Discriminative stimulus effects of opioids in pigeons trained to discriminate fentanyl, bremazocine and water: evidence of pharmacological selectivity

The purpose of the present investigation was to examine the discriminative stimulus effects of opioids with activity at mu and kappa opioid receptors, in pigeons trained to discriminate the mu opioid fentanyl, the kappa opioid bremazocine and water in a three-choice discrimination task. The apparent pkB values obtained for naloxone as an antagonist of the stimulus effects of fentanyl were higher than those obtained against the bremazocine stimulus. The mu opioids morphine and l-methadone substituted for the fentanyl stimulus, the kappa opioids U50,488 and U69,593 substituted for the bremazocine stimulus, and the non-opioid pentobarbital failed to substitute for either the fentanyl or bremazocine stimulus. A series of opioids with activity at both the mu and kappa opioid receptor sites, including nalorphine, butorphanol, buprenorphine, nalbuphine, ethylketocyclazocine, (-)-ketocyclazocine, (-)-n-allylnormetazocine (NANM) and levallorphan, produced high levels of substitution for the fentanyl stimulus without producing appreciable levels of substitution for the bremazocine stimulus. At doses that did not substitute for the fentanyl stimulus, (-)-NANM, levallorphan, nalorphine and nalbuphine partially antagonized the bremazocine stimulus (i.e. produced responding on the water key). Butorphanol and buprenorphine also antagonized the bremazocine stimulus, although this effect was evidenced only at doses that substituted for the fentanyl stimulus. In contrast, even when tested up to doses that markedly decreased rates of responding, ethylketocyclazocine and (-)-ketocyclazocine failed to antagonize the bremazocine stimulus. The present findings indicate that in this three-choice task the fentanyl-like substitution patterns produced by opioids with activity at both the mu and kappa opioid receptors are similar to those reported in pigeons trained to discriminate either fentanyl or bremazocine from saline (i.e. two-choice tasks). In this task, however, the level of kappa antagonist activity evidenced by these opioids was considerably less than that obtained in pigeons trained to discriminate bremazocine from saline.     

Opioids and rate of positively reinforced behavior: II. Antagonism by β-funaltrexamine.

Lever pressing by rats (Rattus norvegicus) was maintained under a fixed-ratio 20 schedule of food presentation. Response rate-decreasing effects of the opioid compounds fentanyl, U50,488, butorphanol, and nalorphine were examined alone and in combination with the irreversible, μ-selective opioid antagonist β-funaltrexamine (β-FNA) antagonized the rate-decreasingly effects of both fentanyl and butorphanol. β-FNA was more potent and the duration of antagonism was greater, against butorphanol than against fentanyl. β-FNA also antagonized the effects of the higher nalorphine doses: however, lower doses of nalorphine, which were without effect alone, decreased response rates in the presence of β-FNA. The dose–effect curve for U50,488 was shifted leftward in the presence of β-FNA. These data suggest that, β-FNA may be useful in assessing μ-receptor activity related to the effects of opioids on rate of operant behavior and the efficacy with which opioids produce these effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Drug discrimination history: Pigeons trained to discriminate opioids with activity at different receptor types.

In pigeons (Columba livia; N?=?5) trained to discriminate the mu (μ) opioid butorphanol from saline, various μ (morphine, fentanyl) but not kappa (κ; bremazocine, U50,488, U69,593) opioids produced at least 80% drug-appropriate responding. Subsequently, pigeons were retrained to discriminate the κ opioid bremazocine from saline; in this condition, both μ and κ opioids produced at least 80% drug-appropriate responding, naloxone was more potent as an antagonist of the butorphanol stimulus, and chronic bremazocine treatment selectively produced tolerance to the bremazocine stimulus. Although butorphanol can function as a κ antagonist, the effects produced by combinations of butorphanol and bremazocine during training with bremazocine were generally effect-additive. The findings indicate that the mechanisms underlying the stimulus effects of μ opioids are not altered by subsequent training with a κ opioid. Conversely, a history of discrimination training with a μ opioid does not alter the discriminative control produced by κ opioids during subsequent training with a κ opioid. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic l-alpha acetylmethadol in rhesus monkeys: discriminative stimulus and other behavioral measures of dependence and withdrawal

