Biomedical subjects

C P France

Publications and source records attributed to C P France.

At least 19 recordsLinked to original sources

PubMed2005

Cross-tolerance and mu agonist efficacy in pigeons treated with LAAM or buprenorphine.

The mechanism responsible for decreased opioid use during opioid substitution therapy is not fully understood. To examine whether l-alpha-acetylmethadol (LAAM) or buprenorphine attenuate behavioral effects of opioids through cross-tolerance, discriminative stimulus effects of high and low efficacy mu agonists were examined following 3- or 7-day treatment with LAAM or buprenorphine in pigeons discriminating between saline and heroin or between saline and buprenorphine, respectively. Heroin, buprenorphine and nalbuphine occasioned high levels of drug-appropriate responding in both groups; kappa opioids and non-opioids occasioned predominantly saline-appropriate responding. Administration of LAAM (3.2 mg/kg) or buprenorphine (3.2 mg/kg) occasioned predominantly heroin- or buprenorphine-appropriate responding, respectively. After discontinuation of LAAM treatment, the potency in occasioning heroin-key responding was markedly decreased for nalbuphine, slightly decreased for buprenorphine, and unchanged for heroin. Following discontinuation of buprenorphine treatment, the potency in occasioning buprenorphine-key responding was decreased for nalbuphine and unchanged for buprenorphine and heroin. Thus, greater cross-tolerance developed from LAAM and buprenorphine to low efficacy mu agonists as compared to a higher efficacy agonist. Failure of LAAM and buprenorphine treatment to modify the effects of heroin, under conditions that attenuate the effects of lower efficacy mu opioids, provides a possible rationale for why heroin abuse persists in some patients receiving large doses of agonists in substitution therapy.

Analgesics, Opioid↗

PubMed2005

Monoaminergic drugs and directly observable signs of LAAM withdrawal in rhesus monkeys.

Monoaminergic ligands modified a naltrexone discriminative stimulus in rhesus monkeys dependent on 2 mg/kg per day of the mu opioid L-alpha-acetylmethadol (LAAM). This study examined a role for monoamines in the directly observable and physiologic manifestations of LAAM withdrawal induced by naltrexone in the same monkeys. The effects of saline, clonidine (0.032 mg/kg), haloperidol (0.032 mg/kg), cocaine (1.0 mg/kg), amphetamine (1.0 mg/kg) and imipramine (10.0 mg/kg) were examined in LAAM-dependent monkeys that subsequently received saline or naltrexone (0.0001-1.0 mg/kg). Naltrexone dose-dependently increased respiration, abdominal rigidity and salivation. Clonidine attenuated each of these withdrawal signs, whereas haloperidol increased some (i.e. respiration) and decreased others (i.e. salivation). When administered alone, cocaine and amphetamine increased respiration and also increased the respiratory stimulant effects of naltrexone; cocaine and amphetamine did not attenuate any measure of withdrawal. With the exception of a decrease in naltrexone-induced salivation, imipramine was without effect. These results are strikingly different from results in these same LAAM-dependent monkeys showing that cocaine and amphetamine, but not clonidine, markedly attenuated a naltrexone discriminative stimulus. That monoaminergic ligands differentially alter the directly observable and discriminative stimulus effects of naltrexone in LAAM-dependent monkeys supports the view that monoamines differentially mediate the physical manifestations (norepinephrine) and subjective experience (dopamine) of opioid withdrawal.

Adrenergic alpha-Agonists↗

PubMed2005

SR 141716A differentially attenuates the behavioral effects of delta9-THC in rhesus monkeys.

