Effects of a kappa receptor agonist, ethylketocyclazocine, on water consumption in water-deprived and nondeprived rats in diurnal and nocturnal tests

In 24 hr water-deprived male hooded rats, ethylketocyclazocine (EKC), 0.1-3.0 mg/kg, dose-dependently suppressed water intake. Within the first 30 min access to water, drinking was virtually abolished by 1.0 and 3.0 mg/kg EKC. Significant reductions in the level of water intake were found after 0.1 mg/kg EKC. After 2 hr access to water, the suppressant effect was attenuated indicating some recovery. The antidipsogenic action of EKC in water-deprived rats was comparable in its effect for both daytime and nocturnal testing. Circadian variation may not be an important modulator of the antidipsogenic action. Naloxone, an opiate receptor antagonist, when administered in a dose of 0.3 mg/kg also significantly reduced drinking in deprived animals. EKC (0.3 mg/kg) and naloxone (0.3 mg/kg) when administered together displayed mutual antagonism. Drinking was at control levels. In nondeprived male rats, EKC exerted some dipsogenic action, most noticeably during diurnal testing. Within 30 min access to water, 0.1 mg/kg EKC significantly elevated the level of water intake. This effect did not occur during nocturnal testing, when the only immediate effect of EKC was a suppression of drinking at 1.0 and 3.0 mg/kg dose levels. After 2 hr access to water, there was a significant peak effect to enhance drinking at the 0.3 mg/kg dose level during the daytime. Effects of EKC during the night were less pronounced. The dipsogenic action of EKC (0.3 and 1.0 mg/kg) in satiated animals during the day was abolished by naloxone and Mr-2266BS, also an opiate receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)     

Extinction and reacquisition of differential responding in rats trained to discriminate between chlordiazepoxide and saline

In order to assess the resistance of drug discriminative responding to prolonged reinforcement omission, rats were trained to discriminate between either 6.0 mg/kg PO or 30.0 mg/kg PO. CDP and saline, using a food reinforced (VI40-FR10) operant procedure. Dose generalization tests were conducted for both groups. Sessions were then run without reinforcement while drug (D) and saline (S) administrations were continued (extinction phase). After a maximum of 30 sessions without reinforcement, or when the rats emitted less than ten responses on either lever during three successive sessions (extinction criterion), reinforcement was reinstated. Finally, additional dose generalization tests with CDP were run. The discriminative responding controlled by the D and S administrations was not affected significantly by prolonged reinforcement omission in either group. For both groups, response rates were decreased and latencies to initiate responding were increased during the extinction phase. Response rate reduction occurred more rapidly for the drug condition in the high training dose group. This group also reached the extinction criterion sooner than the low training dose group. The reacquisition process occurred very rapidly. Response rates increased substantially after the first reinforcement had been obtained. After ten reacquisition sessions, response rates and latencies had reached values similar to those observed before extinction was initiated. Data revealed no differences between groups and the course of reacquisition did not differ between the S and D conditions. The generalization tests executed before the extinction phase and after the reacquisition phase yielded similar results and were in agreement with earlier findings. The major conclusion was that the resistance to extinction of the discriminative accuracy was substantial.     

Midazolam cue in rats: Generalization tests with anxiolytic and other drugs

Some characteristics of the discriminative stimulus (cue) effects of midazolam, a short-acting benzodiazepine, have been determined in rats. A standard two-bar operant conditioning procedure with food reinforcers delivered on a tandem schedule was used. The 0.4 mg/kg dose of midazolam used for training was well discriminated, typically yielding at least 95% correct responding. Other benzodiazepines increased the percentage of drug-appropriate responding in a dose-related manner and were generalized at doses which had little effect on the overall rate of responding. Doses of pentobarbitone which greatly reduced the overall rate of responding were also generalized with midazolam. Amphetamine, oxotremorine, picrotoxin, morphine, nicotine, quipazine and Ro 15-1788 were not generalized, even at doses which severely suppressed overall response rates. The midazolam cue possesses a considerable degree of specificity and provides a potentially useful assay for drug action at the benzodiazepine receptor complex.     