This study characterized discriminative stimulus and other effects of naltrexone in rhesus monkeys treated daily with the long-acting opioid l-alpha acetylmethadol (LAAM). An initial dose-finding study assessed the rate-decreasing effects of naltrexone in three monkeys receiving LAAM daily (0.32-1.78 mg/kg); subsequently, these monkeys and a fourth received 1.0 mg/kg/12 hr of LAAM although discriminating between naltrexone and saline. Responding occurred on the saline lever after the administration of LAAM, whereas >90% drug-lever responding occurred after the administration of 0.1 mg/kg of naltrexone that also elicited signs of withdrawal. Naloxone and quadazocine, but not morphine, nalbuphine or ketamine, substituted for naltrexone. Morphine and nalbuphine shifted the naltrexone dose-effect curve to the right. Compared to precipitated withdrawal, deprivation-induced withdrawal occasioned less naltrexone-lever responding and fewer observable signs of withdrawal. Maximal naltrexone-level responding occurred 24 to 48 hr after the discontinuation of LAAM treatment; the frequency of other withdrawal signs also peaked 24 to 48 hr after the discontinuation of LAAM. Partial naltrexone-lever responding occurred for up to 10 days after discontinuation of LAAM treatment; 4 and 8 days after the discontinuation of LAAM treatment, 0.1 mg/kg of naltrexone did no further increase naltrexone-lever responding or withdrawal signs suggesting that less-then-maximal naltrexone-lever responding was not due to long-lasting effects of LAAM or its metabolites. The discriminative stimuli that are associated with LAAM deprivation might be different from the stimuli associated with either training condition. This study is the first antagonist discrimination in non-humans primates treated chronically with LAAM and the results indicate that the naltrexone stimulus is related to opioid withdrawal.     

Discriminative stimulus and anxiolytic-like effects of the novel compound CL 273,547.

CL 273,547 is a novel nonbenzodiazepine with anxiolytic activity, but with a lesser tendency to produce sedative effects. CL 273,547 was established as a discriminative stimulus in rats (Rattus norvegicus). Triazolam and CL 284,846 substituted for CL 273,547 and decreased response rates. Buspirone did not substitute for CL 273,547, whereas pentobarbital substituted in the majority of the rats. Effects on punished responding of pigeons (Columba livia) also were examined as a preclinical evaluation of anxiolytic-like activity. CL 273,547 increased punished responding in pigeons at doses that had little effect on responding that was not punished. The benzodiazepine receptor antagonist flumazenil partially blocked the discriminative stimulus effects of CL 273,547 in rats and the effects of CL 273,547 on punished responding of pigeons. These results suggest that the nonbenzodiazepine CL 273,547 has benzodiazepine-like discriminative stimulus and anxiolytic effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amphetamine-like discrimination stimulus effects of ephedrine and its stereoisomers in pigeons.

This study assessed the discriminative stimulus effects of (±)-ephedrine and its stereoisomers in pigeons discriminating 1.0 mg/kg of amphetamine from saline. Amphetamine, (±)-, (-)-, and (+)-ephedrine, and cocaine occasioned greater than 80% drug-key responding with the following rank order of potency: amphetamine > cocaine > (-)-ephedrine ≥ (±)-ephedrine ≥ (+)-ephedrine. Neither the α-adrenergic antagonist, phentolamine, nor the β-adrenergic antagonist, propranolol, antagonized the effects of amphetamine or (±)-ephedrine. In contrast, the dopamine receptor antagonist, haloperidol, antagonized the discriminative stimulus effects of amphetamine and (±)-ephedrine as well as those of (-)- and (+)-ephedrine. These results indicate that, like cocaine, (±)-ephedrine and its stereoisomers share discriminative stimulus effects with amphetamine. Moreover, these effects appear to be the result of increased activity in dopaminergic systems. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Assessment of the kappa agonist and antagonist properties of mixed action opioids, mu opioids, and a delta opioid in pigeons.

