β-funaltrexamine antagonizes the discriminative stimulus effects of morphine but not naltrexone in pigeons

Antagonistic actions of the irreversible, -selective antagonist -funaltrexamine (-FNA) were evaluated in pigeons trained to discriminate among intramuscular injections of morphine (5.6 mg/kg), saline, and naltrexone (10.0 mg/kg). -FNA administered alone (1.0 or 10.0 mg/kg) failed to mimic the discriminative stimulus effects of morphine or naltrexone. -FNA attenuated the discriminative stimulus effects of morphine. A three-fold larger dose of morphine was required for complete generalization when pigeons were pretreated with a dose of 1.0 mg/kg -FNA. A dose of 10.0 mg/kg -FNA completely antagonized the morphine discriminative stimulus, so that pigeons responded predominantly on the saline key up to doses of morphine that suppressed responding. Doses of -FNA that attenuated the effects of morphine had no effect on the discriminative stimulus effects of naltrexone. These results demonstrate that, like naltrexone, -FNA attenuates the discriminative stimulus effects of morphine in pigeons and, at sufficiently large doses, antagonizes morphine in an unsurmountable manner. -FNA does not, however, share discriminative stimulus properties with naltrexone in these pigeons, and fails to attenuate the discriminative stimulus effects of naltrexone, lending support to the suggestion that naltrexone exerts discriminative stimulus effects under these experimental conditions predominantly by a non-mu opioid mechanism.     

S(−)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats

Rationale  Racemic propranolol (PRO), a β-adrenoceptor antagonist, has been evaluated as a test agent but not as a discriminative stimulus. Its S(−) stereoisomer is thought to subserve the effects of (±)PRO. Materials and methods  Rats were trained to discriminate S(−)PRO (5 mg/kg) from saline in a two-lever food-reinforced operant conditioning task. Results  The S(−)PRO stimulus was shown to be centrally mediated, dose-related, time dependent, and stereoselective: S(−)PRO (ED₅₀ = 2.2 mg/kg) was twice as potent as (±)PRO and approximately four times as potent as R(+)PRO. The S(−)PRO stimulus generalized fully to the β-adrenoceptor agent pindolol, the α₁-adrenoceptor agonist methoxamine, cocaine, and the serotonergic agents TFMPP and RU 24969; partial generalization occurred to (−)ephedrine and nisoxetine but not to fenfluramine or 5-OMe DMT. The S(−)PRO stimulus was blocked completely (and competitively) when prazosin, an α₁-adrenoceptor antagonist, was given in combination with the training dose of S(−)PRO. Moreover, prazosin exerted antagonism of the S(−)PRO-like effect of (±)PRO or R(+)PRO but produced only partial antagonism of the S(−)PRO-like effect of cocaine. In a second study, rats were trained to discriminate 8 mg/kg of cocaine from saline. The cocaine stimulus generalized to S(−)PRO, (±)PRO, and R(+)PRO. Prazosin partially attenuated the stimulus effect of cocaine (8 mg/kg) but completely blocked the cocaine-like effects of (±), S(−), and R(+)PRO. Conclusions  PRO and cocaine exhibited cross-substitution, but their stimulus effects were antagonized differentially by prazosin. PRO (and its optical isomers) can exert a stimulus effect that is based, at least in part, on increased α₁-adrenoceptor activity. PRO might be better characterized as an adrenoceptor partial agonist. This study was supported, in part, by the National Institute on Drug Abuse (NIDA) grant DA-01642.     

Central and peripheral involvement of μ receptors in gastric secretory effects of opioids in the dog

