Parametric changes in response equilibrium during an intra-cranial self stimulation (ICSS) task: can reward value be assessed independently of absolute threshold?

Traditional ICSS methodologies have attempted to evaluate changes in the rewarding value of brain stimulation by assessing the lowest value of the stimulation that will support responding. However, orderly changes in suprathreshold indicants of hedonic magnitude such as titration point have been shown. In the present experiments, rats were trained to respond on two ICSS autotitration schedules in which every response on one lever produced stimulation of the medial forebrain bundle, and every Xth response decreased either the stimulation current or the stimulation frequency. At any time, a response on a second "reset" lever restored the stimulation current or frequency available on the stimulation lever to its starting level and operationally defined changes in "reward value". In order to study this titration point measure, two response requirements (responses/stepdown; step size) and two stimulation parameters (initial stimulation level; train duration) were systematically varied. Under both current and frequency titration schedules, data indicated that response rate and titration point remained stable over repeated trials and multiple testing days--parameters being constant. Across all conditions, compared to the frequency titration schedule, subjects responding under the current titration schedule showed significantly higher titration points and lower rates of responding. Indicating the independence of rate and titration point data, parametric manipulations did not affect titration point and rate data concurrently. Results support the conclusion that titration point is a relative measure of "reward value" that is generally independent of response rate, but that is affected by manipulations that alter the amount of stimulation available between "resets". Additional work is needed in order to determine the relationship between the magnitude of stimulation needed to maintain minimal responding and that needed to maintain response equilibrium in an autotitration task.

Effects of naloxone and diprenorphine on amphetamine-stimulated behavior in guinea pigs and rats.

Amphetamine (0.1-10 mg/kg), naloxone (0.1-10 mg/kg) and diprenorphine (0.03-10 mg/kg) were studied for their ability to modulate locomotor behavior in the guinea pig. Naloxone, administered alone, caused a non-significant decrease in locomotor activity and had a similar non-significant effect on amphetamine-stimulated activity. Diprenorphine induced a significant suppression of locomotor activity, the magnitude of which was inversely related to dose: smaller doses of diprenorphine caused a greater suppression of locomotor activity than larger doses. Two doses of diprenorphine (0.1 and 1.0 mg/kg) were tested in combination with amphetamine in the guinea pig. They significantly reduced amphetamine-stimulated behavior and were equipotent in this regard. In contrast, diprenorphine had no effect on amphetamine-stimulated activity in rats. However, in keeping with other reports, naloxone (10 mg/kg) significantly reduced amphetamine-stimulated behavior. The differences in the actions of diprenorphine and naloxone on the behavior of guinea pigs and rats may reflect a different underlying distribution of subtypes of opioid receptor in the two species.

Stress-induced potentiation of morphine-induced analgesia in morphine-tolerant rats.

This study was designed to evaluate whether or not rats that were tolerant to the analgesic action of morphine were also tolerant to stress-induced potentiation of morphine-induced analgesia. Rats were trained to drink either solutions of morphine (0.5 mg/ml) or drug-free tap water on a limited access schedule (10 min every 6 hr). The daily intake of morphine averaged 46 mg/kg. Nontolerant and rats tolerant to morphine were tested for morphine-induced analgesia (tail-flick assay), while either unstressed or stressed (i.e. immobilized in Plexiglas cylinders). Morphine produced dose- and time-dependent increases in tail-flick latencies in all groups. Increased sensitivity to analgesia induced by morphine was evident for both nontolerant and tolerant, stressed rats, when compared to their unstressed counterparts. Stress-induced potentiation of morphine-induced analgesia was characterized by dose-related increases in the peak effect and duration of the effect. Stress potentiated the analgesic effect of morphine, comparably in nontolerant (1.7-fold) and tolerant (1.5-fold) rats. Differential tolerance to analgesia induced by morphine and to stress-induced potentiation of morphine-induced analgesia suggests that different mechanisms mediate these two effects.

Depletion of catecholamines in the brain of rats differentially affects stimulation of locomotor activity by caffeine, D-amphetamine, and methylphenidate.