The present study examined the kappa agonist and antagonist effects of various opioids in pigeons (Columba liva) trained to discriminate the kappa opioid bremazocine from saline. The mixed action opioids oxilorphan and (–)-cylorphan and the opioid antagonist naltrexone produced a dose-related antagonism of the bremazocine stimulus. With oxilorphan, the doses required to decrease responding were approximately 300 tomes larger than those required to antagonize the bremazocine stimulus, whereas with (–)-cylorphan and naltrexone the separation between these doses was relatively small. The mixed action opioid proxorphan substituted partially for and antagonized partially the bremazocine stimulus. Selected mu and delta opioids failed to substitute for or antagonize the bremazocine stimulus. The present findings suggest that mixed action opioids are active at the kappa receptor and that their effects can be distinguished from those of kappa, mu, and delta opioids. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of kappa opioid agonists on the discriminative stimulus effects of cocaine in rhesus monkeys.

The 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. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Food-deprivation level alters the effects of morphine on pigeons' key pecking

Four pigeons pecked response keys under a multiple fixed-ratio 30 fixed-interval 5-min schedule of food presentation. Components alternated separated by 15-s timeouts; each was presented six times. Pigeons were maintained at 70%, 85%, and greater than 90% of their free-feeding weights across experimental conditions. When response rates were stable, the effects of morphine (0.56 to 10.0 mg/kg) and saline were investigated. Morphine reduced response rates in a dose-dependent manner under the fixed-ratio schedule and at high doses under the fixed-interval schedule. In some cases, low doses of morphine increased rates under the fixed-interval schedule. When pigeons were less food deprived, reductions in pecking rates occurred at lower doses under both schedules for 3 of 4 birds compared to when they were more food deprived. When pigeons were more food deprived, low doses of morphine increased rates of pecking in the initial portions of fixed intervals by a greater magnitude. Thus, food-deprivation levels altered both the rate-decreasing and rate-increasing effects of morphine. These effects may share a common mechanism with increased locomotor activity produced by drugs and with increased drug self-administration under conditions of more severe food deprivation.     

Butorphanol-mediated antinociception in mice: partial agonist effects and mu receptor involvement

In the present experiments, we characterized the agonist and antagonist effects of butorphanol in mice. In the mouse radiant-heat tail-flick test, the mu agonists morphine and fentanyl and the kappa agonist U50,488H were fully effective as analgesics, whereas butorphanol was partially effective (producing 82% of maximal possible analgesic effect). Naltrexone was approximately equipotent in antagonizing the effects of morphine, fentanyl and butorphanol; in vivo apparent pA2 values for these naltrexone/agonist interactions were 7.5 (unconstrained). Naltrexone was approximately 10 times less potent in antagonizing the effect of U50,488H (average apparent pK(B) = 6.7). The selective mu antagonist beta-funaltrexamine (0.1-1.0 mg/kg) antagonized the effects of butorphanol in a dose-dependent insurmountable manner. Pretreatment with nor-binaltorphimine (32 mg/kg), a kappa-selective antagonist, did not reliably antagonize butorphanol, and naltrindole (20 and 32 mg/kg), a delta-selective antagonist, failed to antagonize the effects of butorphanol. Low doses of butorphanol (1.0, 1.8 or 3.2 mg/kg) caused parallel, rightward shifts in the dose-effect curve for morphine and parallel leftward shifts in the dose-effect curve for U50,488H. Taken together, the results of the present study suggest that butorphanol is a partial agonist in the mouse radiant-heat tail-flick test and that activity at mu receptors accounts for the majority of its antinociceptive effects.     

