RESUMEN
Monoamine releasers constitute one class of drugs currently under investigation as potential agonist medications for the treatment of cocaine dependence. The efficacy and safety of monoamine releasers as candidate medications may be influenced in part by their relative potency to release dopamine and serotonin, and we reported previously that releasers with approximately 30-fold selectivity for dopamine versus serotonin release may be especially promising. The present study examined the effects of the releasers benzylpiperazine, (+)phenmetrazine, and 4-benzylpiperidine, which have 20- to 48-fold selectivity in vitro for releasing dopamine versus serotonin. In an assay of cocaine discrimination, rhesus monkeys were trained to discriminate 0.4 mg/kg i.m. cocaine from saline in a two-key, food-reinforced procedure. Each of the releasers produced a dose- and time-dependent substitution for cocaine. 4-Benzylpiperidine had the most rapid onset and shortest duration of action. Phenmetrazine and benzylpiperazine had slower onsets and longer durations of action. In an assay of cocaine self-administration, rhesus monkeys were trained to respond for cocaine injections and food pellets under a second order schedule. Treatment for 7 days with each of the releasers produced a dose-dependent and selective reduction in self-administration of cocaine (0.01 mg/kg/injection). The most selective effects were produced by phenmetrazine. Phenmetrazine also produced a downward shift in the cocaine self-administration dose effect curve, virtually eliminating responding maintained by a 30-fold range of cocaine doses (0.0032-0.1 mg/kg/injection) while having only small and transient effects on food-maintained responding. These findings support the potential utility of dopamine-selective releasers as candidate treatments for cocaine dependence.
Asunto(s)
Monoaminas Biogénicas/metabolismo , Estimulantes del Sistema Nervioso Central/farmacología , Trastornos Relacionados con Cocaína/psicología , Cocaína/antagonistas & inhibidores , Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Inhibidores de Captación de Dopamina/antagonistas & inhibidores , Inhibidores de Captación de Dopamina/farmacología , Fenmetrazina/farmacología , Piperazinas/farmacología , Piperidinas/farmacología , Animales , Discriminación en Psicología/efectos de los fármacos , Dopamina/metabolismo , Alimentos , Macaca mulatta , Masculino , Norepinefrina/metabolismo , Recompensa , Serotonina/metabolismo , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismoRESUMEN
Cocaine blocks uptake of the monoamines dopamine, serotonin and norepinephrine, and monoamine uptake inhibitors constitute one class of drugs under consideration as candidate "agonist" medications for the treatment of cocaine abuse and dependence. The pharmacological selectivity of monoamine uptake inhibitors to block uptake of dopamine, serotonin and norepinephrine is one factor that may influence the efficacy and/or safety of these compounds as drug abuse treatment medications. To address this issue, the present study compared the effects of 7-day treatment with a non-selective monoamine uptake inhibitor (RTI-112) and a dopamine-selective uptake inhibitor (RTI-113) on cocaine- and food-maintained responding in rhesus monkeys. Monkeys (N=3) were trained to respond for cocaine injections (0.01 mg/kg/inj) and food pellets under a second-order schedule [FR2(VR16:S)] during alternating daily components of cocaine and food availability. Both RTI-112 (0.0032-0.01 mg/kg/hr) and RTI-113 (0.01-0.056 mg/kg/h) produced dose-dependent, sustained and nearly complete elimination of cocaine self-administration. However, for both drugs, the potency to reduce cocaine self-administration was similar to the potency to reduce food-maintained responding. These findings do not support the hypothesis that pharmacological selectivity to block dopamine uptake is associated with behavioral selectivity to decrease cocaine- vs. food-maintained responding in rhesus monkeys.