Mu-opioid component of the ethylketocyclazocine (EKC) discriminative stimulus in the rat

The opioid receptor selectivity of the EKC discriminative stimulus was characterized in Fischer rats trained to discriminate 0.3 mg/kg EKC (SC) from saline in a twochoice discrete-trial avoidance paradigm. The putative kappa-opioid receptor agonists EKC and U50,488H completely generalized with the EKC aue at doses of 0.3 and 10 mg/kg, respectively. The putative mu-opioid receptor agonists morphine (M) and fentanyl also dose-dependently generalized with the EKC stimulus. The generalization of M with EKC was not symmetrical, EKC and U50,488H produced little or no M-appropriate responding in rats trained to discriminate 3.0 mg/kg M (SC) from saline. This generalization pattern may reflect a lack of opioid receptor selectivity of the EKC stimulus. However, distinct muopioid and kappa-opioid components of the EKC cue could be identified using graded doses of naloxone in EKC-trained rats. The discriminative effects of morphine and fentanyl were blocked completely by doses of 0.1–1.0 mg/kg naloxone, whereas doses of naloxone 3–10 times greater were necessary to block the discriminative effects of EKC and U50,488H. These results suggest that EKC produces a complex discriminative stimulus with mu-opiod and kappa-opioid components that can be separated using antagonists such as naloxone.     

Effects of selective dopamine receptor agonists in rats trained to discriminate apomorphine from saline

Rats (N = 12) were trained to discriminate apomorphine (0.25 mg/kg, IP) from saline in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. When the discrimination was acquired, various doses of apomorphine as well as several other dopamine receptor agonists were injected before test sessions. Apomorphine (0.03-0.25 mg/kg, IP) produced a dose-related increase in the percent of responses that occurred on the drug lever during test sessions. The selective DA2 receptor agonist piribedil (0.25-8.0 mg/kg, IP) produced a dose-related increase in drug lever responding that was similar to that seen with apomorphine. On the other hand, administration of the selective DA1 receptor agonist SKF 38393 (1.0-32 mg/kg, IP) resulted in principally saline lever responding, even at doses that substantially reduced the rate of responding. Administration of dopamine (1.0-8.0 mg/kg, IP), which does not readily cross the blood-brain barrier, also resulted in principally saline lever responding. These results suggest that the discriminative stimulus properties of apomorphine are based on its action at a receptor that is similar to the DA2 receptor that has been characterized in the periphery and that this receptor is centrally located.     

Effects of dopamine D1 receptor agonists in rats trained to discriminate dihydrexidine

Rationale The full D₁ receptor agonist dihydrexidine (DHX) [(+/−)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine hydrochloride] is under clinical development (DAR-100) for Parkinson’s disease and schizophrenia. Despite the clinical development of DHX, very little is known about its discriminative stimulus properties in rats. To more fully characterize the discriminative stimulus properties of DHX, we trained rats to discriminate DHX (3 mg/kg, i.p.) from vehicle. Methods: Substitution tests in rats discriminating DHX (3 mg/kg, i.p.) from vehicle were performed with structurally distinct D₁ receptor agonists with both partial and full intrinsic efficacy. In addition, the peripherally restricted D₁ agonist, fenoldopam, was evaluated.Results SKF 75670A, ABT-431, dinapsoline, SKF 81297, and SKF 82958 all fully substituted in a dose-dependent manner. The rank order of potency for substitution was SKF 82958<ABT-431<SKF 75670A≤dinapsoline<SKF 81297<DHX. Fenoldopam (10 and 30 mg/kg) did not substitute and was without effect on rates of responding.Conclusions DHX produces prominent dopamine D₁ receptor agonist effects in vivo and is likely to produce subjective effects in humans similar to other D₁ receptor agonists.     