The effects of dermorphin and morphine on gastric acid secretion were studied in conscious dogs with both gastric fistulas (GF) and Heidenhain pouches (HP). Under basal conditions demorphin and morphine, infused systematically at graded doses, produces a significant increase in acid secretion from both GF and HP. This increase was significantly inhibited by naloxone, naltrexone methylbromide and N-methyl-levallorphan methanesulphonate. Dermorphin did not modify the acid output stimulated by 2-deoxy-D-glucose from GF, while morphine significantly inhibited it; on the contrary acid secretion from HP was increased in this test by both dermorphin and morphine. Acid secretion from GF stimulated by pentagastrin was unaffected by morphine and significantly enhanced by dermorphine. Under this conditions a significant increase in acid secretion from HP was recorded with dermorphin and morphine. Naloxone and N-methyl-levallorphan methanesulphonate, given during pentagastrin-stimulated secretion, significantly inhibited acid output ‘per se’ from GF and HP and prevented the stimulatory effect of dermorphin and morphine. Bethanechol-induced secretion from GF and HP was significantly increased by both dermorphin and morphine. The present results demonstrate that opioids have simultaneous yet opposite effects on acid secretion in the dog and that μ receptors are involved in both the excitatory and inhibitory effects. Excitatory effects do not seem to be mediated via a vagal pathway (peripheral ?), in contrast to the inhibitory effects (central ?). The inhibitory effects of opiate antagonists on pentagastrin-stimulated secretion suggest a physiological role of peripheral opioid receptors in gastric acid secretion.     

Antagonism of discriminative stimulus effects of Δ9-THC and (R)-methanandamide in rats

Rationale In previous drug discrimination studies we observed surmountable antagonism by Δ⁹-tetrahydrocannabinol (THC) in the presence of constant doses of SR-141716 [N-(piperidin-1-yl)-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] (0.3 and 1 mg/kg), but there was only marginal evidence for surmountable antagonism with combinations of SR-141716 and (R)-methanandamide, a chiral analog of the endocannabioid anandamide. Objective Here we examine antagonism where the cannabinoid CB1 receptor agonist [Δ⁹-THC and (R)-methanandamide] dose is held constant (i.e., the training dose) and the antagonist {i.e., SR-141716 and AM-251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; 2 ml/kg]} dose varied. We also tested the cannabinoid CB2 receptor antagonist SR-144528 {N-[(1S)-endo-1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide}. Methods Different groups of rats were trained to discriminate between vehicle and three different doses of Δ⁹-THC (1.8, 3, and 5.6 mg/kg, presumably reflecting different efficacy demands) as well as 10 mg/kg (R)-methanandamide. Dose-generalization tests involved different doses of the cannabinoid CB1 receptor agonists. Antagonist tests varied the dose of the antagonist (range: 0.1 and 3 mg/kg for SR-141716 and AM-251, and 1 to 10 mg/kg for SR-144528). Results SR-141716 and AM-251 doses dependently blocked the agonist-induced discriminative stimulus effects. SR-141716 tended to be slightly more potent than AM-251. The effective dose 50 (ED₅₀) of SR-141716 was higher in the 5.6 mg/kg Δ⁹-THC-trained group relative to the two other Δ⁹-THC-trained groups. The cannabinoid CB2 receptor antagonist SR-144528 combined with the training dose of 1.8 mg/kg Δ⁹-THC, as well as when combined with the training dose of 10 mg/kg (R)-methanandamide, did not markedly change drug-appropriate (agonist) responses. Conclusion Data support that the discriminative stimulus effects of (R)-methanandamide and its overlap with the Δ⁹-THC cue are, indeed, CB1 receptor mediated events as revealed in antagonism tests with the selective central CB1 receptor antagonists SR-141716 and AM-251. The activation of cannabinoid CB2 receptors appears to be insignificant for these discriminations.     

Transfer of the discriminative stimulus effects of Δ9-THC and nicotine from one operant response to another in rats

Objective  

Transfer of the discriminative stimulus effects of two drugs from one operant (original-response) to a topographically different response (transfer-response) that was spared drug discrimination training was investigated.     

Ethanol-like discriminative stimulus effects of the neurosteroid 3α-hydroxy-5α-pregnan-20-one in femaleMacaca fascicularis monkeys