Behavioral pharmacological similarities between methylphenidate and cocaine in cocaine abusers.

Six human participants with recent histories of cocaine use were trained to discriminate 200 mg oral cocaine hydrochloride. A range of doses of oral cocaine (50–300 mg), methylphenidate (15–90 mg), triazolam (0.125–0.75 mg), and placebo were then tested to determine whether they shared discriminative–stimulus and participant-rated effects with 200 mg cocaine. Cocaine and methylphenidate dose-dependently increased cocaine-appropriate responding, produced prototypical stimulant-like participant-rated drug effects (e.g., increased participant ratings of Drug Liking), and increased heart rate and blood pressure. Triazolam produced low levels of cocaine-appropriate responding and impaired performance. Thus, consistent with previous studies, humans can reliably discriminate oral cocaine. Consistent with in vivo behavioral neuropharmacological data, the discriminative–stimulus, participant-rated, and physiological effects of oral cocaine and methylphenidate were similar. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral evaluation of modafinil and the abuse-related effects of cocaine in rhesus monkeys.

Modafinil is a central nervous system stimulant used to promote wakefulness, and it is being evaluated clinically as an agonist medication for treating stimulant abuse. This is the first report of the effects of modafinil on the abuse-related effects of cocaine in nonhuman primates. The behavioral effects of modafinil were examined in three studies. First, the discriminative stimulus effects of modafinil (3.2–32 mg/kg) were evaluated in rhesus monkeys (Macaca mulatta) trained to discriminate either low (0.18 mg/kg, IM) or high (0.4 mg/kg, IM) doses of cocaine from saline. Modafinil dose-dependently substituted for cocaine in 6 of 7 monkeys. In the second study, the effects of chronically administered modafinil (32–56 mg/kg/day, IV) on food- and cocaine-maintained (0.001–0.1 mg/kg/inj) operant responding were examined. Modafinil was administered 3 times/hr for 23 hr/day to ensure stable drug levels. Chronic treatment with 32 mg/kg/day modafinil selectively reduced responding maintained by intermediate and peak reinforcing doses of cocaine, but responding maintained by higher doses of cocaine was unaffected. Food-maintained behavior did not change during chronic modafinil treatment. In a third study, modafinil (32 and 56 mg/kg/day, IV) was examined in a reinstatement model. Modafinil transiently increased responding during extinction. These findings indicate that modafinil shares discriminative stimulus effects with cocaine and selectively reduces responding maintained by reinforcing doses of cocaine. In addition, modafinil reinstated cocaine-seeking behavior, which may reflect its cocaine-like discriminative stimulus effects. These data support clinical findings and indicate that these preclinical models may be useful for predicting the effectiveness of agonist medications for drug abuse treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Analgesic potency of mu and kappa opioids after systemic administration in amphibians

The relative analgesic potency of 11 opioid agents was assessed by using the acetic acid test in amphibians. Systemic administration of the mu agonists, fentanyl, levorphanol, methadone, morphine, meperidine and codeine; the partial mu agonist, buprenorphine; and the kappa agonists nalorphine, bremazocine, U50488 and CI-977 was made by s.c. injection into the dorsal lymph sac of the Northern grass frog, Rana pipiens. All agents produced a dose-dependent and long-lasting analgesia which persisted for at least 4 hr. The analgesic effects of single doses of each agent were significantly blocked or reduced by pretreatment with naltrexone. Systemic opioids produced log dose-response curves which yielded ED50 values ranging from 1.4 nmol/g for fentanyl to 320.9 nmol/g for nalorphine. Comparison of ED50 values gave a rank order of analgesic potency = fentanyl > CI-977 > levorphanol > U50488 > methadone > bremazocine > morphine > buprenorphine > meperidine > codeine > nalorphine. The relative analgesic potency of mu opioids in amphibians was significantly correlated with relative analgesic potency of these same agents obtained on the mouse writhing and hot plate tests. These data suggest that the amphibian model may serve as an adjunct or alternative model for the testing of opioid agents. Furthermore, given the inactivity of kappa opioids on rodent hot plate and tail-flick tests, the acetic acid test in amphibians may be especially well-suited for the assessment of opioid analgesia after administration of kappa-selective opioids.     