The purpose of this study was to assess the role of catecholamines in brain, in the stimulation of locomotor activity, induced by caffeine, as compared to the psychomotor stimulants D-amphetamine and methylphenidate. Adult male rats were pretreated with either (1) 2.5 mg/kg (i.p.) reserpine, 24 hr prior to testing of locomotor activity, (2) 50 mg/kg (i.p.) alpha-methyl-para-tyrosine (AMPT) 6 hr and 2 hr prior to testing of locomotor activity, (3) 200 micrograms/rat (i.c.v.) 6-hydroxydopamine (6-OHDA), or 25 mg/kg (i.p.) desmethylimipramine (DMI) and 200 micrograms/rat 6-OHDA (i.c.v.), 6-8 weeks prior to testing. Each treatment group had a matched control group. Levels of catecholamines in the forebrain were determined in each of the treatment and corresponding control groups. All rats were tested with doses of caffeine, D-amphetamine and methylphenidate (excluding the 6-OHDA-treated animals), administered in random order intraperitoneally 35 min before locomotor activity was measured for 30 min. Pretreatment with either reserpine or AMPT attenuated the stimulation of locomotor activity induced by caffeine and D-amphetamine but not that induced by methylphenidate. The dose-response curve for amphetamine was shifted downward and to the right by reserpine but was flattened by AMPT. The dose-response curve for caffeine was displaced downward in a similar manner by both reserpine and AMPT. Treatment with 6-OHDA or DMI + 6-OHDA produced the expected changes in the content of catecholamines in brain, but failed to modify dose-response curves for caffeine or amphetamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and pharmacology of site-specific cocaine abuse treatment agents: 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane dopamine uptake inhibitors.

As part of a program to develop site-specific medications for cocaine abuse, a series of 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Selected compounds were tested for their ability to substitute for cocaine in rat drug discrimination tests. Synthesis was accomplished by a series of Diels-Alder reactions, using cis- and trans-cinnamic acid derivatives (nitrile, acid, acid chloride) with cyclohexadiene and cyclopentadiene. Standard manipulations produced the aminomethyl side chain. Many of the compounds bound with high affinity (median IC50 = 223 nM) to the cocaine binding site as marked by [3H]WIN 35,428. Potency in the binding assay was strongly enhanced by chlorine atoms in the 3- and/or 4-position on the aromatic ring and was little affected by corresponding methoxy groups. In the [2.2.2] series there was little difference in potency between cis and trans compounds or between N, N-dimethylamines and primary amines. In the [2.2.1] series the trans exo compounds tended to be least potent against binding, whereas the cis exo compounds were the most potent (4-Cl cis exo: IC50 = 7.7 nM, 27-fold more potent than 4-Cl trans-exo). Although the potencies of the bicyclic derivatives in the binding and uptake assays were highly correlated, some of the compounds were 5-7-fold less potent at inhibiting [3H]dopamine uptake than [3H]WIN 35,428 binding (for comparison, cocaine has a lower discrimination ratio (DR) of 2.5). The DR values were higher for almost all primary amines and for the trans-[2.2.2] series as compared to the cis-[2.2.2]. Most of the compounds had Hill coefficients approaching unity, except for the [2. 2.2] 3,4-dichloro derivatives, which all had nH values of about 2.0. Two of the compounds were shown to fully substitute for cocaine in drug discrimination tests in rats, and one had a very long duration of action.

Failure of naloxone to modify the effects of chlorpromazine and d-amphetamine on avoidance behavior in the squirrel monkey.

Lever-pressing by squirrel monkeys was maintained under a continuous avoidance schedule in which each response postponed for 30 s the delivery of an electric shock to the tail. Dose-response curves were determined for chlorpromazine (0.03--0.3 mg/kg) and d-amphetamine (0.03--1.0 mg/kg) administered alone and administered concomitantly with 1.0 or 10 mg/kg of naloxone. The dose-response curves for chlorpromazine and d-amphetamine were similar to those previously reported for monkeys under other schedules of shock-maintained behavior: Chlorpromazine decreased responding in a dose-related manner while d-amphetamine increased responding at low doses and disrupted behavior at the highest dose. Naloxone did not modify the effects of chlorpromazine and d-amphetamine. These results suggest that interactions observed previously between naloxone and nonopiate drugs on behavior in pigeons and rodents are not general phenomena in all animal species.

Discriminative stimulus effects of dextromethorphan in the rat.