Reinforcement schedule effects in rats trained to discriminate 3,4-methylenedioxymethamphetamine (MDMA) or cocaine

Rationale Relatively few studies have compared the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) and cocaine, and findings from different laboratories are somewhat inconsistent. One possible reason for discrepant results may be the use of different reinforcement schedules during discrimination training.Objective The present study compared fixed ratio (FR) 20 and variable interval (VI) 15-s reinforcement schedules to determine their influence on discrimination acquisition, response rates, frequency of reinforcements, and stimulus generalization in rats trained to discriminate cocaine or MDMA.Materials and methods Thirty-two male Sprague–Dawley rats were trained to discriminate cocaine (10 mg/kg; n=16) or MDMA (1.5 mg/kg; n=16) from saline under either a FR 20 or a VI 15-s schedule of food reinforcement. Stimulus generalization tests were conducted with a range of doses of cocaine, MDMA, d-amphetamine, and lysergic acid diethylamide in all four training groups.Results The FR 20 schedule facilitated more rapid discrimination acquisition compared to the VI 15-s schedule and established differential response rates and frequency of reinforcement under drug and vehicle conditions. However, reinforcement schedule had little influence on stimulus generalization between MDMA and cocaine. Cocaine produced partial substitution for MDMA in both training groups (FR 20, 51%; VI 15-s, 58%). Likewise, MDMA produced only partial substitution for cocaine in both training groups (FR 20, 40%; VI 15-s, 72%).Conclusions The present findings suggest that the number of sessions required to establish discriminative stimulus control varies with different reinforcement schedules. Nevertheless, training schedules alone do not appear to have significant effects on stimulus generalization between MDMA and cocaine.     

Effects of the delta opioid agonist BW373U86 in pigeons trained to discriminate fentanyl,bremazocine and water in a three-choice drug discrimination procedure

The delta opioid agonist BW373U86 was examined alone and in combination with mu agonists in pigeons trained to discriminate the mu agonist fentanyl (0.056 mg/kg), the kappa agonist bremazocine (0.017 mg/kg), and distilled water in a three-choice drug discrimination procedure. BW373U86 (0.01–10 mg/kg) produced a dose-dependent increase in fentanyl-appropriate responding and complete generalization to fentanyl in four of five subjects. BW373U86 did not elicit bremazocine-appropriate responding in any of the subjects. Fentanyl-appropriate responding elicited by BW373U86 was antagonized by the delta selective antagonist naltrindole (0.1–10 mg/kg) but not by the mu selective antagonist naloxone (0.1–30.0 mg/kg). When BW373U86 was administered in combination with the mu agonists fentanyl, morphine and nalbuphine, a low dose of BW373U86 (0.01 mg/kg) that elicited primarily water-appropriate responding when administered alone did not produce a significant change in the ED₅₀ values for fentanyl, morphine or nalbuphine. Higher doses of BW373U86 (0.1–1.0 mg/kg) increased levels of fentanyl-appropriate responding elicited by low doses of fentanyl, morphine and nalbuphine to levels similar to those produced by BW373U86 alone. These results indicate that BW373U86 shares discriminative stimulus properties with the mu agonist fentanyl in pigeons, possibly by acting at delta opioid receptors. However, BW373U86 does not potentiate the discriminative stimulus effects of mu agonists or share discriminative stimulus effects with the kappa agonist bremazocine.     

Differential generalization to pentobarbital in rats trained to discriminate lorazepam,chlordiazepoxide, diazepam,or triazolam