Asunto(s)
Cocaína/análogos & derivados , Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Alimentos , Inhibidores de la Monoaminooxidasa/farmacología , Tropanos/farmacología , Animales , Interpretación Estadística de Datos , Relación Dosis-Respuesta a Droga , Macaca mulatta , Masculino , Esquema de Refuerzo , AutoadministraciónRESUMEN
Monoamine releasers constitute one class of drugs under investigation as candidate medications for the treatment of cocaine abuse. Promising preclinical and clinical results have been obtained with amphetamine, which has high selectivity for releasing dopamine/norepinephrine versus serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that nonselective monoamine releasers or serotonin-selective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine. To address this issue, the present study evaluated the effects of five monoamine releasers in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. The releasers varied along a continuum from dopamine/norepinephrine-selective to serotonin-selective [m-fluoroamphetamine (PAL-353), methamphetamine, m-methylamphetamine (PAL-314), 1-napthyl-2-aminopropane (PAL-287), fenfluramine]. In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine (0.4 mg/kg i.m.) in a two-key, food-reinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/norepinephrine versus serotonin release. In drug self-administration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/injection) and food (1-g pellets) under a second-order fixed-ratio 2 (variable-ratio 16:S) schedule. In general, monoamine releasers produced dose-dependent and sustained decreases in cocaine self-administration. However, the dopamine/norepinephrine-selective releasers decreased cocaine self-administration with minimal effects on food-maintained responding, whereas the more serotonin-selective releasers produced nonselective reductions in both cocaine- and food-maintained responding. These results are consistent with the conclusion that dopamine/norepinephrine-selective releasers retain cocaine-like abuse-related effects but may also be capable of producing relatively selective reductions in the reinforcing effects of cocaine.
Asunto(s)
Trastornos Relacionados con Cocaína/tratamiento farmacológico , Cocaína/administración & dosificación , Aprendizaje Discriminativo/efectos de los fármacos , Dopamina/metabolismo , Norepinefrina/metabolismo , Serotonina/metabolismo , Animales , Macaca mulatta , Masculino , Refuerzo en Psicología , AutoadministraciónRESUMEN
Buprenorphine is an opioid with high affinity for delta, mu and kappa opioid receptors. The delta receptor-mediated effects of buprenorphine have not been studied. Thus, the present study examined the delta receptor-mediated effects of buprenorphine in rhesus monkeys. assays of receptor binding and agonist-stimulated GTP S binding confirmed that buprenorphine had high affinity for, and low efficacy at, delta receptors. In an assay of schedule-controlled responding for food presentation in four monkeys, buprenorphine produced little effect alone, but it antagonized the effects of the delta agonist SNC80, the mu agonist morphine and the kappa agonist U50,488. Buprenorphine was approximately 30-fold less potent as a delta antagonist than as a mu or kappa antagonist. In three monkeys trained to discriminate SNC80 from saline, buprenorphine alone produced only saline-appropriate responding, and buprenorphine pretreatment antagonized the discriminative stimulus effects of SNC80. In a fourth monkey, buprenorphine produced a partial substitution for SNC80 that could be blocked by the delta-selective antagonist naltrindole but not by the mu-selective antagonist quadazocine. These results indicate that, in rhesus monkeys, buprenorphine has very low efficacy at delta receptors, and that buprenorphine produces delta receptor-mediated effects with lower potency than it produces mu or kappa receptor-mediated effects.