This study was performed to characterize pharmacologically the discriminative stimulus effects of dextromethorphan, an antitussive that binds with high affinity to a subtype of sigma site in the brain. Dextrorphan, a metabolite of dextromethorphan, has phencyclidine (PCP)-like effects. Therefore, training was conducted with dextromethorphan injected by the SC route, which minimizes dextrorphan formation compared to the IP route. The training dose used, 30 mg/kg, by the SC route did not occasion selection of the PCP-appropriate choice lever in rats discriminating IP injections of 2.0 mg/kg PCP from saline. (In contrast, by the IP route the ED50 of dextromethorphan for PCP-appropriate lever selection was 21.7 mg/kg). In rats discriminating 30 mg/kg (SC) of dextromethorphan from distilled water, dextromethorphan was slightly more potent SC than it was IP (ED50s for dextromethorphan-appropriate lever selection: 8.5 and 14.9 mg/kg, respectively). These animals generalized dose-dependently and completely to PCP and to other PCP-receptor ligands, but selected the vehicle-appropriate choice lever when tested with sigma-site ligands, mu-opioid agonists, and naltrexone. Concurrent administration of naltrexone or sigma-site ligands with 30 mg/kg dextromethorphan did not block dextromethorphan-appropriate responding. These results show that the discriminative effects of SC dextromethorphan are PCP-like and are not mediated by the high-affinity dextromethorphan binding site or by the mu-opioid receptor. Because little dextrorphan is formed when dextromethorphan is given SC and because dextromethorphan itself has low affinity for the PCP receptor, the discriminative effects of SC dextromethorphan probably are mediated by a recognition site related closely to but different from the PCP receptor.

Phencyclidine-like discriminative stimulus properties of opioids in the squirrel monkey.

The opioids SKF 10047, dl-cyclazocine, and dextrorphan have been shown to have phencyclidine (PCP)-like discriminative stimulus properties in the rat. In order to extend the generality of this observation, the stimulus effect of these and other opioids were evaluated in squirrel monkeys trained to discriminate between IM injections of saline and 0.25 mg/kg of PCP in a two-choice discrete-trial avoidance paradigm. Stimulus control of behavior was characterized by the reliable completion of at least 22 trials of a 25-trial session on the appropriate choice lever after an injection of saline or PCP. In tests of stimulus generalization, SKF 10047, d-cyclazocine, dextrorphan, normetazocine, dl-cyclazocine, l-cyclazocine, and dextromethorphan occasioned dose-related increases in PCP-appropriate responding. The first four of these compounds and, under some conditions, l- and dl-cyclazocine, produced stimulus control of behavior comparable to that produced by the PCP training dose. Six other opioids occasioned responding only on the saline-appropriate liver: ethylketocyclazocine. Ketocyclazocine, levorphanol, levallorphan, pentazocine, naltrexone. Naltrexone (1.0 or 4.0 mg/kg) attenuated slightly the PCP-like stimulus effects of SKF 10047 and dextrorphan, but increased PCP-appropriate responding with l- and dl-cyclazocine and levorphanol by enabling higher doses of these drugs to be tested without disruption of responding. The PCP-like stimulus effects of certain opioids appear to be mediated at neuronal substrates acted upon by PCP rather than at sites typically associated with opiate activity. These neuronal sites of action common to opioids and PCP may correspond to the sigma "opiate" receptor.

Discriminative stimulus effects of buprenorphine in the rat.

Buprenorphine, a potent "low efficacy" or "partial" morphine-like opioid agonist, has morphine-like discriminative effects in animals and humans discriminating morphine or a related drug. The purpose of the present study was to characterize further the discriminative effects of buprenorphine in subjects trained to discriminate buprenorphine itself. Rats trained to discriminate between SC injections of saline and either 0.03 or 0.1 mg/kg buprenorphine generalized completely to morphine and to other morphine-like agonists. These drugs were approximately 3 times more potent in the rats trained with 0.03 mg/kg buprenorphine than in those trained with 0.1 mg/kg; however, the potency of buprenorphine itself did not differ significantly between groups. Indicative of efficacy differences among mixed-action opioids, rats discriminating 0.03 mg/kg buprenorphine generalized completely to butorphanol and pentazocine and partially to nalbuphine, whereas those discriminating 0.1 mg/kg generalized completely to butorphanol, partially to pentazocine, and little to nalbuphine. Stimulus control of behavior by 0.1 mg/kg buprenorphine was blocked surmountably by low doses of antagonists, stereoselective, and pharmacologically selective. These results are consistent with those of other studies showing that the discriminative effects of buprenorphine are morphine-like and mediated by the mu-opioid receptor, and extend the conditions under which this has been demonstrated to stimulus control maintained by buprenorphine itself.