The present study was designed to characterize the discriminative stimulus effects of ethanol and the neurosteroid 3-hydroxy-5-pregnan-20-one (allopregnanolone) in non-human primates. Female cynomolgus monkeys (Macaca fascicularis) were trained in a two-le-ver procedure to discriminate 1.0 g/kg ethanol (IG, 30 min pretreatment) from water using food reinforcement. Consistent with previous results in a variety of species, pentobarbital (0.56–17 mg/kg, IG) resulted in a dose-dependent substitution for the discriminative stimulus effects of ethanol, with an average ED₅₀ value of 1.9 mg/kg. Administration of allopregnanolone (0.3–5.6 mg/kg, IV) also produced complete substitution for the discriminative stimulus effects of ethanol, with an ED₅₀ value of 1.0 mg/kg. Plasma allopregnanolone levels 35 min following the administration of 3.0 mg/kg allopregnanolone ranged from 33 to 69 ng/ml. The ethanollike discriminative stimulus effects of 1.0 mg/kg allopregnanolone (IV) were present for 60 min, with a return to complete water-appropriate responding at 90 min post-treatment. The results indicate that the endogenous neuroactive steroid allopregnanolone produces subjective effects in cynomolgus monkeys that are similar to ethanol. These findings suggest that changes in the endogenous levels of allopregnanolone could alter sensitivity to the subjective effects of ethanol.     

Sex differences in the potency of κ opioids and mixed-action opioids administered systemically and at the site of inflammation against capsaicin-induced hyperalgesia in rats

Rationale Sex differences in the potency of the antinociceptive effects of κ opioids have been reported in various acute pain models with evidence suggesting that these sex differences are mediated by activity in the N-methyl-d-aspartate (NMDA) system. Objectives The purpose of the present study was to evaluate sex differences in the antihyperalgesic actions of selected κ and mixed-action opioids in a persistent pain model and determine if the NMDA system modulates these effects in a sexually dimorphic manner. Methods Using gonadally intact male and female F344 rats, hyperalgesia was induced by local administration of capsaicin in the tail, after which the tail was immersed in a mildly noxious thermal stimulus (45°C water), and tail-withdrawal latency measured. Opioids were then administered systemically (s.c.) and locally (in the tail) alone, and in selected combinations with the noncompetitive NMDA antagonist dextromethorphan. Results When administered systemically and locally, the κ opioids spiradoline, U69,593 and U50,488, and the mixed-action opioids butorphanol and nalbuphine, produced dose-dependent antihyperalgesic effects. Whereas the κ opioids were generally more potent in males, sex differences were not observed with the mixed-action opioids. Peripheral receptor activity was confirmed for local administration of κ opioids by the antagonism observed after local, but not intracerebroventricular (i.c.v.), administration of the κ antagonist nor-binaltorphamine (nor-BNI). Dextromethorphan was equally potent in attenuating the antihyperalgesia induced by κ opioids in both males and females. Conclusions These findings demonstrate sex differences in κ opioid activity in a persistent pain model. Although an NMDA antagonist blocked the effects of κ opioids in this model, these effects were not sexually dimorphic as reported in most acute pain models.     

Role of GABAA/benzodiazepine receptors containing α1 and α5 subunits in the discriminative stimulus effects of triazolam in squirrel monkeys

RATIONALE: Conventional benzodiazepines (BZs), clinically used for treatment of anxiety and insomnia, bind to GABA(A) receptors containing alpha(1), alpha(2), alpha(3), or alpha(5) subunits. The role of these different GABA(A) receptor subtypes in mediating the subjective effects of BZs remains largely unknown. OBJECTIVE: The purpose of the present study was to evaluate the role of GABA(A) receptors containing the alpha(1) or alpha(5) subunits in the discriminative stimulus (DS) effects of the conventional BZ agonist triazolam. METHODS: Squirrel monkeys were trained to discriminate triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 schedule of food reinforcement. RESULTS: The GABA(A)/alpha(1)-preferring agonists zolpidem and zaleplon engendered responses predominantly on the triazolam lever (73-80% drug-lever responding), and the GABA(A)/alpha(1) partial agonist CL 218,872 engendered an average maximum of less than 50% triazolam-lever responding. The GABA(A)/alpha(1)-preferring antagonists beta-carboline-3-carboxylate-t-butyl ester (betaCCT) and 3-(propyloxy)-beta-carboline (3-PBC) blocked the DS effects of triazolam and zolpidem in a surmountable manner. Schild analyses for betaCCT and 3-PBC in combination with triazolam and zolpidem suggest that the interactions between these compounds were competitive in nature and mediated by a common population of receptors, presumably GABA(A)/alpha(1) receptors. In contrast, the GABA(A)/alpha(5)-preferring agonist QH-ii-66 did not engender triazolam-lever responding regardless of dose and did not alter the DS effects of triazolam when administered in combination. CONCLUSIONS: The results are consistent with GABA(A)/alpha(1) receptor involvement in mediating the DS effects of triazolam. In contrast, binding to GABA(A)/alpha(5) receptors may not play a critical role in mediating triazolam's DS effects.     