The prototypic cannabinoid CB1 antagonist SR 141716A is one important pharmacologic tool for examining CB1 receptors that mediate the behavioral and physiologic effects of delta9-tetrahydrocannabinol (delta9-THC). This study examined the effects of SR 141716A on the rate-decreasing, hypothermic and discriminative stimulus effects of delta9-THC in rhesus monkeys. In monkeys (n=4) responding under a multiple fixed ratio (FR-10:FR-10) schedule of food presentation and stimulus-shock termination, the potency of i.m. delta9-THC to decrease responding in the food component (ED50=0.64 mg/kg) was threefold greater than its potency in the stimulus-shock termination component (ED50=2.14 mg/kg). In the same monkeys, hypothermia was induced by delta9-THC at a dose (e.g. 0.32 mg/kg) that did not alter responding in either schedule component; the maximum decrease was 2.1 degrees C at a dose of 3.2 mg/kg. A dose of 0.32 mg/kg of SR 141716A, significantly attenuated delta9-THC-induced hypothermia without attenuating the rate-decreasing effects of delta9-THC in either component of the multiple schedule. The largest dose of i.m. SR 141716A that was studied, 1.0 mg/kg, significantly decreased rectal temperature and responding in the food component but did not significantly decrease responding in the stimulus-shock termination component of the multiple schedule. In a separate group of monkeys (n=3) that discriminated i.v. delta9-THC (0.1 mg/kg) while responding under an FR-5 schedule of stimulus-shock termination, SR 141716A (0.32 and 1 mg/kg) significantly increased the ED50 of the delta9-THC by 2.3- and 3.7-fold, respectively. Collectively, these results demonstrate that the behavioral effects of delta9-THC are not equally attenuated by SR 141716A.

Animals↗

PubMed2004

The Discriminative stimulus effects of gamma-hydroxybutyrate and related compounds in rats discriminating baclofen or diazepam: The role of GABA(B) and GABA(A) receptors.

The discriminative stimulus effects of gamma-hydroxybutyrate (GHB) can be mimicked by GABA(A) receptor-positive modulators (e.g., diazepam) and GABA(B) receptor agonists (e.g., baclofen). The purposes of this study were to see whether stimulus control could be established with baclofen and to further characterize the role of GABAergic mechanisms in the behavioral actions of GHB by evaluating GHB and related compounds in rats discriminating either diazepam or baclofen. Training criteria were satisfied with baclofen and diazepam after 69 and 44 sessions, respectively. GHB and its precursors gamma-butyrolactone and 1,4-butanediol occasioned >80% responding on the drug-associated lever in rats discriminating baclofen and <11% in rats discriminating diazepam. Diazepam and other GABA(A) receptor-positive modulators occasioned intermediate levels of responding on the baclofen lever, whereas baclofen occasioned less than 4% responding on the diazepam lever. The GABA(B) receptor antagonist CGP 35348 [(3-aminopropyl)(diethoxymethyl) phosphinic acid] partially antagonized the effects of baclofen as well as the baclofen-like effects of GHB, and flumazenil partially antagonized the effects of diazepam. This study established stimulus control with baclofen, and substitution data provided direct evidence for a role of GABAergic, especially GABA(B), mechanisms in the discriminative stimulus effects of GHB. The lack of substitution by GHB or its metabolic precursors for diazepam indicates a comparatively smaller role of GABA(A) mechanisms in these effects of GHB. The inability of CGP 35348 to completely attenuate the effects of baclofen and GHB suggests that multiple receptors could be involved in the discriminative stimulus effects of GHB.

Adjuvants, Anesthesia↗

PubMed2002

Determinants of the behavioral effects of opioids and their antagonists: contributions of the Laboratory of Psychobiology.

RATIONALE: The behavioral pharmacology of opioids has been influenced significantly by the research and writings of Drs. Peter B. Dews, Roger T. Kelleher, and William H. Morse, their colleagues, and their students. OBJECTIVE: Their conceptual and methodological approach to the topic is reviewed briefly, and three areas of research are described to provide an empirical perspective. RESULTS: The objective of determining the general effects of opioids on behavior is described; the effects of opioids on schedule-controlled behavior and punished behavior are described and compared to non-opioids. The differential effects of opioid antagonists on responding reinforced by different stimuli are also presented. CONCLUSION: The conceptual and methodological approach taken by the group, as well as their discoveries in the behavioral pharmacology of opioids, will continue to exert a positive influence on the field.