In drug discrimination studies benzodiazepinetrained animals have typically responded on the drug lever when tested with barbiturates. In a recent study, greater specificity appeared to be shown when lorazepam was used as a training drug. The generality and limits of this finding were explored in the present set of experiments. The asymmetrical cross-generalization found in lorazepam-and pentobarbital-trained baboons was replicated in rats and was shown not to be a function of either lorazepam (0.1., 0.32, or 1.0 mg/kg) or pentobarbital (10 or 25 mg/kg) training dose (i.e., pentobarbital-trained rats responded on the drug lever in tests with lorazepam, but lorazepam-trained rats did not show comparable pentobarbital generalization). In the next experiment, groups of rats were trained to discriminate chlordiazepoxide (10 mg/kg), triazolam (0.1 mg/kg), or diazepam (1.0 mg/kg). Generalization to both lorazepam and pentobarbital was shown by these rats. Finally after daily pentobarbital administration, lorazepam-trained rats made a sufficient number of responses after high pentobarbital doses to permit extension of the range of pentobarbital doses tested. Pentobarbital generalization increased, but still did not occur in all rats and was unreliable in successive tests in the same rats. These results suggest less homogeneity in the discriminative stimulus effects of depressant drugs than generally has been recognized.Portions of these data were presented at the meetings of the Federation of American Societies of Experimental Biology, Anaheim, 1985 (Ator and Griffiths 1985) and Behavioral Pharmacology Society, Rockville MD (1987)     

Discriminative stimulus effects of nicotine in rats trained under different schedules of reinforcement

There have been few comparisons between different schedules of reinforcement for establishing drugs as discriminative stimuli. Fixed-ratio (FR) 10 and tandem variable-interval 1-min FR-10 schedules have been compared directly in a conventional, nicotine-saline discrimination paradigm with food reinforcement in rats. The discrimination was acquired rapidly under both schedules, with stimulus control by nicotine (0.1 mg/kg SC) being very slightly superior under the FR schedule. In 5-min extinction tests with nicotine, rats maintained under the FR schedule yielded a clear dose-response curve with a bar-selection (quantal) index; in these rats, discrimination of nicotine appeared generally poor, and dose-response curves were shallow, when the percentage of drug-appropriate responding (quantitative index) was calculated. In contrast, rats under the tandem schedule yielded clear dose-response data with both indices. In tests with (+)-amphetamine full generalization was obtained with both schedules, and with both quantitative and quantal indices. Tests of generalization to morphine were negative regardless of the training schedule or index employed. In rats under the FR-10 schedule, overall response rates declined both within and across extinction tests; the relatively high rates of responding maintained by the tandem schedule were more sensitive to the response rate-decreasing effects of morphine and amphetamine. The results confirm that orderly data may be obtained with either a FR or a tandem schedule provided that an appropriate index of discriminative response is employed. The results generally support the validity of current practices, and there will probably be no marked differences between conclusions depending on which schedule is used.     

Effects of sibutramine and rimonabant in rats trained to discriminate between 22- and 2-h food deprivation

Objective  The objective of the study was to evaluate whether sibutramine and rimonabant, drugs that decrease food intake in human and non-human animals, affect the discriminative stimulus effects associated with acute food deprivation (“hunger”). Materials and methods  Rats were trained to discriminate between 22- and 2-h food deprivation in a two-lever choice procedure. After rats acquired the discrimination, subjects were food-restricted for 22 h and administered with sibutramine (0.32–10 mg/kg, p.o.) or rimonabant (0.32–10 mg/kg, s.c.) before a generalization test session. Results  Sibutramine (3.2 mg/kg) produced significant decreases in 22-h deprivation-appropriate responding, response rates (resulting in lever pressing rates similar to those following 2-h food deprivation), and food intake measured 1 h after the generalization test. A larger sibutramine dose eliminated responding and significantly reduced food intake. Rimonabant did not alter the discriminative stimulus effects of 22-h food deprivation, but rimonabant did significantly reduce both response rates and food intake. Conclusion  Sibutramine appears to decrease food intake by reducing hunger sensations associated with food deprivation. In contrast, rimonabant does not alter the discrimination of acute food deprivation. The use of food-deprivation discrimination techniques may be useful in identifying the role of specific neuroactive compounds in eating stimulated by a sense of hunger and may aid in medication development for more effective treatments for obesity and other eating-related conditions.     