Differential interaction of GBR 12909, a dopamine uptake inhibitor, with cocaine and methamphetamine in rats discriminating cocaine.

RATIONALE: Inhibitors of neuronal dopamine uptake, such as GBR 12909, decrease IV cocaine self-administration by laboratory animals and have been proposed as potential therapeutic agents for abuse of psychomotor stimulant drugs. OBJECTIVES: This study was performed to determine how GBR 12909 alters the discriminative stimulus effects of methamphetamine and cocaine. METHODS: Rats were trained to discriminate between IP injections of 10 mg/kg cocaine and saline and were tested for stimulus generalization to cocaine, GBR 12909, and methamphetamine. Based upon the ED50 of the individual drugs, combinations of GBR 12909 and either cocaine or methamphetamine were tested that comprised a) 1 part GBR 12909 and 2 parts cocaine or methamphetamine, or b) 2 parts GBR 12909 and 1 part cocaine or methamphetamine. RESULTS: GBR 12909 and cocaine were equipotent and 30-fold less potent than methamphetamine in producing cocaine-like discriminative effects. GBR 12909 and cocaine produced cocaine-like discriminative effects synergistically in the ratio of 1 part GBR 12909:2 parts cocaine (0.16+0.32 to 1.92+ 3.87 mg/kg) and nearly synergistically in the ratio of 2 parts GBR 12909:1 part cocaine (0.32+0.16 to 3.92+ 1.91 mg/kg). GBR 12909 and methamphetamine (0.32+0.02 to 3.20+0.22 mg/kg or 0.65+0.01 to 6.53+0.1 mg/kg) were simply additive in both sets of fixed-ratio dose combinations. CONCLUSIONS: The synergy of GBR 12909 and cocaine and the additivity of GBR 12909 and methamphetamine run counter to the presumed mechanisms of action of these drugs at dopamine nerve terminals, which might have implications for the use of GBR 12909 in the treatment of addiction to cocaine or amphetamines.

Influence of naloxone upon motor activity induced by psychomotor stimulant drugs.

Naloxone, an opioid receptor antagonist, attenuates a wide range of behavioral effects of d-amphetamine, such as the stimulation of motor activity. To investigate the pharmacological selectivity of the naloxone/amphetamine interaction, we assessed the effects of naloxone (5.0 mg/kg SC) upon motor activity induced in rats by a range of psychomotor stimulant drugs with a mechanism of action either similar to or different from that of d-amphetamine. Each of the drugs tested caused dose-dependent increases in both gross and fine activity. Naloxone attenuated the gross but not the fine activity response to d- and l-amphetamine, but had no influence upon the other catecholamine-releasing drugs, methamphetamine and phendimetrazine. In contrast, naloxone increased the gross but not the fine activity response to the catecholamine uptake inhibitors cocaine and mazindol, but had no effects upon the motor response to methylphenidate. The responses to other stimulant drugs (apomorphine, caffeine, scopolamine) were unaffected by naloxone pretreatment. The present findings extend the range of conditions under which naloxone and, by inference, endogenous opioid systems, modulate the behavioral response to psychomotor stimulants. However, the differential effects of naloxone upon the motor response to individual stimulant drugs support previous suggestions of fundamental differences in mechanisms of action among these compounds.

Pharmacologic specificity of tolerance to caffeine-induced stimulation of locomotor activity.

