mechanisms underlying the subjective effects of drugs in humans. However, surprisingly little information exists concerning the mechanisms underlying the discriminative stimulus (DS) effects of heroin. This study characterized the DS effects of heroin in rhesus monkeys trained to discriminate i.v. heroin from saline. In drug substitution experiments, heroin, its metabolites 6-monoacetylmorphine, morphine, morphine-6-glucuronide, and morphine-3-glucuronide, and the mu-agonists fentanyl and methadone engendered dose-dependent increases in heroin-lever responding, reaching average maximums of >80% (full substitution) at doses that did not appreciably suppress response rate. In contrast, the delta-agonist SNC 80, the kappa-agonist spiradoline, and the dopamine uptake blockers/releasers cocaine, methamphetamine, and GBR 12909 did not engender heroin-like DS effects regardless of dose. In antagonism studies, in vivo apparent pA2 and pK(B) values for naltrexone combined with heroin, morphine, and 6-monoacetylmorphine (8.0-8.7) were comparable with those reported previously for naltrexone antagonism of prototypical mu-agonists. The results show that the DS effects of heroin are pharmacologically specific and mediated primarily at mu-opioid receptors. Moreover, the acetylated and glucuronated metabolites of heroin appear to play significant roles in these effects. Despite previous speculation that morphine-3-glucuronide lacks significant opioid activity, it substituted fully for heroin in our study, suggesting that it can exhibit prominent mu-agonist effects in vivo.
Asunto(s)
Discriminación en Psicología/efectos de los fármacos , Heroína/farmacología , Narcóticos/farmacología , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Opioides/efectos de los fármacos , Animales , Dopamina/metabolismo , Agonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Generalización Psicológica , Heroína/administración & dosificación , Heroína/farmacocinética , Inyecciones Intravenosas , Macaca mulatta , Masculino , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Narcóticos/administración & dosificación , Narcóticos/farmacocinéticaRESUMEN
RATIONALE: Triazolam is a high-efficacy benzodiazepine (BZ) agonist, which might be hypothesized to engender highly pharmacologically specific discriminative stimulus (DS) effects and distinguish among BZ agonists with different intrinsic efficacy. OBJECTIVES: The pharmacological specificity of the triazolam stimulus was determined by examining the effects of conventional and atypical BZ agonists, and other ligands active at the gamma-aminobutyric acidA (GABAA) receptor complex. Receptor mechanisms underlying the DS effects of triazolam were examined further using the BZ receptor antagonist flumazenil. METHODS AND RESULTS: Squirrel monkeys were trained to discriminate triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 (FR 10) schedule of food reinforcement. While the BZ agonists midazolam, diazepam, and lorazepam substituted fully for triazolam, chlordiazepoxide, oxazepam and nordiazepam produced only partial substitution, suggesting these latter compounds may have reduced intrinsic efficacy. The BZ/alpha1-preferring agonist zolpidem substituted fully for triazolam, and potencies for triazolam-like effects of BZ agonists were significantly correlated with potencies for their zolpidem-like effects (Rowlett et al. 1999). Flumazenil antagonized the DS effects of triazolam, but the slope of the Schild plot was significantly different from unity, suggesting multiple receptors may be involved in the DS effects of triazolam. CONCLUSIONS: BZ agonists can be distinguished on the basis of substitution for triazolam and, thus, the triazolam discrimination may be a useful tool for identifying compounds of different efficacy at BZ receptors. BZ/alpha1 receptors appear to play a prominent role in the DS effects of triazolam, but the contribution of other subtypes of BZ receptors cannot be ruled out.
Asunto(s)
Ansiolíticos/farmacología , Discriminación en Psicología/efectos de los fármacos , Agonistas del GABA/farmacología , Moduladores del GABA/farmacología , Triazolam/farmacología , Animales , Barbitúricos/farmacología , Aprendizaje Discriminativo , Relación Dosis-Respuesta a Droga , Flumazenil/antagonistas & inhibidores , Flumazenil/farmacología , Masculino , Receptores de GABA-A/efectos de los fármacos , SaimiriRESUMEN
Zolpidem is an imidazopyridine with high affinity at gamma-aminobutyric acid(A) (GABA(A)) receptors expressing alpha1 subunits. In squirrel monkeys trained to discriminate a high dose of zolpidem (> or =3.0 mg/kg) from saline, zolpidem and another GABA(A)/alpha1 receptor-preferring agonist, zaleplon, substituted dose-dependently for zolpidem, whereas the non-selective agonists diazepam and triazolam were did not substitute at any dose tested. These findings offer the first evidence for a selective role of GABA(A)/alpha1 receptors in the interoceptive effects of high doses of zolpidem.