Opioid modulation of the discriminative stimulus effects of cocaine: comparison of µ, kappa and delta agonists in squirrel monkeys discriminating low doses of cocaine

Modulation of the discriminative stimulus effects of cocaine by the μ agonist morphine, the kappa agonist U 50, 488, and the delta agonist BW 373U86 was investigated in squirrel monkeys using a two-lever drug discrimination procedure. Monkeys initially were trained to discriminate intramuscular injections of 0.3 or 0.56mg/kg cocaine from vehicle and subsequently retrained to discriminate a 3- to 5.6-fold lower dose of cocaine (0.1 or 0.18mg/kg). After retraining, dose-response functions for the discriminative stimulus effects of cocaine were shifted to the left and ED(50) values were reduced 2- to 6-fold compared to values obtained with the higher training doses. In drug substitution experiments, morphine (0.03-1.0mg/kg), U 50,488 (0.1-3.0mg/kg) and BW 373U86 (0.001-0.1mg/kg) did not reproduce the discriminative stimulus effects of the low training doses of cocaine, although U 50,488 engendered a majority of responses on the cocaine-associated lever in two of three monkeys. In drug interaction experiments, pretreatment with morphine (0.3mg/kg) potentiated the discriminative stimulus effects of the low training doses of cocaine such that the cocaine dose-response functions were shifted to the left and ED(50) values were reduced 3- to 7-fold. Pretreatment with U 50,488 (0.3mg/kg), on the other hand, attenuated the discriminative stimulus effects of the low training doses of cocaine such that the cocaine dose-response functions were shifted to the right and ED(50) values were increased approximately 4-fold. The cocaine-modulating effects of morphine and U 50,488 in these experiments were qualitatively similar to those observed previously when the monkeys were trained to discriminate higher doses of cocaine. In contrast to the effects of the μ and kappa agonists, pretreatment with BW 373U86 (0.01 or 0.03mg/kg) did not systematically alter the discriminative stimulus effects of cocaine regardless of training dose.     

Sex-related differences in the antinociceptive effects of opioids: importance of rat genotype, nociceptive stimulus intensity, and efficacy at the µ opioid receptor

RATIONALE: Recent studies indicate that morphine is more potent as an antinociceptive agent in male than female rodents and monkeys. OBJECTIVES: To evaluate the influence of sex, nociceptive stimulus intensity and an opioid's relative efficacy on opioid-induced antinociception in rat strains (F344 and Lewis) that display differential sensitivity to morphine antinociception. METHODS: Antinociceptive testing was conducted using a rat warm-water (50-56 degrees C) tail-withdrawal procedure. Dose-response and time-course determinations were performed with various opioids. RESULTS: Across the nociceptive stimulus intensities tested, the high-efficacy mu opioids morphine, etorphine, and levorphanol were equally effective in males and females, but on average 2.5-fold more potent in males. At moderate stimulus intensities, the low-efficacy mu opioid buprenorphine was approximately 0.4-fold more potent in males, and at higher stimulus intensities more potent and effective (greater maximal effect) in males. At low stimulus intensities, the low-efficacy mu opioid dezocine and the mu/kappa opioid butorphanol were greater than 8.9-fold more potent in males, and at moderate stimulus intensities were more potent and effective in males. At a low stimulus intensity, the mu/kappa opioid nalbuphine was more potent and effective in males. At stimulus intensities in which buprenorphine, dezocine, butorphanol, and nalbuphine produced maximal effects in males but not females, these opioids antagonized the effects of morphine in females. Genotype-related differences were noted as opioids were generally more potent in F344 than Lewis males, whereas no consistent differences were observed between F344 and Lewis females. CONCLUSIONS: That sex differences in the potency and effectiveness of opioids increased with decreases in the opioid's relative efficacy and with increases in the nociceptive stimulus intensity suggests that the relative efficacy of mu opioids as antinociceptive agents is greater in male than female rats.     