Asunto(s)
Analgésicos Opioides/farmacología , Buprenorfina/farmacología , Condicionamiento Operante/efectos de los fármacos , Aprendizaje Discriminativo/efectos de los fármacos , Receptores Opioides delta/antagonistas & inhibidores , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Animales , Benzamidas/farmacología , Unión Competitiva , Encéfalo/metabolismo , Línea Celular , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Alimentos , Técnicas In Vitro , Macaca mulatta , Masculino , Piperazinas/farmacología , Receptores Opioides delta/agonistas , Receptores Opioides kappa/efectos de los fármacos , Receptores Opioides mu/efectos de los fármacos , Esquema de RefuerzoRESUMEN
Conscious squirrel monkeys were treated i.v. with cocaine and various dopamine agonist drugs. Cocaine produced a dose-dependent increase in blood pressure, heart rate, and the rate-pressure product (RPP). The dopamine D1 receptor agonist (+/-)-6-chloro-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 82958) produced effects comparable to cocaine. The D1 agonist (+/-)-6-chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) also produced increases in blood pressure and heart rate but was much less potent than either cocaine or SKF 82958. The partial D1 agonist (+/-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SKF 77434) did not significantly affect any cardiovascular parameters. The D2 agonist quinpirole slightly decreased blood pressure and increased heart rate. As such, the RPP only slightly increased. The selective dopamine uptake inhibitor 1-[2-[bis-(4-fluorphenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909) produced increases in blood pressure, heart rate, and RPP, but again these effects were smaller and only seen at doses higher than cocaine. Effects similar to those with GBR 12909 were seen with the dopamine autoreceptor antagonist cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232). The combination of GBR 12909, SKF 82958, or SKF 77434 with cocaine produced effects that were clearly subadditive. The effects of quinpirole in combination with cocaine were comparable to, or lower than, those of cocaine alone on blood pressure and RPP. The effects on heart rate were additive. Only UH 232 produced additive effects with cocaine for all three measures. As dopamine agonists have been proposed as potential treatments for cocaine abuse, these results suggest that dopamine D1 agonists and uptake inhibitors can be used safely in combination with cocaine. Caution may be warranted, however, with the use of dopamine autoreceptor antagonists in the treatment of cocaine abuse.
Asunto(s)
Cocaína/farmacología , Agonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Hemodinámica/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Interacciones Farmacológicas , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , SaimiriRESUMEN
A series of new N-substituted derivatives of morphinan was synthesized and their binding affinity for the three opioid receptors (mu, delta, and kappa) was determined. A paradoxical effect of N-propargyl (MCL-117) and N-(3-iodoprop-(2E)-enyl) (MCL-118) substituents on the binding affinities for the mu and kappa opioid receptors was observed. All of these novel derivatives showed a preference for the mu and kappa versus delta binding.
Asunto(s)
Morfinanos/farmacología , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistas , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Combinación de Medicamentos , Humanos , Morfinanos/síntesis química , Morfinanos/química , Morfinanos/uso terapéutico , Antagonistas de Narcóticos/farmacología , Antagonistas de Narcóticos/uso terapéutico , Receptores Opioides mu/antagonistas & inhibidoresRESUMEN
The simultaneous intravenous (i.v.) administration of heroin and cocaine, called a "speedball," is often reported clinically, and identification of effective pharmacotherapies is a continuing challenge. We hypothesized that treatment with combinations of a dopamine reuptake inhibitor, indatraline, and a mu partial agonist, buprenorphine, might reduce speedball self-administration by rhesus monkeys more effectively than either drug alone. Speedballs (0.01 mg/kg/inj cocaine + 0.0032 mg/kg/inj heroin) and food (1 g banana pellets) were available in four daily sessions on a second-order schedule of reinforcement [fixed ratio (FR)4; variable ratio (VR)16:S]. Monkeys were treated for 10 days with saline or ascending dose combinations of indatraline (0.001-0.032 mg/kg/day) and buprenorphine (0.00032-0.01 mg/kg/day). Two combinations of indatraline (0.32 and 0.56 mg/kg/day) + buprenorphine (0.10 and 0.18 mg/kg/day) significantly reduced speedball self-administration in comparison to the saline treatment baseline (p <.01-.001), whereas the same doses of each compound alone had no significant effect on speedball-maintained responding. Daily treatment with 0.56 mg/kg/day indatraline + 0.18 mg/kg/day buprenorphine produced a significant downward shift in the speedball dose-effect curve (p <.01) and transient changes in food-maintained responding. These findings suggest that medication mixtures designed to target both the stimulant and opioid component of the speedball combination may be an effective approach to polydrug abuse treatment.