Asunto(s)
Discriminación en Psicología/efectos de los fármacos , Agonistas del GABA/farmacología , Agonistas de Receptores de GABA-A , Piridinas/farmacología , Acetamidas/farmacología , Animales , Diazepam/farmacología , Relación Dosis-Respuesta a Droga , Moduladores del GABA/farmacología , Masculino , Subunidades de Proteína , Pirimidinas/farmacología , Esquema de Refuerzo , Saimiri , Triazolam/farmacología , ZolpidemRESUMEN
Drug discrimination procedures have been used to study receptor mechanisms of benzodiazepine (BZ) agonists with the goal of developing new therapeutic agents that retain positive effects of conventional BZ ligands yet have reduced side effects. The present review provides a synthesis of existing literature on discriminative stimulus effects of BZ agonists in order to elucidate their underlying receptor mechanisms, specifically in terms of intrinsic efficacy and receptor selectivity. The available evidence suggests that receptor selectivity is a critical determinant of the discriminative stimulus effects of BZ agonists. In particular, BZ-1 receptors appear to play a fundamental role, whereas the role of BZ-2 receptors remains elusive. In addition, data from many drug discrimination studies suggest that the conventional BZ agonist chlordiazepoxide may have reduced intrinsic efficacy compared with other BZ agonists.
Asunto(s)
Ansiolíticos/farmacología , Conducta Animal/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Receptores de GABA-A/efectos de los fármacos , Animales , Benzodiazepinas , Humanos , Esteroides/farmacologíaRESUMEN
Dopaminergic mechanisms are thought to be critical in mediating relapse to cocaine-seeking behavior. This study examined the different roles of D1- and D2-like receptor mechanisms in the relapse process. Squirrel monkeys were given extended histories of i. v. cocaine self-administration under conditions in which responding was maintained jointly by response-contingent cocaine injections and a cocaine-paired visual stimulus (second-order schedule). Responding was then extinguished by substituting saline for cocaine injections and omitting presentations of the cocaine-paired stimulus. Subsequently, noncontingent priming injections of cocaine combined with restoration of the cocaine-paired stimulus induced dose-dependent reinstatement of drug-seeking behavior, with response rates approaching those maintained by active cocaine self-administration. The priming effects of cocaine were attenuated by several D1- and D2-like receptor antagonists and low efficacy agonists but not by the D3-preferring antagonists UH 232 and AJ-76. The priming effects of cocaine were mimicked by the D2-like receptor agonists R(-)-propylnorapomorphine hydrochloride (NPA) and quinpirole, less consistently by 7-OH-DPAT, and not by the D1-like receptor agonists SKF-81297 and SKF-82958, the D3-preferring agonist PD-128,907, or any low efficacy agonist. Cotreatment with NPA, PD-128,907, and 7-OH-DPAT did not alter reinstatement of drug-seeking behavior induced by a maximally effective priming dose of cocaine, whereas cotreatment with D1-like receptor agonists attenuated the priming effects of cocaine. The results suggest that D1- and D2-like receptors play fundamentally different roles in the relapse process. Although stimulation of D2-like, but probably not D3-like, receptors appears necessary for induction of relapse, either stimulation or blockade of D1-like receptors appears to be inhibitory with respect to relapse.
Asunto(s)
Conducta Animal/efectos de los fármacos , Trastornos Relacionados con Cocaína/fisiopatología , Cocaína/administración & dosificación , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/fisiología , Animales , Conducta Animal/fisiología , Condicionamiento Clásico , Modelos Animales de Enfermedad , Antagonistas de los Receptores de Dopamina D2 , Masculino , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D2/agonistas , Saimiri , AutoadministraciónRESUMEN
RATIONALE AND OBJECTIVES: Opioid agonists frequently have been reported to share discriminative stimulus (DS) effects with cocaine; however, the pharmacological basis of these shared effects is not understood completely. The present study assessed the ability of heroin and its deacetylated metabolites, 6-monoacetylmorphine (6-MAM) and morphine, to engender cocaine-like DS effects and investigated the role of opioid receptor subtypes in modulating these DS effects. METHODS: Squirrel monkeys were trained to discriminate 0.3 mg/kg cocaine (i.m.) from vehicle under a 10-response fixed-ratio schedule of food reinforcement, and responding on the drug lever was assessed after varying i.m. doses of heroin, 6-MAM, and morphine. The potential role of opioid receptor mechanisms in modulating the cocaine-like DS effects of heroin and its metabolites was assessed with the mixed mu/kappa opioid antagonist naltrexone, the delta-selective antagonist naltrindole, and the kappa-selective antagonist nor-binaltorphimine. RESULTS: Heroin, 6-MAM, and morphine engendered dose-related increases in responding on the cocaine lever in three of four monkeys. Naltrexone shifted the dose-response functions for heroin and its metabolites to the right, and in vivo apparent pA2 analyses revealed that naltrexone antagonized the effects of the opioids in a manner consistent with mu receptor antagonism (apparent pA2 values ranging from 8.20 to 8.47). Naltrindole only minimally altered the dose-response functions of heroin, 6-MAM, and morphine, whereas nor-binaltorphimine did not block the cocaine-like DS effects of the three opioid agonists, suggesting that neither delta nor kappa receptors played a prominent role in the cocaine-like DS effects of heroin and its metabolites. CONCLUSIONS: These results suggest that heroin and its deacetylated metabolites engendered cocaine-like DS effects in a similar fashion. Furthermore, the cocaine-like DS effects of these opioids were modulated by a predominantly mu-opioid receptor mechanism.