The pharmacologic specificity of tolerance to caffeine-induced stimulation of locomotor activity was studied in adult male rats that were given access to either caffeine solution (0.5 or 1.0 mg/ml) or plain water for 10 min every 6 h on a chronic daily basis; daily caffeine intake averaged 41 and 62 mg/kg, respectively. Dose-effect curves were determined for behavioral stimulant and depressant drugs in control and caffeine-treated groups. Drugs were injected IP and locomotor activity was measured for 30 min beginning 35 min later. Rats tolerant to stimulation of locomotor activity by caffeine were also tolerant to theophylline and 7-(2-chloroethyl)theophylline, but not to any of six nonxanthine stimulants, including cocaine, methylphenidate, and d-amphetamine. The adenosine analogs, R(-)-N6-2-(phenylisopropyl)adenosine(R(-)-PIA) and 5'-(N-ethyl)carboxamidoadenosine (NECA), decreased locomotor activity of control and caffeine-treated (0.5 mg/ml) rats; dose-effect curves in rats consuming caffeine chronically were displaced to the right of the control curves by 10-fold for R(-)-PIA and 100-fold for NECA. Dose-effect curves for the nonadenosine behavioral depressants chlorpromazine and diazepam were unchanged by chronic treatment with caffeine, but the curve for pentobarbital, which is thought to inhibit adenosine receptor binding, was shifted to the right by a factor of 3. Rats withdrawn from chronic caffeine for 24 h were still completely tolerant to caffeine-induced stimulation of locomotor activity. Dose-effect curves for R(-)-PIA and d-amphetamine in rats withdrawn from chronic caffeine for 24 h were not different from curves in control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of d-amphetamine, morphine, naloxone, and drug combinations on visual discrimination in rats.

The effects of d-amphetamine, morphine, and naloxone on visual discrimination were investigated using a two-choice discrete-trial procedure in which rats were trained to discriminate the position of a lightflash. Morphine (0.3-5.6 mg/kg) but not amphetamine (0.1-1.0 mg/kg) caused a significant dose-dependent disruption in discriminative performance. Both amphetamine and morphine increased response latencies. Naloxone (1.0 mg/kg) prevented the disruption of any aspect of performance by up to 100 mg/kg morphine. Performance after naloxone/amphetamine co-administration was not significantly different from that observed after amphetamine alone. Naloxone alone (0.3-10 mg/kg) had no effect on discrimination, spatial bias or response latencies. These results suggest that morphine and amphetamine affect different components of discrimination performance.

Morphine-like discriminative stimulus effects of opioid peptides: possible modulatory role of D-Ala2-D-Leu5-enkephalin (DADL) and dynorphin A (1-13).

The role of the different opioid receptors was studied in rats trained to discriminate SC injections of 3.0 mg/kg morphine from saline by tests for generalization to graded doses of morphine and receptor-selective peptides administered into the lateral cerebral ventricle. Dose-dependent morphine-like stimulus effects were produced over a wide range of doses (0.001-30 micrograms), depending upon ligand and animal, by morphine, by the mu-selective peptides DAGO[D-Ala2-NMePhe4-Gly(ol)-enkephalin] and FK33824[D-Ala2,NMePhe4-Met(O)5-(ol)-enkephalin], and by the delta-selective peptide, DADL[D-Ala2,D-Leu5)enkephalin]. The order of relative potency of these substances was: FK33824 greater than DAGO greater than morphine greater than DADL. In contrast, DPLPE[D-Pen2,L-Pen5)enkephalin], which has much greater delta receptor selectivity than does DADL, and dynorphin A(1-13) (0.1-10 micrograms), a kappa-receptor agonist, engendered choice responding appropriate for saline. When 1.0 micrograms DADL, a dose lacking morphine-like discriminative effects, was administered concurrently with SC morphine, the stimulus effects of morphine were potentiated. Concurrent administration of 10 micrograms dynorphin A(1-13) and morphine attenuated the stimulus effects of morphine inconsistently. These results support previous findings that mu-opioid receptors are of primary importance in mediating the morphine-like discriminative effects of opioid peptides. They also suggest that morphine-like discriminative effects can be modulated by other types of opioid receptors.

Suppression of deprivation-induced water intake in the rat by opioid antagonists: central sites of action.