Assessment of the discriminative stimulus effects of cocaine in the rat: lack of interaction with opioids

The present study examined the effects of several opioid agonists and antagonists in rats trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, food-reinforced, discrimination task. Neither fentanyl, a mu agonist, nor the delta agonist BW 373U86 elicited cocaine-appropriate responding. Although pretreatment with fentanyl failed to alter the discriminative stimulus effects of low doses of cocaine, cocaine reversed the rate-suppressant effects of fentanyl. Although the kappa agonist U50,488H decreased response rates, it did not substitute for cocaine. Injection of U50,488H in combination with the training dose of cocaine (10 mg/kg) reversed the rate-suppressant effects of U50,488H but failed to affect the cocaine cue. Administration of U50,488H (3 mg/kg), in conjunction with several doses of cocaine, did not shift the cocaine dose-response curve. Naltrindole and naltrexone, delta and mu antagonists respectively, did not block the effects of cocaine. Further, naltrindole did not substitute for the cocaine cue. Complete generalization was observed to the dopamine uptake inhibitor bupropion (30 mg/kg). These results suggest that fentanyl and U50,488H, at doses that purportedly influence mesolimbic dopamine levels, do not alter the discriminative stimulus effects of cocaine. Moreover, activation of delta receptors and blockade of mu and delta receptors are similarly ineffective.     

Evaluation of the reinforcing and discriminative stimulus effects of cocaine in combination with (+)-AJ76 or clozapine

Because self-administration and discrimination of a drug by animals correlate with its abuse and subjective effects in humans, interventions that modify the reinforcing and discriminative stimulus effects of the drug may be useful in the treatment of its abuse. The present study was designed to evaluate the effects of the putative dopamine autoreceptor antagonist (+)-AJ76 (AJ) or the atypical antipsychotic clozapine (CLZ) on the reinforcing and discriminative stimulus effects of cocaine in monkeys. One group of rhesus monkeys (n = 6) was allowed to self-administer cocaine (0.03 or 0.1 mg/kg/injection i.v. fixed-ratio 10, 2 hr/day). A second group of monkeys (n = 5) was trained to discriminate cocaine (0.2 or 0.4 mg/kg i.m., 10 min presession) from saline in a two lever, food-reinforced, drug discrimination paradigm. When behavior was stable, AJ or CLZ was administered i.m., 15 or 30 min presession. Intermediate doses of both compounds (1.0-3.0 mg/kg of AJ; 0.3-1.0 mg/kg of CLZ) increased cocaine self-administration, while responding remained evenly distributed over the session. A higher dose of CLZ decreased cocaine self-administration in an apparently nonspecific manner. When combined with saline, partial substitution for cocaine was seen in one of three monkeys with AJ and in none with CLZ. In combination with the training dose of cocaine in the discrimination experiment, both AJ and CLZ decreased drug appropriate responding by at least 50% in two of four monkeys, but had little or no effect in the other monkeys up to doses that completely suppressed lever pressing (6.4 mg/kg of AJ; 3.2 mg/kg of CLZ). Taken together, the present findings suggest that any blockade of the reinforcing and discriminative stimulus effects of cocaine by AJ and CLZ was, at best, partial. Furthermore, the stimulant effects of AJ observed in rats were not prominent in monkeys.     