Δ9-THC as a discriminative stimulus in rats and pigeons: Generalization to THC metabolites and SP-111

In a drug discrimination paradigm pigeons and rats were trained with an operant procedure to discriminate between the presence and absence of the effects of ⁹-THC (1.0 and 3.0 mg/kg, injected IM 90 min and I.P. 30 min before the start of the session). Once trained, various THC metabolites as well as a water-soluble derivative of THC (SP-111), were substituted for ⁹-THC to test for generalization to the training drug. Generalization to ⁹-THC occurred with the 11-hydroxy metabolites and the potency order was 11-OH-⁹-THC >11-OH-⁸-THC ⁹-THC. Among the other metabolites tested (8-OH-⁹-THC, 8, 11-di-OH-⁹-THC, 8-OH-⁹-THC, 8, 11-di-OH-⁹-THC), it was only 11-di-OH-⁹-THC that completely substituted for ⁹-THC in pigeons, albeit at very high dose levels (rats were not tested with these metabolites). SP-111 generalized to ⁹-THC in both species. However, the onset of action of SP-111 was slower than that for ⁹-THC, especially in pigeons. These studies show the importance of obtaining complete dose-effect determinations over time when assessing structure-activity relationships with drug-discrimination procedures.A brief account of the results, which are summarized in Neuropharmacology 18:1023–1024, 1979), was presented at the British Association for Psychopharmacology Summer Conference, July 15–17, Birmingham, England, 1979     

Effects of a newly synthesized κ-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats

RATIONALE: We previously demonstrated that the prototypical kappa-opioid receptor agonist U-50,488H did not affect the discriminative stimulus effects of cocaine, and the dose of U-50,488H which significantly induced aversive effects attenuated the rewarding effects of cocaine. OBJECTIVES: In the present study, the effects of a newly synthesized kappa-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine were examined in rats. METHODS: In the drug discrimination procedure, the effects of TRK-820 on the discriminative stimulus effects of cocaine were examined in rats that had been trained to discriminate between 10 mg/kg cocaine and saline. TRK-820-induced place preference or place aversion and the effects of TRK-820 on the cocaine (4 mg/kg)-induced place preference were examined using a conditioned place preference procedure in rats. RESULTS: TRK-820 did not engender cocaine-like responding in rats trained to discriminate between 10 mg/kg cocaine and saline. In combination tests, low doses of TRK-820, which did not affect the response rate, significantly attenuated the discriminative stimulus effects of cocaine, and these effects of TRK-820 were reversed by a kappa-opioid receptor antagonist, nor-BNI. In the conditioned place preference procedure, low doses of TRK-820, which did not affect the response rate in the drug discrimination, did not produce either place preference or place aversion, whereas, higher dose (80 microg/kg) of TRK-820 slightly but significantly induced a place aversion. Under these conditions, the cocaine-induced place preference was completely attenuated by low doses of TRK-820. These results may prompt further investigation of the effectiveness of the new kappa-opioid receptor agonist TRK-820 as a novel pharmacotherapeutic compound for the treatment of cocaine addiction.     

μ-, δ- and κ-opioid receptor agonists do not alter the discriminative stimulus effects of cocaine or d-amphetamine in rats

Opioid receptor agonists can modulate the activity of dopamine neurons and could therefore, modify the behavioral effects of drugs that act through the dopamine systems, such as d-amphetamine and cocaine. We tested the ability of agonists selective for the μ- (morphine, methadone, buprenorphine, nalbuphine and heroin), δ- (DPDPE and SCH32615), and κ- (U69593 and bremazocine) opioid receptors to alter the discriminative stimulus effects of d-amphetamine and cocaine in rats. Separate groups of male Sprague-Dawley rats were trained to discriminate between 1.0 mg/kg d-amphetamine or 10 mg/kg cocaine from saline. Rats were pretreated with vehicle or an agonist, then dose-response curves for d-amphetamine or cocaine were generated. None of the opioid agonists changed significantly the ED₅₀ values of cocaine and d-amphetamine. As a positive control, we tested for antagonism of these effects by the D1 and D2 dopamine receptor antagonists, SCH23390 and eticlopride, respectively. Both antagonists at least partially attenuated the stimulus effects of both training drugs. Our results suggest that any modulation of dopaminergic neurotransmission by the agonists tested in the present study is not sufficient to affect the stimulus effects of d-amphetamine and cocaine in rats.     

