Behavioural effects of glutamate receptor agonists in morphine-dependent rats

Glutamate receptors are implicated in the development and expression of drug dependence. Substantial experimental evidence suggests that antagonists acting at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors attenuate the severity of opioid withdrawal. However, it is less clear whether opioid withdrawal can be potentiated by agonists of glutamate receptors. The present study evaluated the behavioural effects of various agonists of glutamate receptors, as well as a nitric oxide (NO) donor, in morphine-dependent rats trained to discriminate 0.1 mg/kg of naloxone from saline. None of the following drugs produced appreciable levels of naloxone-like responding (substitution tests) or potentiated the discriminative stimulus effects of naloxone: NMDA (3-56 mg/kg), glycine (100-1000 mg/kg), glutamate (1000-3000 mg/kg), kainate (0.3-3 mg/kg), isosorbide dinitrate (30-300 mg/kg). Nevertheless, expression of some morphine withdrawal-like somatic and behavioural signs ('wet-dog'-like shaking, scream on touch, ptosis, tremor, chewing, weight loss) was facilitated by NMDA, glycine, and isosorbide dinitrate. These results suggest that, compared to somatic symptoms, subjective effects of opioid withdrawal (as reflected by discriminative stimulus effects) are not mimicked by direct activation of glutamate receptors.     

Discriminative stimulus effects of tizanidine hydrochloride: Studies with rats trained to discriminate either tizanidine,clonidine, diazepam,fentanyl, or cocaine

Male Sprague Dawley rats were trained in a two-lever food-reinforced procedure to discriminate between the effects of saline and either tizanidine hydrochloride, clonidine hydrochloride, diazepam, fentanyl, or cocaine hydrochloride. Tizanidine-trained rats dose-dependently generalized the effects of tizanidine and clonidine but not pentobarbital, diazepam, morphine, or cocaine. Clonidine-trained rats dose-dependently generalized the effects of clonidine and tizanidine but not pentobarbital, diazepam, or morphine. Diazepam-trained rats dose-dependently generalized the effects of diazepam but did not generalize tizanidine. Fentanyl-trained rats dose-dependently generalized the effects of fentanyl but did not generalize tizanidine. Cocaine-trained rats did not generalize the effects of tizanidine to the cocaine discriminative stimulus. Yohimbine hydrochloride but not naloxone hydrochloride dose-dependently antagonized the discriminative stimuli produced by both tizanidine and clonidine. These data demonstrate that tizanidine shares discriminative stimulus properties with clonidine but not with pentobarbital, diazepam, fentanyl, morphine, or cocaine. The discriminative stimuli produced by tizanidine and clonidine are mediated via an agonistic interaction with alpha₂-adrenergic receptors and not via an agonistic interaction with opioid receptors.     

The discriminative stimulus effects of N-methyl-D-aspartate antagonists in phencyclidine-trained rats

The discriminative stimulus effects of two competitive N-methyl-D-aspartate (NMDA) antagonists, 2-amino-7-phosphonoheptanoate (APH) and 3-[(+-)-2-carboxypiperazin-4-yl]propyl-1-phosphonate (CPP), were assessed in rats trained to discriminate phencyclidine from saline. Systemically administered APH (10-60 mg/kg i.p.) failed to elicit phencyclidine-lever responding; however, partial generalization from phencyclidine occurred following intracerebroventricular (i.c.v.) administration of APH (1.5-30 micrograms). Systemic and central administration of CPP (3-30 mg/kg i.p.; 0.1-10 micrograms i.c.v.) also resulted in partial generalization from phencyclidine. Partial generalization was also obtained with methohexital (5-30 mg/kg i.p.). However, generalization to APH, CPP and methohexital was usually accompanied by decreased response rates, and response rate decreases frequently occurred without appreciable phencyclidine-lever selection, indicating that these drugs also had no phencyclidine-like behavioral effects. The drug di-ortho-tolyl guanidine (DTG) which binds with high-affinity to sigma receptors failed to elicit phencyclidine-lever responding, even at doses which reduced response rates. These findings suggest that although competitive NMDA antagonists share some discriminative stimulus properties with phencyclidine, there is not a complete overlap in the discriminative stimulus properties of competitive and non-competitive NMDA antagonists. Furthermore, the discriminative stimulus effects of APH and CPP were no more similar to phencyclidine than those of methohexital.     