Asunto(s)
Buprenorfina/farmacología , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Interacciones Farmacológicas/fisiología , Dependencia de Heroína/tratamiento farmacológico , Indanos/farmacología , Metilaminas/farmacología , Narcóticos/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Animales , Cocaína/farmacología , Trastornos Relacionados con Cocaína/fisiopatología , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Combinación de Medicamentos , Femenino , Heroína/farmacología , Dependencia de Heroína/fisiopatología , Macaca mulatta , Masculino , AutoadministraciónRESUMEN
The effects of SNC80 and other structurally related delta-opioid receptor agonists were assessed under conditions of chemically induced hypersensitivity to thermal stimuli in four rhesus monkeys. The shaved tail of each monkey was exposed to warm water (38, 42, 46, and 50 degrees C), and the tail-withdrawal latency from each temperature was recorded. The effects of drugs on the temperature that produced a 10-s tail-withdrawal latency (the T(10) value) were examined. Capsaicin (0.01-0.32 mg) injected into the tail of monkeys dose dependently decreased the T(10), indicating that capsaicin increased sensitivity to thermal stimuli. A dose of 0.1 mg of capsaicin decreased the T(10) from 48.0 to 42.1 degrees C (a -5.9 degrees C change) 15 min after injection. SNC80 (1.0-10.0 mg/kg s.c.) dose dependently blocked the capsaicin-induced decrease in the T(10), and 10.0 mg/kg SNC80 fully blocked the effects of capsaicin. The delta-selective antagonist naltrindole (0.1-1.0 mg/kg) dose dependently antagonized the effects of SNC80, whereas a mu-selective dose of the opioid antagonist quadazocine (0.1 mg/kg) did not. Two other delta-selective agonists, SNC162 (1.0-10.0 mg/kg) and SNC243A (1.0-10.0 mg/kg), also dose dependently blocked capsaicin-induced thermal hypersensitivity. In contrast, neither SNC67 (10.0 mg/kg), which is the (-)-enantiomer of SNC80, nor the nonsteroidal anti-inflammatory drug (NSAID) ketorolac (1.0-10.0 mg/kg) modified the effects of capsaicin. SNC80 was also effective in reversing thermal hypersensitivity induced by prostaglandin E(2) (0.0158 mg) and Freund's complete adjuvant (10% concentration). These findings suggest that delta-agonists have antinociceptive effects in primates under conditions of chemically induced thermal hypersensitivity and might be effective under a broader range of conditions than clinically available NSAIDs.
Asunto(s)
Analgésicos/farmacología , Benzamidas/uso terapéutico , Hiperalgesia/prevención & control , Dolor/prevención & control , Piperazinas/uso terapéutico , Receptores Opioides delta/agonistas , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/uso terapéutico , Benzamidas/farmacología , Capsaicina , Dinoprostona/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Adyuvante de Freund/farmacología , Hiperalgesia/inducido químicamente , Ketorolaco/efectos adversos , Ketorolaco/uso terapéutico , Macaca mulatta , Masculino , Morfina/efectos adversos , Morfina/uso terapéutico , Dimensión del Dolor , Piperazinas/farmacologíaRESUMEN
Cocaine stimulates luteinizing hormone (LH) release in rhesus monkeys and in men, but its effects on LH in women are unknown. Cocaine (0.2 and 0.4 mg/kg i.v.) was administered to groups of follicular and luteal phase women (N = 22) and to men (N = 12) to examine the influence of gender and menstrual cycle phase on cocaine and LH interactions. All subjects met American Psychiatric Association Diagnostic and Statistical Manual IV criteria for cocaine abuse, and menstrual cycle phase was verified by estradiol and progesterone measures. Baseline LH levels were equivalent between groups. Peak cocaine levels did not differ significantly between men and women and averaged between 87 +/- 21 and 124 +/- 18 ng/ml after 0.2 mg/kg cocaine and between 227 +/- 22 and 287 +/- 21 ng/ml after 0.4 mg/kg cocaine. The lower dose of cocaine (0.2 mg/kg) significantly increased LH levels in men (P < 0.001) but not in women at either phase of the menstrual cycle. The higher dose of cocaine (0.4 mg/kg) stimulated significant increases in LH in men (P < 0.001) and in women at both phases of the menstrual cycle (P < 0.004-0.001). Although cocaine's effects on LH in women were dose-dependent, there were no significant differences as a function of menstrual cycle phase. LH remained significantly elevated longer in men (32 min) than in women (8 and 12 min). This gender difference in cocaine's potency in stimulating LH was unexpected.