Lack of involvement ofδ-opioid receptors in mediating the rewarding effects of cocaine

The non-selective opioid antagonist naltrexone and the partial agonist buprenorphine have been reported to reduce cocaine self-administration (SA) and relapse in both humans and rhesus monkeys. Data suggesting an involvement of-opioid receptors in modulating the conditioned rewarding effects of cocaine were also recently presented. In view of such findings, the present SA and place conditioning studies were conducted to examine the influence of the selective-opioid receptor antagonist naltrindole upon the rewarding effects of cocaine. Sprague-Dawley rats were trained to self-administer cocaine (1.0 mg/kg per infusion) on an FR2 schedule of reinforcement. Dose-response and antagonist testing commenced once stable rates of cocaine SA were achieved. For antagonist testing, rats received naltrindole (0.03–10.0 mg/kg, IP) 30 min prior to the start of 2-h SA sessions. SA behavior in response to cocaine delivery (0.25 and 1.0 mg/kg per infusion) was then determined. Naltrindole in doses of 0.03–3.0 mg/kg did not alter the number of cocaine infusions taken by the rats. A higher dose of naltrindole (10.0 mg/kg), which markedly depressed locomotor activity, resulted in a 16% reduction of cocaine (0.25 mg/kg per infusion) SA behavior. When SA sessions were terminated and naltrindole (1.0 mg/kg) was administered repeatedly for 3 days, no alterations in the re-acquisition of cocaine SA were seen. Place conditioning studies also failed to find an effect of naltrindole (0.1–3.0 mg/kg) on cocaine (10 mg/kg) — induced conditioned place preferences. Naltrindole, by itself, did not induce significant place conditioning. These data fail to indicate a role of-opioid receptors in modulating either the positive reinforcing or conditioned rewarding effects of cocaine. Furthermore, they suggest that the therapeutic actions of naloxone, naltrexone and buprenorphine on cocaine SA behavior may not result from the specific blockade of-opioid receptors.     

Discriminative effects of combinations of Δ9-Tetrahydrocannabinol and pentobarbital in pigeons

The purpose of the present study is to examine potentially additive effects of pentobarbital and ⁹-Tetrahydrocannabinol ⁹-THC using a drug discrimination paradigm. Three groups of pigeons were trained to discriminate between the effects induced by i.m. administrations of either (a) 0.25 mg/kg ⁹-THC and vehicle, (b) 4 mg/kg pentobarbital and saline, and (c) ⁹-THC and pentobarbital. Test probes under extinction conditions produced orderly dose generalization gradients among the drug-vs nondrug-trained animals. ED₅₀ for pentobarbital was 1.60 mg/kg and ED₅₀ for ⁹-THC was 0.10 mg/kg. Tests in birds discriminating between pentobarbital and ⁹-THC suggested a sharpening of the drug cue effects; tests with the vehicles resulted in approximately a random key selection (33%–66%) while tests with combinations of the two training drugs suggested that ⁹-THC was the more salient cue in this group. Tests with combinations of various doses of pentobarbital and ⁹-THC in the drug-vs nondrug-trained birds did not increase responding on the respective drug-training associated key. Thus the cue effects of pentobarbital and ⁹-THC were not summational under these experimental conditions. In conclusion, rather low doses of pentobarbital and ⁹-THC are effective as discriminative cues in pigeons and the cues thus induced are different. Combinations of the two drugs are not necessarily summational, and the pentobarbital vs the ⁹-THC discriminations augmented the discriminable effects of the two drugs. In addition, the analeptic drug, bemegride, antagonizes the pentobarbital (4 mg/kg) stimulus in the group trained to discriminate between this barbiturate and saline, which agrees with earlier drug antagonism data obtained among mammals (gerbils and rats), required to discriminate between barbiturates and the nondrug condition.     