The discriminative stimulus effects of MK-801: Generalization to other N-methyl-D-aspartate receptor antagonists

Rats were trained to discriminate a dose of the NMDA antagonist MK-801 from saline using a standard, two-lever, operant procedure. The acquisition of this discrimination was rapid, rats reaching criterion performance in a mean of 32 sessions. The discriminative stimulus produced by MK-801 generalized to phencyclidine and (+)N-allylnormetazocine but only low levels of generalization were seen with (-)N-allylnormetazocine and with the anti- ischaemic drug ifenprodil and its derivative SL 82.0715. The MK-801 stimulus was partially antagonized by haloperidol. The results show that MK-801 can produce a discriminative stimulus which is shared by other non-competitive NMDA antagonists which have similar behavioural effects in other procedures. However, ifenprodil and SL 82.0715, which have also been shown to antagonize the effects of NMDA, do not produce similar behavioural effects or discriminative stimuli presumably because they act through a different site.     

Drug discrimination based on the competitive N-methyl-d-aspartate antagonist,NPC 12626

The discriminative stimulus effects of the N-methyl-d-aspartate (NMDA) antagonists 3-([+/-]-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and phencyclidine were assessed in a drug discrimination based on the competitive NMDA antagonist 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626). Adult male Sprague-Dawley rats were trained to discriminate NPC 12626 from saline using a standard two-lever fixed ratio 32 schedule of food reinforcement. NPC 12626 dose-dependently substituted for the training dose (20 mg/kg IP) with an ED₅₀ of 9.5 mg/kg. The competitive NMDA antagonist CPP completely substituted for NPC 12626 (ED₅₀=1.4 mg/kg IP). The non-competitive NMDA antagonist phencyclidine, as well as pentobarbital and NMDA, failed to substitute completely for NPC 12626, even at doses of these drugs that reduced response rates. These data indicate that the discriminative stimulus properties of NPC 12626 are selective and shared by CPP but not by phencyclidine, pentobarbital or NMDA. The emerging evidence for differences in the discriminative stimulus effects of competitive NMDA antagonists and phencyclidine suggests that competitive antagonists such as NPC 12626 and CPP may not have phencyclidine-like abuse liability.     

Evaluation of the effects of opioid agonists and antagonists under a fixed-consecutive-number schedule in rats

The effects of several opioid agonists and the opioid antagonist naloxone were examined in rats responding under a fixed-consecutive-number (FCN) schedule. Under this schedule, a reinforced response run consisted of responding eight or more times on one response lever, and then responding once on a second response lever. In one component of this schedule, an external discriminative stimulus signalled the completion of the response requirement on the first lever, whereas no stimulus change was programmed in the other. Morphine, l-methadone, U50488, ketocyclazocine, phencyclidine, and (+/-)N-allylnormetazocine decreased the percent of reinforced response runs (accuracy) under the FCN schedule without the external discriminative stimulus, but had no effect under the FCN schedule with the external discriminative stimulus. Naloxone and bremazocine, in contrast, had no effect on the accuracy of the discrimination under either FCN schedule. With the exception of bremazocine and U50488, which increased rates of responding at low doses, all drugs produced comparable decreases in rates of responding under both FCN schedules. During tests of antagonism, a 0.1 mg/kg dose of naloxone reversed completely the accuracy-decreasing effects produced by U50488 and morphine. The rate-decreasing effects of morphine and U50488 were reversed completely by a 0.01 and 1.0 mg/kg dose of naloxone, respectively. These results suggest that the addition of an external discriminative stimulus can modulate the disruptive effects of opioids, and that mu, sigma and some kappa agonists produce similar effects when evaluated under the FCN schedules.     