Cocaine-opioid interactions in groups of rats trained to discriminate different doses of cocaine

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 μ opioid agonist morphine or the κ 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 μ and κ opioid receptors in modifying the discriminative stimulus effects of cocaine. Received: 9 December 1998 / Final version: 24 June 1999     

Route of administration influences substitution patterns in rats trained to discriminate methadone vs. vehicle

Replacement therapy with the synthetic μ-opioid agonist methadone is an efficacious treatment for opioid abuse. While much is known about methadone's pharmacology, its discriminative stimulus properties remain largely unexplored. The present study sought to establish methadone discrimination in rats. Moreover, some research suggests that route of administration alters the discriminative stimulus of methadone. Thus, the present study also compared intraperitoneal (i.p.) and subcutaneous (s.c.) routes of administration. Male Sprague–Dawley rats were trained to discriminate 3.0 mg/kg methadone (i.p.) from vehicle in a two-lever discrimination procedure. Generalization tests were conducted with a variety of compounds administered i.p. and s.c. Methadone fully substituted for itself, yielding ED₅₀s of 1.5 mg/kg (i.p.) and 0.2 mg/kg (s.c.). Naltrexone (i.p.), an opioid antagonist produced a dose-dependent reduction in methadone-appropriate responding. The methadone stereoisomers fully substituted for methadone when given s.c.; however, when administered i.p., (+) and (−) methadone produced partial and no substitution, respectively. Heroin fully generalized to methadone regardless of administration route, while morphine fully substituted when given s.c., but not i.p. The kappa-agonist U50-488 failed to generalize to methadone with either route of administration. These results demonstrated that methadone's discriminative stimulus is mediated through μ-opioid receptor activity and is similar to that of commonly abused opioids (heroin, morphine). Additionally, route of administration produced differential results for many of the drugs tested, suggesting decreased drug bioavailability following i.p. administration due to hepatic first pass metabolism. Taken together, these results suggest that methadone's shared subjective effects with abused opioids, as well as its unique metabolic properties contribute to its efficacy in opioid maintenance therapy.     

Effects of altering motivation for food in rats trained with food reinforcement to discriminate between d-amphetamine and saline injections

Previous studies have shown that altering motivation typically affects stimulus generalization in animals trained to discriminate exteroceptive stimuli, but few studies have evaluated the effects of manipulating motivation on drug stimuli. In the few published studies, motivation levels were manipulated by arranging different feeding conditions prior to stimulus generalization tests with rats trained to discriminate morphine from vehicle and in pigeons trained to discriminate phencyclidine or pentobarbital from vehicle. In the present study, rats maintained at 80% of free-feeding weights were trained to discriminate between injections of 1.0 mg/kg d-amphetamine and saline in a two-lever food-reinforced operant procedure. Generalization tests were then conducted with a range of d-amphetamine doses (0, 0.03, 0.1, and 0.3, 1.0 mg/kg) when the rats were not fed before experimental sessions (high motivation) and when they were pre-fed 1 g of food (moderate motivation) or their daily ration of food (low motivation) 1 h before test sessions. Changing the motivation level significantly affected response rate and latency to the first response in generalizations tests, but did not significantly affect mean percentage of drug-appropriate responding (a continuous measure) or percentage of animals that selected the drug-appropriate lever (a quantal measure). The present findings indicate that manipulating motivation for food minimally impacts d-amphetamine discrimination, however, the range of conditions used to examine the effects of motivating operations on stimulus control by d-amphetamine drugs and other drugs is limited and the topic may warrant further investigation.     

Effects of antidepressants in rats trained to discriminate the beta-2 adrenergic agonist clenbuterol.