Asunto(s)
Cocaína/farmacología , Aprendizaje Discriminativo/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Heroína/farmacología , Antagonistas de Narcóticos/farmacología , Receptores Opioides/efectos de los fármacos , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacología , Animales , Aprendizaje Discriminativo/fisiología , Heroína/metabolismo , Masculino , Naltrexona/análogos & derivados , Naltrexona/farmacología , Receptores Opioides/fisiología , SaimiriRESUMEN
Previous studies suggest that D1 receptor partial agonists may be viable candidates for development as pharmacotherapies for cocaine addiction. This study investigated the ability of the D1 receptor partial agonists SKF 83959 and SKF 77434 to modulate the behavioral effects of cocaine and compared these effects with those of the reference D1 receptor antagonist SCH 39166 and D1 receptor agonists SKF 81297 and 6-Br-APB. Squirrel monkeys were trained either to respond under a fixed-interval schedule of stimulus-shock termination or to discriminate cocaine from vehicle (procedures useful for evaluating the behavioral stimulant and subjective effects of cocaine, respectively). Additional monkeys were studied with quantitative observational techniques to evaluate the effects of the drugs on various forms of motor behavior. Like SCH 39166, but unlike SKF 81297 and 6-Br-APB, the D1 receptor partial agonists attenuated the behavioral stimulant and discriminative stimulus effects of cocaine in a dose-dependent manner, although maximum antagonism produced by SKF 77434 was not always as great as that produced by SKF 83959 or SCH 39166. In observational studies, SKF 83959 and SKF 77434 produced less severe disruptions in motor behavior than did SCH 39166 and, for SKF 83959, showed a greater separation between the dose required to antagonize the behavioral effects of cocaine and the dose that induced catalepsy (>/=33-fold). These results suggest that D1 receptor partial agonists can act as functional cocaine antagonists with less severe behavioral effects than D1 receptor antagonists. The prominent cocaine-antagonist properties and the low incidence of motoric side effects of SKF 83959 may reflect its unique binding profile at D1 as well as nondopaminergic receptors.
Asunto(s)
2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/análogos & derivados , Cocaína/antagonistas & inhibidores , Agonistas de Dopamina/farmacología , Receptores de Dopamina D1/agonistas , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Benzazepinas/farmacología , Catalepsia/inducido químicamente , Aprendizaje Discriminativo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Rigidez Muscular/inducido químicamente , SaimiriRESUMEN
The present study examined whether zolpidem, an imidazopyridine with selectivity for benzodiazepine (BZ)/gamma-aminobutyric acid(A) receptors containing the alpha1-subunit, had discriminative stimulus effects similar to typical BZs and other sedative/hypnotic drugs in primates. Squirrel monkeys (Saimiri sciureus) were trained to discriminate zolpidem (1.0 mg/kg i.v.) from vehicle under a 10-response fixed-ratio schedule of food delivery. Under test conditions, zolpidem (0.1-3.0 mg/kg) increased responding on the drug lever to an average maximum of 90% of total responding. When pretreatment times were varied from 5 to 50 min, the discriminative stimulus effects of zolpidem were maximal at 5 min and near control levels 35 min after administration. Flumazenil antagonized both the discriminative stimulus and rate-decreasing effects of zolpidem in a dose-dependent and surmountable fashion (in vivo apparent pA(2) values of 7.3 and 6.6 for the discriminative stimulus and rate-suppressing effects, respectively). The BZs triazolam, midazolam, diazepam, and N-desmethyldiazepam engendered dose-related increases in drug-lever responding that reached zolpidem-like levels (90%) in the majority of monkeys tested. In contrast, lorazepam, chlordiazepoxide, and oxazepam engendered average maximums of 70% or less and substituted fully for zolpidem in one or two monkeys only. Representative barbiturates as well as drugs that bind to non-BZ sites (muscimol, baclofen, buspirone, cyproheptadine, diphenhydramine) engendered 0 to 45% of responses on the drug lever up to doses that markedly reduced response rate. These results support the view that zolpidem's selectivity for the alpha1-subunit of the BZ/gamma-aminobutyric acid(A) receptor complex confers a distinctive profile of interoceptive effects that overlaps partially with those of typical BZs but not with those of barbiturates.