Evaluation of the phencyclidine-like discriminative stimulus effects of novel NMDA channel blockers in rats

Rationale Because of their potential therapeutic effects, N-methyl-d-aspartate (NMDA) receptor antagonists have been investigated for clinical use. Unfortunately, many channel-blocking antagonists have been associated with the production of side effects, including motor impairment and phencyclidine (PCP)-like subjective effects.Objective This study investigated the relationship between NMDA receptor channel blockade and production of PCP-like side effects by evaluating a variety of NMDA channel blockers with different binding characteristics for the production of PCP-like discriminative stimulus effects.Methods The NMDA channel blockers were tested in rats trained to discriminate 2 mg/kg PCP, i.p., from saline using a standard two-lever drug discrimination procedure with responding under a fixed ratio (FR) 32 schedule of food reinforcement.Results The high-affinity channel blockers PD 138289, PD 137889 and FR 115427, produced full, dose-dependent substitution for PCP. Of the moderate-affinity channel blockers, MRZ 2/579 fully substituted for PCP while 1-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline, 8-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline and alaproclate produced partial substitution. Drugs with the lowest affinity for the channel site and/or higher affinity for non-NMDA CNS sites, antazoline, idazoxan, 1-phenyl-1,2,3,4-tetrahydroisoquinoline, -benzyl-N-methylphenethylamine and orphenadrine, failed to substitute for PCP.Conclusions The results demonstrate that the cellular actions of the individual channel-blocking NMDA antagonists, in particular affinity for the channel site and NMDA receptor specificity, are important determinants of their discriminative stimulus effects. While higher affinity channel blockers show a correlation between affinity and PCP-like discriminative stimulus effects, behavioral disruption through action at non-NMDA receptors probably prevents achieving sufficient concentrations of the lower affinity compounds at NMDA receptors to produce PCP-like discriminative stimulus effects.     

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

The discriminative stimulus effects of several μ-opioid agonists were examined under conditions of opioid sensitization or tolerance, i.e., before and after 1-week SC infusions of naloxone or μ-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 μ-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 μ-opioid tolerance did seem to vary with the efficacy of the three μ-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 μ-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 μ-opioid agonists.     

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.     

Discriminative stimulus effects of site-selective N-methyl-d-aspartate antagonists in NPC 17742-trained rats and squirrel monkeys

 Drug discrimination studies in rats and monkeys with competitive N-methyl-d-aspartate (NMDA) antagonists as training drugs have shown that these drugs typically cross-substitute for each other, whereas phencyclidine (PCP)-like NMDA channel blockers produce partial, if any, substitution. In the present study, rats and squirrel monkeys were trained to discriminate the competitive NMDA antagonist, NPC 17742, from vehicle in a two-lever drug discrimination procedure for food reinforcement. The competitive NMDA antagonists, NPC 12626, SDZ EAA 494 (d-CPPene), and MDL 100,453 fully substituted for NPC 17742 in monkeys or in rats. The relative potencies of these compounds were similar across species. Open channel blockers, PCP and dizocilpine, and the tricyclic antidepressant and low affinity PCP-site ligand, desipramine, produced minimal responding on the NPC 17742-associated lever in rats or monkeys. The glycine-site modulators, (+)-HA-966, ACEA 1021 and milacemide, and the polyamine/NR2B-selective antagonist, eliprodil, also failed to substitute fully for NPC 17742 in rats and monkeys. These data complement and extend results of previous studies which have shown a lack of PCP-like discriminative stimulus effects of these non-competitive NMDA antagonists by further showing that they also do not share discriminative stimulus effects with those produced by many competitive NMDA antagonists. These observations would support a prediction that differences in side-effect profiles should emerge among types of NMDA antagonists. Received: 22 November 1996 / Final version: 13 March 1997     

The discriminative stimulus effects of N-methyl-d-aspartate antagonists in phencyclidine-trained rats

The discriminative stimulus effects of two competitive N-methyl-d-aspartate (NMDA) antagonists, 2-amino-7-phosphonoheptanoate (APH) and 3-[(±)-2-carboxypiperazin-4-yl]propyl-1-phosphonate (CPP), were assessed in rats trained to discriminate phencyclidine from saline. Systemically administered APH (10–60 mg/kg i.p.) failed to elicit phencyclidine-lever responding; however, partial generalization from phencyclidine occurred following intracerebraventricular (i.c.v.) administration of APH (1.5–30/ig). Systemic and central administration of CPP (3–30 mg/kg i.p.; 0.1–10 μg i.c.v.) also resulted in partial generalization from phencyclidine. Partial generalization was also obtained with methohexital (5–30 mg/kg i.p.). However, generalization to APH, CPP and methohexital was usually accompanied by decreased response rates, and response rate decreases frequently occurred without appreciable phencyclidine-lever selection, indicating that these drugs also had no phencyclidine-like behavioral effects. The drug di-ortho-tolyl guanidine (DTG) which binds with high-affinity to sigma receptors failed to elicit phencyclidine-lever responding, even at doses which reduced response rates. These findings suggest that although competitive NMDA antagonists share some discriminative stimulus properties with phencyclidine, there is not a complete overlap in the discriminative stimulus properties of competitive and non-competitive NMDA antagonists. Furthermore, the discriminative stimulus effects of APH and CPP were no more similar to phencyclidine than those of methohexital.     