The effects of naltrexone methobromide, a quaternary derivative of the opioid antagonist naltrexone, were investigated on deprivation (24 h)-induced water intake in the unilaterally cannulated rats. Naltrexone methobromide reduced post-deprivational water intake with an ED50 of 7.3 micrograms when tested at 30 min (peak effect) after intracerebroventricular administration. It also dose-dependently (0.3-10 micrograms) depressed water intake, with peak effects at 15 min, after microinjection into the paraventricular hypothalamic nucleus and into the supraoptic hypothalamic nucleus. The drug did not produce any other effects on behaviors. The ED50S were 1.4 micrograms when given into the paraventricular nucleus, and 3.3 micrograms when given into the supraoptic nucleus, respectively. Although injections of higher doses (1.0, 3.0 and/or 10 micrograms) of the drug into the preoptic area, zona incerta, and corpus callosum significantly suppressed water intake, other behavioral manifestations, such as rotational behaviors, convulsions, body shakes, head swaying, and/or backward locomotion were manifested simultaneously with the reduction in drinking. When injected into the lateral hypothalamic area, water intake was not significantly affected by the drug. These findings suggest that the paraventricular and supraoptic hypothalamic nuclei are important sites of action in the naltrexone-induced suppression of water intake.

Three-choice drug discrimination: phencyclidine-like stimulus effects of opioids.

To assess the commonalities and differences in the discriminative stimulus properties of phencyclidine (PCP) and psychotomimetic opioids, rats were trained to discriminate PCP (2.0 mg/kg), cyclazocine (1.0 mg/kg), and saline in a three-choice discrete-trial avoidance paradigm. Stimulus control of behavior, defined as the reliable completion of 18 trials of a 20-trial session on the appropriate choice lever after administration of PCP, cyclazocine, or saline, was established in an average of 157 sessions. In tests of stimulus generalization, SKF-10,047 and dextrorphan engendered lever choices appropriate to both PCP and cyclazocine, sometimes in the same animal and at the same dose. The rats responded almost exclusively on the PCP-appropriate lever after ketamine and on the saline lever after morphine and d-amphetamine, indicating pharmacologic specificity. Naltrexone, in doses that had little effect on stimulus control of behavior by PCP, completely blocked cyclazocine-like stimulus control. Decreases in cyclazocine choices in the presence of naltrexone were associated with increases in PCP choices. These results support conclusions derived from two-choice procedures that psychotomimetic opioids have PCP-like stimulus effects, and provide direct evidence that these effects of cyclazocine are mediated by a component of action insensitive to an opiate antagonist.

Schedule-controlled behavior in the morphine-dependent and post-dependent rat.

Chronic morphine treatment has been reported to induce long-lasting changes in the responses of animals to the subsequent administration of morphine or narcotic antagonists. However, there have been few systematic studies in which the effects of morphine or narcotic antagonists have been compared in the same group of animals before, during, and after chronic morphine administration. Rats were trained to press a lever on a variable interval (1 min) schedule of food presentation and dose-response curves were determined for morphine (0.3--30 mg/kg) and naloxone (0.003--10 mg/kg) in the same group of animals prior to, during, and following morphine dependence. Dependence was induced and maintained by scheduled access to 0.05% morphine drinking solution for 10 min every 6 h. Response rates and fluid intake remained constant over the 9 month study. The dose-response curves for morphine and naloxone in predependent and dependent animals were similar to those previously reported in studies using other schedules of reinforcement and different techniques for establishing morphine dependence: chronic morphine treatment produced a threefold decrease in the effect of morphine and a dramatic increase in the effectiveness of naloxone in decreasing response rate. The altered sensitivity of dependent rats to morphine and naloxone was completely reversed in the post-dependent animals, within 4 weeks after the withdrawal of morphine. Scheduled access to a morphine solution affords a simple means of maintaining morphine-tolerant and dependent animals for long-term behavioral studies.

Antagonism of the discriminative stimulus effects of the kappa-opioid agonist spiradoline.

This study compared the potency of mixed-action opioids (i.e., agonist-antagonists) and pure antagonists to block the discriminative stimulus effects of spiradoline, a kappa-opioid agonist. Rats were trained to discriminate between 3.0 mg/kg spiradoline and saline (SC) in a two-choice discrete-trial procedure. Graded doses of test drugs were administered in combination with 3.0 mg/kg spiradoline and the dose that reduced selection of the spiradoline-appropriate choice lever by 50% (AD50) was calculated. Ten drugs blocked the discriminative effects of spiradoline in an orderly dose-dependent manner. They spanned a 150-fold potency range from diprenorphine (5 times as potent as naloxone) to nalbuphine (0.03 times as potent as naloxone). Antagonism was stereoselective: 0.1-1.0 mg/kg (-)-N-allylnormetazocine (NANM) reduced spiradoline-appropriate responding by 50% whereas 3.0 mg/kg (+)-NANM did not. (-)-Pentazocine (0.1-10 mg/kg) and butorphanol (0.1-3.0 mg/kg) also did not block the discriminative effects of spiradoline. Antagonism was surmountable when graded doses of spiradoline were tested with a fixed dose of diprenorphine, naloxone, or levallorphan. Apparent pKB values derived from the interactions between those three drugs and spiradoline were in accord with relative antagonist potencies based upon the AD50s. Because the potency of a competitive antagonist is determined by its receptor affinity, the relative potencies of mixed-action opioids and pure antagonists in blocking the discriminative stimulus effects of spiradoline can provide an estimate of the relative in vivo affinities of these drugs for the kappa-opioid receptor.