The ability of indirectly acting agonists such as norepinephrine uptake inhibitors, serotonin reuptake inhibitors, and atypical antidepressants to substitute for clenbuterol, a beta-2 adrenergic agonist, was examined in rats trained to discriminate 0.03 mg/kg clenbuterol and saline using a fixed-ratio 10 (FR 10) schedule with water reinforcement. The beta-2 selective adrenergic agonist clenbuterol produced an orderly dose-response relationship, and its discriminative stimulus effects were antagonized by the beta-adrenergic antagonist propranolol. It was found that the effects of tricyclic antidepressants and selective norepinephrine uptake inhibitors did not generalize to the discriminative stimulus effects of clenbuterol, with the exception of high doses of protriptyline. Moreover, compounds from other drug classes, including fluoxetine and phenelzine, did not substitute for clenbuterol. Atypical antidepressants, such as trazodone, rolipram, and bupropion also did not engender drug-appropriate responding. Prenalterol and dobutamine, both purported to be beta-1 adrenergic receptor agonists, partially substituted for clenbuterol, but at relatively high doses. The present results show that the antidepressants tested do not share discriminative stimulus effects with clenbuterol, a beta-2 adrenergic agonist.     

Effects of NMDA receptor antagonists in squirrel monkeys trained to discriminate the competitive NMDA receptor antagonist NPC 12626 from saline

Because excitatory amino acids have been implicated in several physiological phenomena, antagonists of excitatory amino acid function may have significant therapeutic potential as anticonvulsant, neuroprotectants and anxiolytics. Drug discrimination procedures in animals have proven useful to compare and contrast the behavioral effects of site-selective NMDA antagonists. In the only previous study using a competitive NMDA antagonist as a training drug, rat wwere trained to discriminate NPC 12626 (2-amino-4,5(1,2-cyclohexyl)-7-phosphonoheptanoic acid) from nondrug. The major goal of the present study was to establish and characterize a nonhuman primate model of NPC 12626 discrimination. Adult male squirrel monkeys were trained to discriminate NPC 12626 from saline under a two-lever fixed ratio-30 schedule of food reinforcement. The monkeys required between 80 and 120 training sessions to acquire this discrimination after the training dose had been raised from 3 to 20 mg/kg i.m. The competitive NMDA antagonists CGP 37849 (D,L-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid) and CPPene (D-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid) substituted completely for NPC 12626, while the potent noncompetitive NMDA antagonist, dizocilpine (MK-801), did not. These results reflect a profile of discriminative stimulus effects which support that observed in rats and establish a primate model for use in further study of the behavioral effects of the competitive NMDA antagonists.     

Effects of morphine in rats treated chronically with U-50,488 H, a kappa opioid receptor agonist

The pharmacological effects of morphine, namely analgesic, hyperthermic and cataleptic effects, were assessed in rats rendered tolerant to U-50,488H, a kappa opioid receptor agonist. Male Sprague-Dawley rats were injected intraperitoneally with U-50,488H (25 mg/kg) twice a day for four days. The rats which served as controls were injected similarly with the vehicle. Chronic administration of U-50,488H resulted in the development of tolerance to its analgesic and hypothermic effects, but not to its diuretic effect. The development of tolerance to the pharmacological effects of U-50,488H was associated with decreased binding of [3H]ethylketocyclazocine [( 3H]EKC) to brain and spinal cord membranes. The decreased binding of [3H]EKC in U-50,488H-treated rats was due to changes in the Bmax value; the Kd values remained unaltered. Intraperitoneal administration of morphine (8 mg/kg) to rats produced analgesia (as determined by the tail-flick test) and hyperthermia. A dose of 50 mg/kg of morphine produced cataleptic response. The intensity of analgesic, hyperthermic and cataleptic effects of morphine were unaltered in rats tolerant to U-50,488H. The development of tolerance to analgesic and hypothermic effects of U-50,488H were associated with down-regulation of brain and spinal cord kappa opioid receptors. Finally, U-50,488H does not confer cross-tolerance to morphine, a predominantly mu opioid receptor agonist.     