Characterization of the discriminative stimulus effects of N-methyl- D-aspartate ligands under different ethanol training conditions in the cynomolgus monkey ( Macaca fascicularis)

RATIONALE: The current study was designed to extend our knowledge of the N-methyl- D-aspartate (NMDA) glutamate receptor system in mediating the discriminative stimulus effects of ethanol in non-human primates. OBJECTIVES: To characterize the discriminative stimulus effects of the NMDA uncompetitive antagonists dizocilpine, phencyclidine (PCP) and ketamine in male and female monkeys under different ethanol training conditions. METHODS: Adult male ( n=8) and female ( n=9) cynomolgus monkeys ( Macaca fascicularis) were divided into four groups and trained to discriminate 1.0 g/kg ethanol ( n=8) versus water or 2.0 g/kg ethanol ( n=9) versus water in a 2 x 2 design with training dose and sex as main group factors. Ethanol (20% w/v) solutions were administered intragastrically (IG) and responding was maintained under a fixed ratio schedule of food reinforcement. Dose-response determinations for dizocilpine [IG and intramuscular (IM)], PCP (IM) and ketamine (IM) were made under two training intervals (30 and 60 min). RESULTS: Dizocilpine, PCP and ketamine dose-dependently substituted for ethanol in three of four training conditions, the notable exception being in males trained with 2.0 g/kg ethanol. Ethanol-like discriminative stimulus effects were greater with IM dizocilpine than with IG dizocilpine. At the lower ethanol training dose (1.0 g/kg), there were no sex differences in the ethanol-like discriminative stimulus effects of dizocilpine, PCP or ketamine, nor were there sex differences in the potencies to produce ethanol-like discriminative stimulus effects. Sex differences were readily apparent with the higher ethanol training dose (2.0 g/kg), with the NMDA ligands failing to substitute for ethanol in male monkeys, probably due to the rate-suppressive effects of these compounds. CONCLUSIONS: These data suggest that NMDA receptor-mediated activity is a component to the discriminative stimulus effects of ethanol in male and female nonhuman primates. However, NMDA uncompetitive antagonists were less likely to produce discriminative stimulus effects similar to a high ethanol training dose in male monkeys. In comparison to consistent substitution by GABA(A) positive modulators for ethanol, substitution patterns produced by NMDA uncompetitive antagonists suggest a less robust mediation of the ethanol discriminative stimulus through NMDA receptor systems in nonhuman primates.     

Agonist and antagonist effects of prototype opiate drugs in fentanyl dose-dose discrimination

The experiments characterized the effects of fentanyl, morphine, naloxone, cyclazocine, nalorphine, ketocyclazocine and N-allylnormetazocine in rats that were trained to discriminate 0.04 mg/kg from 0.02 mg/kg fentanyl (dose-dose discrimination). The data are compared to results obtained previously in rats discriminating 0.04 mg/kg fentanyl from saline (drug-saline discrimination). In the dose-dose discrimination fentanyl and morphine produced responding appropriate to 0.04 mg/kg fentanyl at doses which were 3.0- and 1.6-fold higher, respectively, than in drug-saline discrimination. Naloxone antagonized the stimulus effects of 0.04 mg/kg fentanyl at 9.8-fold lower doses than in drug-saline discrimination. The dose-effect curves of fentanyl and naloxone in rats discriminating 0.04 mg/kg from 0.02 mg/kg fentanyl, were steeper than in rats discriminating 0.04 mg/kg fentanyl from saline. While cyclazocine, nalorphine and N-allylnormetazocine acted as mixed and partial agonists/antagonists in drug-saline discrimination, those compounds acted as pure and complete antagonists of 0.04 mg/kg fentanyl in dose-dose discrimination. The rank order of compounds in antagonizing the stimulus effects of 0.04 mg/kg fentanyl in dose-dose discrimination was naloxone > N-allylnormetazocine > cyclazocine > nalorphine. It is suggested that a greater magnitude of opiate activity is required for producing generalization with the same 0.04 mg/kg dose of fentanyl in dose-dose as compared with drug-saline discrimination. Dose-dose discrimination may afford a more accurate method than drug-saline discrimination for assessing the equivalence of the discriminative stimulus properties of drugs. The data obtained in the present study are consistent with the hypothesis that the discriminative stimulus effects of the opiate compounds studied are mediated by a molecular mechanism involving only a single opiate receptor.     