Analgesics, Non-Narcotic↗

PubMed2002

Acute and chronic effects of the neuroactive steroid pregnanolone on schedule-controlled responding in rhesus monkeys.

This study used schedule-controlled responding to examine the acute and chronic effects of the neuroactive steroid and positive -aminobutyric acid A (GABA ) modulator pregnanolone. Pregnanolone, the positive GABA modulator triazolam, the GABA chloride channel site antagonist pentylenetetrazol (PTZ) and the -methyl-d-aspartate (NMDA) antagonist ketamine were administered to monkeys ( = 4) responding under a multiple fixed ratio (FR/FR) schedule of food presentation and stimulus shock termination (SST), before, during and after daily treatment with pregnanolone (3.2 mg/kg subcutaneously). Pregnanolone decreased responding in a dose- and time-related manner, with a duration of action of <2 h. Mutual antagonism occurred between pregnanolone and PTZ in the food component, and PTZ antagonized pregnanolone in the SST component. Daily treatment with pregnanolone increased the sensitivity to PTZ 24 h but not 2 h after daily pregnanolone administration, and daily pregnanolone treatment did not alter the sensitivity to pregnanolone, triazolam or ketamine. Baseline responding in the food component was decreased in some monkeys 24 h after daily pregnanolone administration and in all monkeys 48 h after discontinuation of daily pregnanolone treatment. These results suggest that positive GABA modulation is one mechanism by which pregnanolone decreases FR responding, and that dependence resulting from daily pregnanolone treatment is not necessarily accompanied by tolerance to pregnanolone. Failure of pregnanolone to confer tolerance under these conditions might suggest that neuroadaptations at the GABA receptor complex vary according to the site at which positive GABA modulation occurs.

Animals↗

PubMed2001

Behavioral effects of flunitrazepam: reinforcing and discriminative stimulus effects in rhesus monkeys and prevention of withdrawal signs in pentobarbital-dependent rats.

Flunitrazepam was evaluated in several procedures that have been used extensively to study the behavioral effects and abuse potential of positive GABA(A) modulators. One group of monkeys (n=3) responded to receive injections of methohexital or saline (i.v.) while other groups (n=2-4/group) discriminated vehicle from either pentobarbital or triazolam. Other monkeys (n=2) received diazepam daily and discriminated flumazenil from vehicle. Finally, the ability of flunitrazepam to prevent the emergence of withdrawal signs in pentobarbital-treated rats was evaluated. Flunitrazepam maintained i.v. self-administration that was, on average, less than that maintained by methohexital and greater than that maintained by saline. In drug discrimination studies, flunitrazepam substituted for pentobarbital and for triazolam and failed to substitute for flumazenil. In rats (n=3-6/group), signs of withdrawal were not evident when flunitrazepam treatment replaced pentobarbital treatment; withdrawal signs emerged when either pentobarbital or flunitrazepam treatment was terminated. Taken together with data from previous studies, these data suggest that the abuse liability of flunitrazepam is comparable to that of other benzodiazepines.

Animals↗

PubMed2001

The negative GABA(A) modulator methyl beta-carboline-3-carboxylate attenuates the behavioral effects of the positive GABA(A) modulators triazolam and pregnanolone in rhesus monkeys.