Asunto(s)
Cocaína/farmacología , Fase Folicular , Fase Luteínica , Hormona Luteinizante/metabolismo , Cocaína/sangre , Inhibidores de Captación de Dopamina/sangre , Inhibidores de Captación de Dopamina/farmacología , Estradiol/metabolismo , Femenino , Fase Folicular/sangre , Humanos , Fase Luteínica/sangre , Hormona Luteinizante/efectos de los fármacos , Masculino , Caracteres Sexuales , Testosterona/metabolismoRESUMEN
Effects of D1-like and D2-like agonists were compared in rats (Rattus norvegicus) with differing levels of experience (24 or 9 mo) in a cocaine discrimination procedure (5.6 mg/kg cocaine; fixed-ratio 20 schedule of food presentation). Cocaine, d-amphetamine, and D2-like agonists (quinelorane, 7-OH-DPAT) dose-dependently substituted for cocaine in both groups of rats. In contrast, D1-like agonists (SKF 82958, SKF 77434) substituted for cocaine only in rats with less discrimination experience. Pretreatment with D2-like agonists increased the stimulus effects of low cocaine-doses in both groups, whereas D1-like agonists produced these effects only in rats with less discrimination experience. The data suggest that the stimulus effects of cocaine overlap with those of D2-like agonists across a broader range of conditions than with those of D1-like agonists. Thus, D2-like receptors may play an especially important role in cocaine's behavioral effects.
Asunto(s)
Cocaína/farmacología , Discriminación en Psicología/efectos de los fármacos , Agonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/análogos & derivados , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Benzazepinas/farmacología , Dextroanfetamina/farmacología , Aprendizaje Discriminativo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Sprague-Dawley , Tetrahidronaftalenos/farmacologíaRESUMEN
Cocaine stimulates gonadotropin (luteinizing hormone) release from the anterior pituitary in humans and in rhesus monkeys, but its acute effects on ovarian steroid hormones are unknown. The acute effects of cocaine and placebo on estradiol and progesterone were studied in 13 drug-naive female rhesus monkeys during the mid-follicular (days 8-10) and the mid-luteal (days 21-23) phases of the menstrual cycle. Each monkey was her own control under cocaine and placebo conditions. Samples for ovarian steroid hormone analysis were collected before and at 15-min intervals for 300 min after cocaine or placebo administration. In follicular phase females, estradiol levels increased significantly within 15 min after cocaine (0.8 mg/kg i.v.) administration (P <.008) but did not change after placebo administration. Estradiol remained significantly above baseline for 45 min (P <.002-0.02). In contrast, in mid-luteal phase females, estradiol did not change after cocaine or placebo administration. Basal progesterone levels did not change after cocaine or placebo administration in either mid-follicular or mid-luteal phase females. After hCG (500 I.U. i.m.) was administered to mid-luteal phase females, cocaine (0.4 and 0.8 mg/kg i.v.) and placebo administration did not increase or decrease estradiol or progesterone. One implication of these findings is that cocaine-induced increases in follicular phase estradiol levels could disrupt folliculogenesis and contribute to the menstrual cycle abnormalities observed during chronic cocaine self-administration.
Asunto(s)
Gonadotropina Coriónica/farmacología , Cocaína/farmacología , Estradiol/metabolismo , Ovario/metabolismo , Progesterona/metabolismo , Animales , Cocaína/sangre , Estradiol/sangre , Femenino , Fase Folicular , Fase Luteínica , Macaca mulatta , Progesterona/sangreRESUMEN
The effects of the long-acting opioid antagonist, nalmefene [17-N-cyclopropylmethyl-3,14-beta-dihydroxy-4, 5-alpha-epoxy-6-methylene morphinan hydrochloride] on LH, T, and prolactin release in rhesus monkeys are unknown. The acute effects of nalmefene (0.01 and 0.10 mg/kg, IV) or placebo on LH, PRL, and T were studied, and samples were collected at 10-min intervals for 360 min to permit cluster analysis of pulsatile release patterns. LH increased significantly within 30 min after nalmefene, and remained significantly above baseline levels for 50 to 60 min (p < 0.05). Testosterone increased significantly within 70 to 80 min after nalmefene, and remained significantly above baseline for 60 min (p < 0.05). Although nalmefene antagonizes opioid agonists for 6-8 h, inhibitory feedback by testosterone appeared to limit the duration of its antagonism of endogenous opioid inhibition of LHRH and stimulation of LH. Nalmefene did not change LH or PRL pulse frequency or amplitude significantly in comparison to placebo administration.