Stimulus effects of morphine in the monkey: quantitative analysis of antagonism

The ability of narcotic antagonists to block the discriminative stimulus effects of 3.0 mg/kg (IM) of morphine was evaluated quantitatively in the squirrel monkey using a two-choice discrete-trial avoidance paradigm. The time-course and relative potency of naloxone and naltrexone for antagonizing morphine's stimulus effects in the squirrel monkey was similar to those determined in rats and pigeons. Complete blockade of morphine's effects was attained with 0.03 mg/kg of either antagonist when given simultaneously with morphine, but only naltrexone completely blocked the stimulus effects of morphine when the pretreatment interval was extended to 12 and 18 hr. A Schild plot derived from the degree of antagonism of graded doses of morphine by graded doses of naltrexone (0.003-0.1 mg/kg) yielded a line with a slope of -0.63 +/- 0.2 and an apparent pA2 value of 8.25 +/- 0.2. These results demonstrate the feasibility of quantitatively assessing the drug-receptor interactions that subserve the discriminative stimulus effects of morphine in the squirrel monkey.     

Involvement of cannabinoid CB1 receptors in drug addiction: effects of rimonabant on behavioral responses induced by cocaine

A lot of evidence indicate that endocannabinoids and cannabinoid CB(1) receptors are implicated in drug addiction. In the present study, we investigated the effect of the cannabinoid CB(1) receptor antagonist/partial agonist rimonabant on the cocaine-maintained reinforcement and relapse to cocaine seeking as well as on the cocaine challenge-induced hyperactivity in sensitized rats and on discriminative stimulus effects of cocaine in rats. We found that endocannabinoids were not involved in maintenance of cocaine reinforcement and its subjective effects since pharmacological blockade of cannabinoid CB(1) receptors altered neither self-administration nor discriminative stimulus effects of cocaine. On the other hand, withdrawal from repeated access or exposure to cocaine and then a reinstatement of cocaine-seeking behavior or a sensitized locomotor response to a single cocaine challenge, respectively, was potently reduced by pretreatment with rimonabant. The latter observations may show that repeated cocaine treatment and the drug withdrawal produce--apart from behavioral effects--also different neural consequences in the endocannabinoid systems in rats.     

Lack of evidence for a role of endorphinergic mechanisms in mediating a discriminative stimulus produced by diazepam in rats

Male Sprague-Dawley rats were trained in a two-lever food-reinforced procedure to discriminate between the effect of saline and diazepam (2.5 mg/kg). After acquisition of this discrimination, the ability of morphine to generalize, and naloxone to antagonize the diazepam discriminative stimulus was tested. The rats did not generalized the effect of morphine, and naloxone did not antagonize the diazepam discriminative stimulus whether it was given prior or subsequent to diazepam. These data suggest a lack of involvement of endorphins in mediating the discriminative stimulus property of diazepam.     

An investigation of endogenous neuroactive steroid-induced modulation of ethanol's discriminative stimulus effects

Neuroactive steroids exhibit rapid non-genomic central nervous system activity, including modulation of GABAA and NMDA receptors, two receptors known to mediate the effects of methanol. Neuroactive steroids that modulate GABAA receptors in a manner similar to ethanol were expected to potentiate the discriminative stimulus and/or rate-suppressing effects of ethanol. In contrast, neuroactive steroids that modulate GABAA or NMDA receptors in a manner opposite to ethanol were hypothesized to attenuate the effects of ethanol. Adult male rats were trained to discriminate 1.0 or 2.0 g/kg ethanol (i.g.) from water (i.g.). Animals were pretreated with subthreshold doses (i.p.) of ethanol and neuroactive steroids and exposed to an acute stressor (n = 5), prior to conducting ethanol cumulative-dosing (i.p.) tests. Only ethanol and 3 beta, 5 beta-P pretreatments potentiated the discriminative stimulus effects of ethanol. None of the six neuroactive steroid manipulations attenuated the effects of ethanol. These results demonstrate that a neuroactive steroid, endogenous in humans, can enhance the interoceptive effects of ethanol.     