Sensitization and tolerance to the discriminative stimulus effects of mu-opioid agonists.

The discriminative stimulus effects of several mu-opioid agonists were examined under conditions of opioid sensitization or tolerance, i.e., before and after 1-week SC infusions of naloxone or mu-opioid agonists. Rats were trained to discriminate 3.0 mg/kg morphine from saline using a two-lever, discrete trial, shock-avoidance/escape procedure. The rats generalized completely to morphine, fentanyl, meperidine, buprenorphine, and etorphine, and partially to pentazocine. A 7-day infusion of naloxone (0.3 mg/kg per h) potentiated the discriminative stimulus effects of all of these drugs. The magnitude of the increased potency varied indirectly with the efficacy of the mu-opioid agonists; potency ratios (pre-infusion ED50/post-infusion ED50) ranged from 1.58 (etorphine) to 3.58 (pentazocine). Stimulus generalization to morphine, fentanyl, and meperidine also was examined following infusions of equieffective doses of each of these three drugs. Differences among drugs were generally small, and failed to reach statistical significance. Nonetheless, the induction of mu-opioid tolerance did seem to vary with the efficacy of the three mu-opioid agonists. Thus, meperidine (6.25 mg/kg per h), which has the lowest efficacy of the drugs infused, produced the greatest shift to the right of the stimulus-generalization curves of these three drugs; the post-meperidine PR ranged between 0.40 and 0.61. Fentanyl (0.1 mg/kg per h), a drug with a higher efficacy at mu-opioid receptors, did not produce tolerance to the discriminative stimulus effects of morphine, fentanyl, or meperidine; potency ratios ranged from 0.50 to 0.75. Potency ratios for buprenorphine, etorphine, fentanyl, meperidine, and morphine after 7-day morphine infusions (0.75 mg/kg per h) ranged from 0.38 (buprenorphine) to 0.80 (etorphine). Morphine induced significant tolerance only to the discriminative stimulus effects of fentanyl. Our results suggest that different cellular mechanisms underlie the development of tolerance and sensitization to the discriminative stimulus effects of mu-opioid agonists.

Comparison of the discriminative and antinociceptive effects of morphine and its glucuronide metabolites after central or systemic administration in the rat.

The potential of centrally (ICV) or systemically (SC) administered M6G to substitute for morphine in a drug discrimination task was characterized in the present study. Rats with a cannula in the lateral cerebral ventricle were trained to discriminate between injections of morphine (3 mg/kg, SC) and saline using a discrete-trial avoidance/escape procedure. Substitution tests were conducted with SC or ICV morphine, morphine-3-beta-D-glucuronide (M3G), or morphine-6-beta-D-glucuronide (M6G) and response latency in a tail-flick test was measured before each session began. The stimulus effects of morphine (ED50=1.02 mg/kg SC or 2.1 microg/kg ICV) were fully shared by M6G, with potency dependent on route of administration (ED50=3.12 mg/kg SC or 0.34 microg/kg ICV). The stimulus effects of M6G were highly correlated with its antinociceptive activity (r=0.84 SC or 0.46 ICV) and, at equipotent systemic doses, they lasted longer (t1/2=391 min) than those of morphine (t1/2=185 min). M3G was inactive in both procedures by both routes of administration. Naltrexone SC, given 30 min prior to testing, completely attenuated the stimulus effects of ICV M6G (AD50=0.011 mg/kg), indicating that they are mediated by opioid receptors. The results of this study suggest that M6G might contribute to the interoceptive effects of morphine that underlie its potential for abuse.