Asunto(s)
Hormona Luteinizante/metabolismo , Naltrexona/análogos & derivados , Antagonistas de Narcóticos/farmacología , Prolactina/metabolismo , Testosterona/metabolismo , Animales , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Cinética , Hormona Luteinizante/sangre , Macaca mulatta , Masculino , Naltrexona/administración & dosificación , Naltrexona/farmacología , Antagonistas de Narcóticos/administración & dosificación , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Prolactina/sangre , Testosterona/sangreRESUMEN
Kappa opioid agonists inhibit dopamine release from mesolimbic dopaminergic neurons and attenuate some behavioral effects of cocaine in rodents. Evidence that kappa opioid agonists may act as functional antagonists of cocaine led us to examine their interactions with cocaine's abuse-related effects in rhesus monkeys. In cocaine self-administration studies, four arylacetamides (U50,488, enadoline, (-) spiradoline and PD117302) and four benzomorphans (ethylketocyclazocine [EKC], bremazocine, Mr2033 and cyclazozine) each were administered as continuous infusions over 10 days. EKC, Mr2033, bremazocine, U50,488 and enadoline produced significant dose-dependent and sustained decreases in cocaine self-administration and also decreased food-maintained responding at some doses. Emesis and sedation were occasionally observed during the first two days of kappa agonist treatment, but tolerance developed rapidly to these effects. Cyclazocine, PD117302 and spiradoline did not significantly alter cocaine self-administration. The behavioral effects of EKC and U50,488 were antagonized by both the kappa opioid antagonist nor-binaltorphimine and the non-selective opioid antagonist naloxone. In general, compounds with mixed activity at both kappa and mu opioid receptors (e.g. EKC, Mr2033) decreased cocaine self-administration more consistently and with fewer or less severe undesirable side effects than more selective kappa agonists (e.g. U50,488, spiradoline). Although several kappa agonists decreased cocaine self-administration, EKC and U50,488 did not consistently block the discriminative stimulus effects of cocaine in monkeys trained to discriminate cocaine from saline. The extent to which kappa agonist-induced decreases in cocaine self-administration reflect an antagonism of cocaine's abuse-related effect remains to be determined.
Asunto(s)
Trastornos Relacionados con Cocaína/tratamiento farmacológico , Receptores Opioides kappa/agonistas , Animales , Cocaína/administración & dosificación , Condicionamiento Psicológico/efectos de los fármacos , Aprendizaje Discriminativo/efectos de los fármacos , Humanos , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , AutoadministraciónRESUMEN
Kappa opioid receptors derive their name from the prototype benzomorphan, ketocyclazocine (1a) which was found to produce behavioral effects that were distinct from the behavioral effects of morphine but that were antagonized by the opioid antagonist, naltrexone. Recent evidence suggests that agonists and antagonists at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. Kappa agonists blocked the effects of cocaine in squirrel monkeys in studies of cocaine discrimination and scheduled-controlled responding. Studies in rhesus monkeys suggested that kappa opioids may antagonize the reinforcing effects of cocaine. These studies prompted the synthesis and evaluation of a series of kappa agonists related to the morphinan, L-cyclorphan (3a) and the benzomorphan, L-cyclazocine (2). We describe the synthesis and preliminary evaluation of a series of morphinans, structural analogs of cyclorphan 3a-c, the 10-keto morphinans 4a and b, and the 8-keto benzomorphan 1b, structurally related to ketocyclazocine (1a). In binding experiments L-cyclorphan (3a), the cyclobutyl (3b), the tetrahydrofurfuryl 3c and the 10-keto 4b analogs had high affinity for mu (mu), delta (delta) and kappa (kappa) opioid receptors. Both 3a and 3b were more selective for the kappa receptor than the mu receptor. However, 3b was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only a 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. The cyclobutyl compound 3b was found to have significant mu agonist properties, while 3a was a mu antagonist. All compounds were also examined in the mouse tail flick and writhing assay. Compounds 3a and 3b were kappa agonists. Correlating with the binding results, compound 3a had some delta agonist properties, while 3b was devoid of any activity at the delta receptor. In addition, compounds 3a and 3b had opposing properties at the mu opioid receptor. The cyclobutyl compound 3b was found to have significant mu agonist properties, while 3a was a mu antagonist.