Asunto(s)
Benzodiazepinas/farmacología , Discriminación en Psicología/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Piridinas/farmacología , Animales , Benzodiazepinas/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Flumazenil/farmacología , Moduladores del GABA/farmacología , Agonistas de Receptores de GABA-A , Hipnóticos y Sedantes/antagonistas & inhibidores , Masculino , Midazolam/farmacología , Piridinas/antagonistas & inhibidores , Saimiri , ZolpidemRESUMEN
Animal models have been developed that simulate relevant features of relapse to cocaine-seeking behavior in humans. These models have provided valuable information about pharmacological and environmental factors that precipitate reinstatement of extinguished cocaine-seeking in rats and monkeys, as well as new insights about potential pharmacotherapies for relapse prevention. Reinstatement of cocaine-seeking behavior in animals can be induced by cocaine priming or by cocaine-paired environmental stimuli: however, maximum reinstatement of drug-seeking appears to be induced when cocaine priming and cocaine-paired stimuli are combined. Drugs that share cocaine's indirect dopamine agonist properties or that act as direct agonists at D2-like dopamine receptors also induce reinstatement of cocaine-seeking behavior, whereas with some exceptions (e.g., caffeine, morphine) drugs from other pharmacological classes do not. D1-like receptor agonists block rather than mimic the priming effects of cocaine, suggesting different roles for D1- and D2-like receptor mechanisms in cocaine relapse. Although considerable overlap exists, drugs that exhibit cocaine-like discriminative stimulus and/ or reinforcing effects in other situations do not invariably induce cocaine-like reinstatement of drug-seeking and vice versa, implying that these effects are not simply different behavioral expressions of a unitary neurobiological process. Finally, recent findings with D1-like receptor agonists, partial agonists, and antagonists suggest that some of these drugs may be viable candidates for development as antirelapse pharmacotherapies.
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Trastornos Relacionados con Cocaína/psicología , Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Medio Social , Animales , Humanos , Ratas , RecurrenciaRESUMEN
Morphine and other mu opioids mimic and/or modulate the discriminative stimulus (DS) effects of cocaine, possibly reflecting mutual stimulation of mesolimbic dopamine activity. Less is known about the capacity of cocaine and related stimulants to modulate the DS effects of morphine. The present study investigated the effects of cocaine, amphetamine, and reference drugs, administered alone and with morphine, in squirrel monkeys trained to discriminate morphine from vehicle. Additional studies determined the ability of opioid and dopamine receptor antagonists to attenuate the DS effects of morphine and the morphine-like effects of other drugs. The DS effects of morphine were mimicked by the mu-opioid agonist fentanyl but not the delta-opioid agonists SNC 80 and BW 373U86 or the kappa-opioid agonist U50,488H, and were antagonized by the opioid antagonist naltrexone but not the dopamine antagonist flupenthixol. In three of five monkeys, the DS effects of morphine also were mimicked by cocaine, amphetamine, and the dopamine transport inhibitor GBR 12909 but not the norepinephrine transport inhibitor talsupram or the serotonin transport inhibitor fluoxetine, and were antagonized by flupenthixol but not naltrexone. In this subgroup, pretreatment with cocaine or amphetamine enhanced the DS effects of morphine, whereas in the other two monkeys pretreatment with either stimulant attenuated the DS effects of morphine. The results demonstrated individual differences in morphine-like DS effects of stimulants that are mirrored by individual differences in their interactions with morphine. Furthermore, different mechanisms appear to mediate the DS effects of morphine and the morphine-like DS effects of cocaine and amphetamine.