Increased specificity of ethanol's discriminative stimulus effects in an ethanol-pentobarbital-water discrimination in rats.

Ethanol's modulation of a number of receptor systems results in a heterogeneous discriminative stimulus complex. A previous study found that these heterogeneous discriminative stimulus effects were seemingly diminished when rats were trained to discriminate ethanol (2.0 g/kg) from pentobarbital (10.0 mg/kg). The present experiment was designed to extend these findings by using a lower training dose of ethanol (1.0 g/kg). Adult male Long-Evans rats (n = 7) discriminated pentobarbital (10.0 mg/kg; intragastric (i.g.)) from ethanol (1.0 g/kg; i.g.) from water (2.3 ml; i.g.) in a 3 lever, food-reinforced task. Substitution tests were conducted following intraperitoneal (i.p.) administration of GABA(A) positive modulators, noncompetitive NMDA antagonists, 5-HT1 agonists and isopropanol. The GABA(A) positive modulators diazepam, midazolam and allopregnanolone completely substituted for pentobarbital. Isopropanol completely substituted for ethanol, while the NMDA antagonists dizocilpine and phencyclidine partially substituted for ethanol. The 5-HT agonists RU 24969 and CGS 12066B did not result in complete substitution for ethanol or pentobarbital, although RU 24969 resulted in partial pentobarbital substitution. These data replicate and extend the previous findings that discriminating ethanol from pentobarbital attenuates the ethanol-like effects of GABA(A) positive modulators, NMDA antagonists and 5-HT1 agonists and results in a more specific ethanol cue. The outcome appears to be a conditional basis for the ethanol discrimination, where a full ethanol-like effect is produced only by drugs with pharmacological activity similar to the heterogenous effects of ethanol (e.g. other alcohols).     

Comparison of the stimulus effects of ethylketocyclazocine in fischer and Sprague-Dawley rats

The discriminative stimulus effects of ethylketocyclazocine (EKC) were characterized in Fischer and Sprague-Dawley rats trained to discriminate 0.3 mg/kg of EKC (s. c.) from saline in a two-choice, discrete-trial avoidance paradigm. The putative mu-opioid receptor agonists morphine and fentanyl, as well as the putative kappa-opioid receptor agonists EKC and U50,488H generalized completely with the EKC cue in both strains of rats. Only small quantitative differences between strains were observed in the generalization of these agonists with EKC. However, Sprague-Dawley rats were notably more sensitive than Fischer rats to the depressant effects of fentanyl. Only small quantitative differences between strains were also observed in the dose of naloxone necessary for complete antagonism of the EKC-like stimulus effects of the mu- and kappa-opioid agonists. The mu-opioid agonists were approximately 2–6 times more sensitive to naloxone antagonism than the kappa-opioid agonists in both Fischer and Sprague-Dawley rats. However, due to inter-animal variability, this difference was not statistically significant. The results of this study suggest that one or more opioid receptor subtype(s) may be involved in the production of the EKC cue in both strains of rats.     

NO介导吗啡戒断大鼠脊髓Fos蛋白和NMDA_(1A)受体mRNA表达的增加

目的:观察NO在纳洛酮催促吗啡戒断大鼠脊髓神经元活动变化中的作用。方法:采用Fos免疫组织化学、NADPH-d组织化学、Fos/NADPH-d双标、鞘内注射、反义寡核苷酸和RT-RCR技术。结果:急性应用纳洛酮和慢性应用吗啡对大鼠脊髓Fos蛋白及NADPH-d阳性神经元表达无明显影响,二者也无Fos/NADPH-d双标神经元表达;纳洛酮催促吗啡戒断大鼠脊髓Fos蛋白、NADPH-d阳性神经元、纤维和终末表达明显增加,且出现Fos/NADPH-d双标神经元表达。预先鞘内注射nNOS反义寡核苷酸明显降低吗啡戒断症状评分,减少吗啡戒断大鼠脊髓Fos蛋白及NMDA_(1A)R mRNA表达。结论:NO介导吗啡戒断大鼠脊髓Fos和NMD_(1A)R mRNA表达的增加。