Discriminative stimulus effects of a cocaine/heroin "speedball" combination in rhesus monkeys

Cocaine and heroin often are abused together in a combination known as a "speedball," but relatively little is known about ways in which cocaine and heroin may interact to modify each other's abuse-related effects. The present study evaluated the discriminative stimulus effects of a speedball combination of cocaine and heroin. Three rhesus monkeys were trained to discriminate vehicle from a 10:1 ratio of cocaine (0.4 mg/kg) in combination with heroin (0.04 mg/kg). Both cocaine alone and heroin alone substituted completely for the cocaine/heroin combination, although cocaine and heroin were more potent when administered together than when administered alone. Combined pretreatment with the dopamine antagonist flupenthixol and the opioid antagonist quadazocine dose-dependently antagonized the discriminative stimulus effects of the cocaine/heroin combination, but pretreatment with either antagonist alone was less effective. These findings suggest that either cocaine or heroin alone was sufficient to substitute for the cocaine/heroin training combination. To characterize the discriminative stimulus properties of this speedball more fully, a series of cocaine-like and heroin-like agonists were studied in substitution tests. The indirect dopamine agonists CFT, amphetamine and bupropion and the mu opioid agonists alfentanil, fentanyl and morphine produced high levels of speedball-appropriate responding. However, the indirect dopamine agonist GBR12909, the D1 dopamine agonist SKF82958, the D2 dopamine agonist quinpirole and the partial mu opioid agonist nalbuphine did not substitute for the cocaine/heroin combination. Because these compounds produce discriminative stimulus effects similar to either cocaine or mu opioid agonists alone, these findings suggest that the discriminative stimulus effects of the cocaine/heroin combination do not overlap completely with the effects of cocaine and heroin alone. Finally, a series of compounds that produce partial or no substitution for cocaine or mu agonists alone also did not substitute for the cocaine/heroin combination, which indicates that the discriminative stimulus effects of the combination were pharmacologically selective. Taken together, these findings suggest that a combination of cocaine and heroin produces a pharmacologically selective discriminative stimulus complex that includes aspects of both component drugs.     

The effects of digitalis-like compounds on rat lenses

We examined the effects of several opioids that vary in intrinsic efficacy at the mu-opioid receptor alone and in combination with morphine in a rat warm water tail withdrawal procedure using 50 degrees C and 52 degrees C water (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of antinociception at the low, but not at the high, stimulus intensity, whereas nalbuphine failed to produce antinociception at either stimulus intensity. For cases in which butorphanol and nalbuphine failed to produce antinociception alone, these opioids dose-dependently antagonized the effects of morphine. When levorphanol, dezocine, and buprenorphine were combined with morphine, there was a dose-dependent enhancement of morphine's effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was administered with morphine. In most cases, the effects of these combinations could be predicted by summating the effects of the drugs when administered alone. These results indicate that the level of antinociception produced by an opioid is dependent on the intrinsic efficacy of the drug and the stimulus intensity. Furthermore, the level of antinociception produced by the opioid, not necessarily the opioids' intrinsic efficacy, determines the type of interaction among opioids. Implications: Compared with high-efficacy opioids, lower efficacy opioids produce lower levels of pain relief, especially in situations of moderate to severe pain. When opioids are given in combination, the effects can only be predicted on the basis of the antinociception obtained when the drugs are administered alone.     

Activation of the cloned human kappa opioid receptor by agonists enhances [35S]GTPgammaS binding to membranes: determination of potencies and efficacies of ligands