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Analgésicos Opioides/farmacología , Aprendizaje Discriminativo/efectos de los fármacos , Morfina/farmacología , Anfetamina/farmacología , Anestésicos Locales/farmacología , Animales , Ansiolíticos/farmacología , Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Fentanilo/farmacología , Masculino , Naltrexona/farmacología , Antagonistas de Narcóticos , Piperazinas/farmacología , Receptores Opioides/agonistas , Saimiri , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
RATIONALE: The growing abuse of cocaine combined with morphine-like opiates ("speedballs") in human addicts has prompted efforts to characterize the roles of different opioid receptor subtypes in mediating their combined effects. Previous drug discrimination studies in rats have been inconsistent in showing significant interactions between cocaine and opioid agonists in subjects trained to discriminate a relatively high dose of cocaine from vehicle. It is known, however, that the training dose of cocaine can play a key role in drug-substitution and drug-interaction profiles and, therefore, training rats to discriminate a relatively low dose of cocaine may influence its interactions with opioid agonists. OBJECTIVES: The objectives of this study were to examine the degree to which a relatively high (10 mg/kg) versus a relatively low (3.0 mg/kg) cocaine training dose influenced the interactions between cocaine and either the mu opioid agonist morphine or the kappa opioid agonist U50,488. METHODS: Substitution tests with cumulative doses of cocaine, morphine and U50,488 were conducted, as were studies in which selected doses of morphine or U50,488 were administered prior to cumulative doses of cocaine. RESULTS: In substitution tests, cocaine was 2.9 times more potent under the low- than the high-dose training condition. Morphine substituted fully for cocaine in the majority of subjects trained to discriminate the low, but not the high, dose of cocaine. U50,488 engendered mainly saline-lever responses under both training conditions. In pretreatment studies, morphine enhanced and U50,488 attenuated the discriminative stimulus effects of cocaine in low-dose, but not high-dose, trained rats. In low-dose trained rats, cocaine was five- to eightfold more potent after morphine and three- to fourfold less potent after U50,488 pretreatments. CONCLUSIONS: The results demonstrate that cocaine-opioid interactions are dependent on the training dose of cocaine in rats and suggest an opposing influence of mu and kappa opioid receptors in modifying the discriminative stimulus effects of cocaine.
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Cocaína/farmacología , Discriminación en Psicología/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Narcóticos/farmacología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Analgésicos Opioides/farmacología , Animales , Cocaína/administración & dosificación , Aprendizaje Discriminativo/efectos de los fármacos , Inhibidores de Captación de Dopamina/administración & dosificación , Relación Dosis-Respuesta a Droga , Masculino , Morfina/farmacología , Ratas , Ratas WistarRESUMEN
Previous research in squirrel monkeys has shown enhancement of the discriminative stimulus effects of cocaine by mu-opioid agonists, but not by the delta agonist BW373U86. To examine further the role of mu and delta receptor stimulation in the ability of opioid drugs to modulate the discriminative stimulus effects of cocaine, the present study assessed the effects of cocaine alone and combined with SNC 80, a selective high-efficacy delta agonist, and fentanyl, a selective high-efficacy mu agonist. Five adult male squirrel monkeys were trained to discriminate i.m. injections of 0.3 mg/kg cocaine from saline under a fixed-ratio 10 schedule of food presentation. Cumulative doses of cocaine (0.03-1.0 mg/kg) engendered dose-related increases in drug-lever responding to a maximum of 100%, with a decrease in response rate observed at 1.0 mg/kg. Cumulative doses of SNC 80 (0.03-1.0 mg/kg) or fentanyl (0.001-0.01 mg/kg) resulted in a maximum of 22% and 48% drug-lever responding, respectively, accompanied by pronounced decreases in response rate. Administration of either SNC 80 (0.1-1.0 mg/kg) or fentanyl (0.001-0.01 mg/kg) prior to cumulative doses of cocaine produced dose-dependent leftward shifts in the cocaine dose-response function. When the selective delta antagonist naltrindole (1.0 mg/kg) was combined with SNC 80 (1.0 mg/kg) or fentanyl (0.01 mg/kg) prior to cumulative doses of cocaine, the leftward shift of the cocaine dose-response function produced by SNC 80 was blocked, whereas the leftward shift produced by fentanyl was not. By contrast, the mu antagonist naltrexone (0.3 mg/kg) blocked the cocaine-enhancing effects of fentanyl, but not of SNC 80. Combinations of SNC 80 (0.03-0.3 mg/kg) with fentanyl (0.001-0.003 mg/kg) resulted in leftward shifts in the cocaine dose-response function that were comparable in magnitude to the shifts in the cocaine dose-response function produced by either drug alone. These results suggest that opioid enhancement of the discriminative stimulus effects of cocaine is mediated independently by delta- and mu-receptor mechanisms.