RATIONALE: Many of the effects of benzodiazepines (BZs), barbiturates, and neuroactive steroids are mediated by the gamma-aminobutyric acid (GABA)(A) receptor complex. OBJECTIVES: This study tested the hypothesis that negative GABA(A) modulators attenuate the behavioral effects of different positive GABA(A) modulators that vary in their site of action on the receptor complex. METHODS: Rhesus monkeys responding under a multiple fixed ratio (FR:FR) schedule of food presentation and stimulus-shock termination received GABA(A) modulators under cumulative dosing procedures. RESULTS: The BZ site negative GABA(A) modulator methyl beta-carboline-3-carboxylate (beta-CCM), and not the BZ site neutral modulator flumazenil, decreased FR responding under the multiple schedule. FR responding was also decreased by positive modulators, including the BZ triazolam, the neuroactive steroid pregnanolone, and the barbiturate pentobarbital in that order of potency. beta-CCM, and not flumazenil, antagonized pregnanolone, suggesting that pregnanolone increased GABA-mediated chloride flux at a non-BZ site. beta-CCM antagonized triazolam with the slope of the Schild plot for beta-CCM and triazolam (food component) conforming to unity and yielding a pA2 value of 6.44. The effects of pentobarbital were not altered by beta-CCM, suggesting that barbiturates might act at a population of GABA(A) receptors different from those where neuroactive steroids and BZs act, or that barbiturate site positive GABA(A) modulators are not amenable to modulation by negative modulators. CONCLUSIONS: These results confirm a competitive interaction between beta-CCM and triazolam, and further demonstrate that the effects of neuroactive steroids on FR responding are attenuated by a BZ site negative GABA(A) modulator. Negative GABA(A) modulators might prove especially useful for characterizing important differences among positive GABA(A) modulators that act through different sites on the receptor complex.

Animals↗

PubMed2001

Potency of positive gamma-aminobutyric acid(A) modulators to substitute for a midazolam discriminative stimulus in untreated monkeys does not predict potency to attenuate a flumazenil discriminative stimulus in diazepam-treated monkeys.

In monkeys discriminating midazolam (0.56 mg/kg s.c.) from saline, substitution for midazolam was elicited by various positive gamma-aminobutyric acid(A) (GABA(A)) modulators, including the benzodiazepines (BZs) triazolam, midazolam, and diazepam; the BZ(1)-selective ligands zaleplon and zolpidem; the barbiturates amobarbital and pentobarbital; and the neuroactive steroid pregnanolone. In another group of diazepam (5.6 mg/kg/day p.o.)-treated monkeys discriminating flumazenil (0.32 mg/kg s.c.) from vehicle, these positive GABA(A) modulators shifted the flumazenil dose-effect function to the right, i.e., attenuated diazepam withdrawal. The potency of positive GABA(A) modulators to substitute for midazolam in untreated monkeys did not predict their potency to attenuate the flumazenil stimulus in diazepam-treated monkeys. For instance, larger doses of BZs and BZ(1)-selective ligands were required to attenuate the flumazenil stimulus than to substitute for midazolam. The opposite relationship was revealed for non-BZ ligands, i.e., smaller doses of barbiturates and a neuroactive steroid were required to attenuate the flumazenil stimulus than to substitute for midazolam. The greater potency of non-BZ site ligands to attenuate diazepam withdrawal might be due to actions at a subtype of GABA(A) receptor not modulated by BZ site ligands, to the development of BZ tolerance without cross-tolerance to non-BZ site ligands, or to noncompetitive interactions at the GABA(A) receptor complex. Thus, interactions among GABA(A) modulators in BZ-dependent subjects are not predicted by their acute actions in nondependent subjects. It is not clear whether attenuation of BZ withdrawal is determined by subunit specificity or site of action on the GABA(A) receptor complex.

Animals↗

PubMed2000

Cocaine self-administration in monkeys: effects on the acquisition and performance of response sequences.

A three-component multiple schedule of intravenous cocaine self-administration (0.01-0.3 mg/kg), repeated acquisition and performance was used to examine the effects of self-administered cocaine on learning in rhesus monkeys. A 0.03 mg/kg infusion of cocaine maintained reliable self-administration without markedly decreasing overall response rate or increasing the percentage of errors in the acquisition and performance components in which food was presented. When saline was substituted for 0.03 mg/kg of cocaine, there was little or no effect on responding in the acquisition or performance components while the number of infusions and response rate in the self-administration component decreased. These effects occurred to a greater extent under a FR 90 schedule (Experiment 2) as compared to a FR 30 schedule (Experiment 1) of cocaine self administration. Substitution of higher infusion doses of cocaine also decreased response rate and the number of infusions in the self-administration components, and substantially decreased responding in the acquisition components; decreases in overall accuracy of responding were evident when responding in this schedule component occurred. Taken together, these data indicate that learning is generally more sensitive than performance to the disruptive effects of self-administered cocaine.