Asunto(s)
Trastornos Relacionados con Cocaína/tratamiento farmacológico , Receptores Opioides kappa/agonistas , Analgésicos Opioides/síntesis química , Analgésicos Opioides/química , Analgésicos Opioides/farmacología , Animales , Cobayas , Técnicas In Vitro , Ratones , Dimensión del Dolor/efectos de los fármacos , Receptores Opioides kappa/química , Receptores Opioides kappa/metabolismoRESUMEN
RATIONALE: The reinforcing effects of cocaine have been most compellingly related to its action as an indirect dopamine agonist. Although it is generally believed that both D(1-like )and D(2-like )receptor mechanisms may be involved, recent studies suggest that D(1-like )and D(2-like )agonists have differing profiles of cocaine-related actions. OBJECTIVE: To develop a procedure for rapid assessment of complete dose-effect functions for cocaine self-administration in rhesus monkeys and to compare the effects of D(1-like )and D(2-like )agonists on cocaine self-administration using this procedure. METHODS: Responding was maintained by various doses of cocaine or by food under a multiple-component schedule [fixed ratio (FR) 30; time out period (TO) 10 s] in 2-h sessions. After responding stabilized, the effects of pretreatment with D(1-like )and D(2-like )agonists (administered i.m., 10 min or 30 min prior to the session) were assessed. RESULTS: Complete inverted U-shaped dose-effect functions for cocaine self-administration were obtained in all five rhesus monkeys trained with the rapid assessment procedure. Both the position and shape of the cocaine dose- effect function remained stable in repeated assessments, and levels of responding were controlled by the unit dose of cocaine rather than by other variables (e.g., infusion duration and volume) that were used to vary the cocaine dose. Pretreatment with the D(1-like) agonists SKF 82958 (0.32-1.8 mg/kg) and R-6-Br-APB (0.1-1. 0 mg/kg) produced downward shifts in the cocaine dose-effect function at doses that also markedly decreased food-maintained responding. In contrast, pretreatment with the D(2-like) agonists quinelorane (0.001-0.01 mg/kg) and 7-OH-DPAT (0.01-0.10 mg/kg) shifted the cocaine dose-effect function to the left. D(2-like) agonists also increased responding maintained by the cocaine-associated cue lights alone, and moderately decreased food-maintained responding. CONCLUSIONS: The results suggest that D(1-like) and D(2-like) agonists produce qualitatively different effects on cocaine self-administration that may influence their usefulness for the treatment of cocaine abuse and dependence.
Asunto(s)
Cocaína/administración & dosificación , Agonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/administración & dosificación , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Autoadministración , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/análogos & derivados , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Benzazepinas/farmacología , Trastornos Relacionados con Cocaína/prevención & control , Relación Dosis-Respuesta a Droga , Macaca mulatta , Quinolinas/farmacología , Refuerzo en Psicología , Tetrahidronaftalenos/farmacologíaRESUMEN
This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of kappa agonists related to the morphinan (-)-cyclorphan (3a) and the benzomorphan (-)-cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N-cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)-mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for mu, delta, and kappa opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the kappa receptor than for the mu receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. These findings were confirmed in the antinociceptive tests (tail-flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the delta receptor while 3b did not produce agonist or antagonist effects at the delta receptor. Both 3a,b had comparable kappa agonist properties. 3a,b had opposing effects at the mu receptor: 3b was a mu agonist whereas 3a was a mu antagonist.