Activation of kappa receptors inhibits adenylate cyclase, enhances K+ conductance and reduces Ca++ conductance via pertussis toxin-sensitive G proteins. We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined. The presence of GDP and Mg++ was essential for the kappa agonist (-)-U50,488H-induced increase in [35S]GTPgammaS binding to be observed and the optimal concentration was 3 microM and 5 mM, respectively. The presence of 100 mM Na+ was necessary to produce the maximal signal-to-background ratio. (-)U50,488H-induced increase in [35S]GTPgammaS binding was time- and tissue concentration-dependent. (-)U50,488H increased [35S]GTPgammaS binding in a dose-dependent manner with an EC50 of 3.1 nM. (+)-U50,488H had no effect, which indicates that this effect is stereospecific. Naloxone (1 microM) or norbinaltorphimine (10 nM) shifted the dose-response curve of (-)-U50,488H to the right by 100-fold. These results indicate that enhancement of [35S]GTPgammaS binding by (-)-U50,488H is a kappa receptor-mediated event. Pretreatment of the cells with pertussis toxin, but not cholera toxin, abolished the (-)-U50,488H-induced increase in [35S]GTPgammaS binding, which indicates the involvement of Gi and/or Go proteins. [35S]GTPgammaS binding induced by (-)-U50,488H had a Kd value of 0.34 +/- 0.08 nM and a Bmax value of 431 +/- 29 fmol/mg protein. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. Dynorphin A 1-17, (+/-)-ethylketocyclazocine, (-)-U50,488H, tifluadom and beta-funaltrexamine were full agonists, but nalorphine and pentazocine were partial agonists producing maximal responses of 68% and 23% of those of full agonists, respectively. Nalbuphine and buprenorphine had low levels of agonist activities. Norbinaltorphimine and naloxone were antagonists devoid of activities. Enhancement of [35S]GTPgammaS binding by kappa agonists provides a simple functional measure for receptor activation and can be used for determination of potencies and efficacies of opioid ligands at the kappa receptor.     

CP-135,807, a selective 5-HT1D agonist: effects in drug discrimination and punishment procedures in the pigeon

CP-135,807 [3-(N-methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2- yl)amino-1H-indole] binds with high affinity to central 5-HT1D receptors, and in functional studies produces dose-dependent decreases in extracellular serotonin. These and other findings have suggested that CP-135,807 may act as a terminal 5-HT autoreceptor agonist. In an attempt to characterize the behavioral activity of selective 5-HT1D ligands, adult male Carneau pigeons were trained to discriminate IM injections of 0.1 mg/kg CP-135,807 from saline under a two-key, fixed ratio schedule of food-reinforced key pecking. CP-135,807 and the structurally unrelated 5-HT1D agonist CP-286,601 fully and dose-dependently substituted for the training dose. In contrast, little substitution was observed following administration of 8-OH-DPAT, a potent 5-HT1A agonist, the 5-HT1B agonist CP-94,253, or the serotonin reuptake inhibitor sertraline. In addition, the discriminative stimulus produced by CP-135,807 was not blocked by WAY 100,635, a selective 5-HT1A antagonist, but was completely and dose-dependently antagonized by the selective 5-HT1D antagonist, GR 127935. In subjects trained under a multiple schedule of punished and unpunished responding, 8-OH-DPAT produced large increases in punished responding while having little effect on unpunished responding. In contrast, CP-135,807 and CP-94,253 produced no antipunishment effects, while GR 127935 produced modest increases in punished responding. Collectively, these results suggest that CP-135,807 produces centrally mediated psychoactive effects that differ distinctly from those of 5-HT1A agonists.     

Superordinate categorization via learned stimulus equivalence: Quantity of reinforcement, hedonic value, and the nature of the mediator.

Three experiments examined superordinate categorization via stimulus equivalence training in pigeons. Experiment 1 established superordinate categories by association with a common number of food pellet reinforcers, plus it established generalization to novel photographic stimuli. Experiment 2 documented generalization of choice responding from stimuli signaling different numbers of food pellets to stimuli signaling different delays to food reinforcement. Experiment 3 indicated that different numbers of food pellets did not substitute as discriminative stimuli for the photographic stimuli with which the food pellets had been paired. The collective results suggest that the effective mediator of superordinate categories that are established via learned stimulus equivalence is not likely to be an accurate representation of the reinforcer, neither is it likely to be a distinctive response that is made to the discriminative stimulus. Motivational or emotional mediation is a more likely account. (PsycINFO Database Record (c) 2010 APA, all rights reserved)