Animals↗

PubMed2000

Comparison of noncontingent versus contingent cocaine administration on plasma corticosterone levels in rats.

The purpose of the present study was to compare the effects of contingent and noncontingent cocaine administration on plasma levels of corticosterone in rats. Male rats were trained to self-administer cocaine under a fixed-ratio 5 schedule. The rats were yoked such that the delivery of cocaine (0.25 mg/kg/infusion) to one rat (contingent cocaine) produced the simultaneous noncontingent delivery of the same dose of cocaine (noncontingent cocaine) or saline (noncontingent saline) to other rats. Although saline administration had no effect, plasma corticosterone levels were significantly higher in rat receiving contingent cocaine compared to those receiving noncontingent cocaine. These results demonstrate that the active vs. passive administration of cocaine can differentially affect this neuroendocrine response.

Analysis of Variance↗

PubMed2000

In vivo estimates of efficacy at 5-HT1A receptors: effects of EEDQ on the ability of agonists to produce lower-lip retraction in rats.

RATIONALE: Maximal responses are often used as a measure of intrinsic activity or efficacy, but cannot be directly equated to efficacy. Using irreversible antagonists, estimates of efficacy can be obtained that may be less dependent on specific conditions. OBJECTIVES: To characterize the intrinsic activity of serotonin (5-HT)1A agonists by examining the effects of an irreversible antagonist on their ability to produce 5-HT1A receptor-mediated responses. METHODS: The effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on the ability of 5-HT1A agonists to produce lower-lip retraction (LLR) in rats were studied. RESULTS: In the absence of EEDQ, each 5-HT1A agonist produced full effects, the rank order of potency being: S 14506 > 8-OH-DPAT > buspirone > ipsapirone. EEDQ decreased the number of 5-HT1A binding sites and shifted the dose-response curves (DRCs) of each agonist either to the right or, at higher EEDQ doses, to the right and downward. The manner in which these shifts occurred, however, differed among the compounds. For each agonist, all DRCs obtained after different doses of EEDQ were fitted to models proposed by Furchgott and Black and Leff, and the results indicated the following rank order of efficacy: ipsapirone < buspirone approximately 8-OH-DPAT < S 14506. 5-HT1A agonist-induced LLR appears to be mediated by 5-HT1A receptors, because the 5-HT1A antagonist, WAY 100635, shifted the agonist DRCs to the right in a parallel and dose-related manner, with pA2 values ranging from 7.8 to 8.1. Moreover, pretreatment with WAY 100635 protected against the antagonist activity of EEDQ. CONCLUSIONS: The results suggest that the effects of EEDQ on the ability of 5-HT1A agonists to produce LLR in rats may be useful to obtain estimates of their apparent efficacy at 5-HT1A receptors.

Animals↗

PubMed2000

Agonist efficacy, drug dependence, and medications development: preclinical evaluation of opioid, dopaminergic, and GABAA-ergic ligands.