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Benzomorfanos/síntesis química , Morfinanos/síntesis química , Receptores Opioides kappa/efectos de los fármacos , Receptores Opioides mu/efectos de los fármacos , Ácido Acético , Animales , Benzomorfanos/metabolismo , Benzomorfanos/farmacología , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Etilcetociclazocina/análogos & derivados , Etilcetociclazocina/farmacología , Cobayas , Técnicas In Vitro , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos ICR , Morfinanos/metabolismo , Morfinanos/farmacología , Morfina/antagonistas & inhibidores , Antagonistas de Narcóticos/síntesis química , Antagonistas de Narcóticos/farmacología , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Dimensión del Dolor , Tiempo de Reacción/efectos de los fármacos , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/metabolismoRESUMEN
RATIONALE: Dopaminergic systems thought to mediate the abuse-related effects of cocaine are under inhibitory control by GABAergic systems. These findings suggest that GABA agonists may attenuate some abuse-related effects of cocaine. OBJECTIVE: To assess the effects of GABA receptor agonists and GABA-A receptor modulators on cocaine discrimination in rhesus monkeys. METHODS: Rhesus monkeys were trained to discriminate 0.4 mg/kg cocaine from saline in a two-key, food-reinforced drug discrimination task. The effects of the GABA-A agonist muscimol, the GABA-B agonist baclofen, the barbiturate GABA-A receptor modulator pentobarbital, and the benzodiazepine GABA-A modulators triazolam and imidazenil were examined alone and as pretreatments to cocaine. For comparison, the effects of pentobarbital pretreatment on the cocaine-like discriminative stimulus effects of amphetamine were also examined. RESULTS: When administered alone, the GABA agonists and GABA-A receptor modulators produced primarily saline-appropriate responding. When administered as pretreatments to cocaine, pentobarbital attenuated the discriminative stimulus effects of cocaine in all monkeys tested, and the high efficacy benzodiazepine agonist triazolam attenuated cocaine's effects in three of five monkeys. Muscimol, baclofen and the low efficacy benzodiazepine agonist imidazenil did not alter cocaine's discriminative stimulus effects. Although pentobarbital blocked the effects of the monoamine reuptake blocker cocaine, it did not alter the cocaine-like effects of the monoamine releaser amphetamine. CONCLUSIONS: These results are consistent with the hypothesis that GABA-A receptor modulators attenuate the discriminative stimulus effects of cocaine in rhesus monkeys by decreasing the activity of dopaminergic systems. Direct GABA receptor agonists may be less effective in blocking the abuse-related effects of cocaine in rhesus monkeys.
Asunto(s)
Estimulantes del Sistema Nervioso Central/administración & dosificación , Cocaína/administración & dosificación , Aprendizaje Discriminativo/efectos de los fármacos , Agonistas del GABA/farmacología , Receptores de GABA-A/metabolismo , Anfetamina/administración & dosificación , Anfetamina/farmacología , Análisis de Varianza , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Cocaína/farmacología , Moduladores del GABA/farmacología , Macaca mulatta , Masculino , Pentobarbital/farmacologíaAsunto(s)
Conducta Animal/efectos de los fármacos , Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Animales , Cocaína/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Relación Dosis-Respuesta a Droga , Alimentos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Fenotipo , Esquema de Refuerzo , Refuerzo en Psicología , AutoadministraciónRESUMEN
This study examined the effects of the kappa opioid agonists U50,488 and ethylketocyclazocine (EKC) on cocaine discrimination in rhesus monkeys trained to discriminate cocaine (0.4 mg/kg) from saline. Administration of U50,488 and EKC alone produced primarily saline-appropriate responding. Kappa agonist pretreatments produced variable effects on cocaine discrimination across monkeys, attenuating the discriminative stimulus effects of cocaine in some monkeys, but either having no effect on cocaine discrimination or enhancing the discriminative stimulus effects of cocaine in other monkeys. The effects of kappa agonists on cocaine discrimination were reversed by pretreatment with the opioid antagonist naloxone (1.0 mg/kg). These results indicate that kappa agonists do not consistently block the discriminative stimulus effects of cocaine in rhesus monkeys.