Beta-lactam antibiotic prevents tolerance to the hypothermic effect of a kappa opioid receptor agonist

Beta-lactam antibiotics are the only clinically approved drugs which directly increase glutamate uptake. They activate the glutamate transporter subtype 1 (GLT-1), the protein responsible for 90% of glutamate uptake in the mammalian brain. The capacity of GLT-1 to clear extracellular glutamate suggests that glutamate transporter activators be explored for therapeutic approaches to clinical conditions caused by increased glutamatergic transmission. One of the most common drug effects mediated by increased glutamatergic signaling is opioid tolerance. Therefore, we tested the hypothesis that a beta-lactam antibiotic (ceftriaxone), by increasing glutamate uptake, prevents tolerance to hypothermia induced by a kappa opioid receptor agonist (U-50,488H). A single injection of U-50,488H (20mg/kg, s.c.) caused significant hypothermia in rats. Tolerance to the hypothermic effect of U50,488H was induced by injecting U50,488H (20mg/kg) twice daily for 7days. Pretreatment with ceftriaxone (200mg/kg, i.p.) for 7days did not alter the acute hypothermic response to U50,488H (20mg/kg) but did prevent tolerance to U50,488H-induced hypothermia. Central administration of dl-threo-beta-benzyloxyaspartic acid (TBOA) (0.2mumol, i.c.v.), a glutamate transporter inhibitor, abolished the effect of ceftriaxone. These results identify a functional interaction between ceftriaxone and U50,488H in vivo and provide pharmacological evidence that a beta-lactam antibiotic abolishes tolerance to hypothermia induced by a kappa opioid receptor agonist.     

Generalization and antagonism studies with convulsant,GABAergic and anticonvulsant drugs in rats trained to discriminate pentylenetetrazol from saline

Male hooded rats were trained on an FR 10 schedule of food reinforcement to discriminate the interoceptive stimulus produced by a subconvulsive dose of pentylenetetrazol from that produced by saline, by responding on a lever on one side of a food cup following a 20 mg/kg pentylenetetrazol injection and responding on a lever on the alternate side following a 1 ml/kg saline injection. All of the subjects learned this discrimination reliably. Picrotoxin and strychnine, but not bicuculline nor gamma-hydroxybutyrate, partially generalized to the pentylenetetrazol discriminative stimulus. Valproic acid, sodium pentobarbital and sodium phenobarbital antagonized the pentylenetetrazol discriminative stimulus but etomidate, gamma-hydroxybutyrate, gamma-acetylenic GABA, gamma-vinyl GABA, trimethadione, ethosuximide and diphenylhydantoin did not. These data suggest that the pentylenetetrazol discriminative stimulus is based upon neither a subconvulsant brain state produced by this drug nor a deficiency of GABA neuronal function. Drugs which antagonize the pentylenetetrazol stimulus are all anxiolytic drugs that show no other pharmacological property common to all of them.     

Discriminative stimulus effects of the 5HT1A agonist 8-OH-DPAT: attenuation by mu but not by kappa opioids

The ability of mu and kappa opioids to alter the discriminative-stimulus and rate-decreasing effects of the 5-HT_1A receptor agonist 8-OH-DPAT was examined in rats trained to discriminate either a low (0.1 mg/kg) or a high (0.3 mg/kg) dose of 8-OH-DPAT from water using a two-lever food-reinforced drug discrimination procedure. The mu opioids, morphine and fentanyl, and the kappa opioids, U50,488 and bremazocine, failed to substitute for the 8-OH-DPAT stimulus, even when tested up to doses that substantially reduced rates of responding. During antagonism tests, selected doses of the mu opioids, morphine and fentanyl, administered at various pretreatment times, attenuated the stimulus effects of both training doses of 8-OH-DPAT. Moreover, morphine (135-min pretreat) and fentanyl (15-min pretreat) produced rightward shifts in the 8-OH-DPAT dose-effect curve that were partially surmountable and naltrexone-reversible. In contrast to the effects of the mu opioids, the kappa opioids, U50,488 and bremazocine, failed to alter the stimulus effects of the training dose of 8-OH-DPAT, regardless of dose or pretreatment time. The ratedecreasing effects of 8-OH-DPAT were not altered substantially by either the mu or kappa opioids examined. The present study demonstrates that the stimulus effects, but not the rate-decreasing effects, of 5-HT_1A receptor agonists can be modulated by mu opioids, whereas neither of these effects are changed by kappa opioids.