Discriminative stimulus effects of the α2-adrenoceptor antagonist idazoxan

Rats were trained to discriminate a dose of the ₂-adrenoceptor antagonist idazoxan (10 mg/kg IP) from saline. The discriminative stimulus produced by idazoxan was dose related and generalised to yohimbine. However, generalisation did not occur with a variety of compounds from other pharmacological categories including the ₁-adrenoceptor agonist cirazoline, the ₂-adrenoceptor antagonist prazosin, and the ₂-adrenoceptor agonist clonidine. The idazoxan stimulus was not antagonised by either prazosin or clonidine, although it was clear that idazoxan antagonised the reductions in response rate produced by clonidine. Dose-related responding on the idazoxan-associated lever was produced by the anxiolytics buspirone and ipsapirone and by their metabolite MJ 13653 (1-PP), which has previously been shown to be an ₂-adrenoceptor antagonist. In general, however, high levels of generalisation occurred with these three compounds only at doses which substantially reduced response rates. These results demonstrate that idazoxan can give rise to a discriminative stimulus which is probably mediated through antagonism at ₂-adrenoceptors although the failure of clonidine to block the idazoxan stimulus is difficult to explain.     

Ovarian hormones and chronic administration during adolescence modify the discriminative stimulus effects of delta-9-tetrahydrocannabinol (Δ⁹-THC) in adult female rats

Marijuana abuse during adolescence may alter its abuse liability during adulthood by modifying the interoceptive (discriminative) stimuli produced, especially in females due to an interaction with ovarian hormones. To examine this possibility, either gonadally intact or ovariectomized (OVX) female rats received 40 intraperitoneal injections of saline or 5.6 mg/kg of Δ⁹-THC daily during adolescence, yielding 4 experimental groups (intact/saline, intact/Δ⁹-THC, OVX/saline, and OVX/Δ⁹-THC). These groups were then trained to discriminate Δ⁹-THC (0.32-3.2 mg/kg) from saline under a fixed-ratio (FR) 20 schedule of food presentation. After a training dose was established for the subjects in each group, varying doses of Δ⁹-THC were substituted for the training dose to obtain dose-effect (generalization) curves for drug-lever responding and response rate. The results showed that: 1) the OVX/saline group had a substantially higher mean response rate under control conditions than the other three groups, 2) both OVX groups had higher percentages of THC-lever responding than the intact groups at doses of Δ⁹-THC lower than the training dose, and 3) the OVX/Δ⁹-THC group was significantly less sensitive to the rate-decreasing effects of Δ⁹-THC compared to other groups. Furthermore, at sacrifice, western blot analyses indicated that chronic Δ⁹-THC in OVX and intact females decreased cannabinoid type-1 receptor (CB1R) levels in the striatum, and decreased phosphorylation of cyclic adenosine monophosphate response element binding protein (p-CREB) in the hippocampus. In contrast to the hippocampus, chronic Δ⁹-THC selectively increased p-CREB in the OVX/saline group in the striatum. Extracellular signal-regulated kinase (ERK) was not significantly affected by either hormone status or chronic Δ⁹-THC. In summary, these data in female rats suggest that cannabinoid abuse by adolescent human females could alter their subsequent responsiveness to cannabinoids as adults and have serious consequences for brain development.     

Tolerance and cross-tolerance to the response rate-decreasing effects of µ opioids in morphine-maintained squirrel monkeys

The purpose of the present experiment was to assess the degree of tolerance and cross-tolerance to the response rate-decreasing effects of opioids with different degrees of intrinsic efficacy at the mu receptor. The mu opioids included buprenorphine, etorphine, l-methadone, morphine, and sufentanil. Lever pressing of squirrel monkeys was maintained by a fixed-ratio (FR) 30 schedule of food presentation, and dose-effect curves for each drug were obtained prior to, during, and after daily administrations of morphine. Each of the mu opioids, and the non-opioid pentobarbital, dose-dependently decreased response rates. Daily administration of morphine produced approximately a 0.9 log unit rightward shift in the morphine dose-effect curve. During this chronic-morphine phase of the experiment, the dose-effect curve for pentobarbital was not shifted consistently, whereas the dose-effect curves for buprenorphine, etorphine, l-methadone, and sufentanil were shifted between 0.4 and 0.6 log unit to the right. Therefore etorphine, l-methadone and sufentanil, mu opioids thought to have high intrinsic efficacy, and buprenorphine, a mu opioid thought to have low intrinsic efficacy, all produced a smaller degree of cross-tolerance than that observed for morphine, and pentobarbital, a non-opioid, did not produce cross-tolerance.