BACKGROUND: The general premise that receptor theory provides a useful framework for understanding the behavioral effects of psychoactive drugs has been a central tenet of behavioral pharmacology. OBJECTIVES: The purpose of this review is to reiterate this basic theme and, in particular, the proposition that current concepts of pharmacological efficacy can be effectively used to examine behavioral effects of drugs with abuse or dependence potential in a way that contributes to the discovery of drugs to treat drug dependence. EXPERIMENTAL DATA: The review begins by briefly introducing the concept of efficacy and follows with several illustrations of how our current understanding of efficacy can be used to address important research questions in drug discovery. In the first, the likelihood of developing novel opioid analgesics with reduced abuse potential is addressed by considering the different efficacy requirements for the discriminative-stimulus and antinociceptive effects of mu-opioids. From a pharmacologically different perspective within drug abuse research, the review continues with an exposition of efficacy-related differences in the behavioral effects of dopamine D1 agonists and how such differences might be exploited in different medications strategies for treating cocaine dependence. The principles of pharmacological efficacy also have come to guide the development of novel GABAA-related antianxiety medications, and this is illustrated in a discussion of the utility of low-efficacy agonists in the treatment of benzodiazepine dependence. The second half of the paper provides counterpoint to the several examples of how principles of efficacy can be applied in drug discovery. The counterpoint includes, first, a critical evaluation of how the concept of efficacy has been applied in the development of monoamine transport inhibitors as anti-cocaine medications and, in particular, the difficulties this may pose for data analysis. The review ends with a discussion of efficacy-based analysis in drug discrimination research and illustrates some of the obstacles that may be encountered in pharmacologically classifying drugs on this basis. CONCLUSIONS: Ample evidence indicates that many receptor systems can be activated in a graded manner and that principles of efficacy can be judiciously applied to understand and exploit the behavioral effects of drugs that result from such graded activation. However, as cautioned in the last sections, the misapplication of pharmacological concepts in behavioral studies of drugs may obscure their behavioral pharmacology and potentially confound drug discovery.

Animals↗

PubMed2000

The discriminative stimulus effects of morphine in pigeons responding under a progressive ratio schedule of food presentation.

The purpose of this study was to determine whether progressive ratio (PR) schedules might provide additional information, as compared with fixed ratio or fixed interval schedules, on pharmacologic features of discriminative stimuli (e.g. stimulus intensity). Five pigeons discriminated between 5.6 mg/kg morphine and saline under an arithmetic PR5 schedule of food presentation. The final ratio before pigeons either stopped responding for 5 min or switched responding from the selected to the non-selected key was designated as the last completed ratio (LCR). Pigeons responded 6.8% on the drug key following saline and 96.4% on the drug key following 5.6 mg/kg morphine. The average LCR value for saline was not significantly different from the average LCR value for morphine. A larger dose of morphine (10.0 mg/kg) increased the LCR value and significantly decreased rates of responding. Smaller doses of morphine (0.32 and 1.0 mg/kg) occasioned primarily saline-appropriate responding and decreased LCR values. Buprenorphine substituted for morphine and significantly increased LCR values, whereas nalbuphine produced only partial (20-80%) morphine-key responding and significantly decreased LCR. Cocaine did not substitute for morphine or modify LCR compared with saline control. Together, these results suggest that the stimulus effects of micro-opioids vary on a dimension (e.g. intensity) that can be quantified using PR schedules.

Animals↗

PubMed2000

Chronic l-alpha-acetylmethadol (LAAM) in rhesus monkeys: tolerance and cross-tolerance to the antinociceptive, ventilatory, and rate-decreasing effects of opioids.

Although l-alpha-acetylmethadol (LAAM) is a maintenance treatment for opioid dependence, few studies have systematically assessed the behavioral effects of LAAM and other drugs in LAAM-treated subjects. In the current study, we assessed the ventilatory, antinociceptive, and rate-decreasing effects of drugs (s.c. except dynorphin, which was administered i.v.) in rhesus monkeys (n = 3 or 4) before and during chronic treatment with 1.0 mg/kg/12 h LAAM (s.c.). Minute volume (V(E)) was reduced to 62% of baseline during LAAM treatment and remained depressed after more than 10 months of LAAM treatment. A cumulative dose of 10.0 mg/kg morphine decreased V(E) to similar values under baseline (53%) and LAAM-treated (52%) conditions; however, larger doses of morphine (up to 56.0 mg/kg) could be administered safely to LAAM-treated monkeys. LAAM treatment produced dependence as evidenced by a 220% increase in V(E) after a dose of naltrexone (0.032 mg/kg) that did not modify ventilation under baseline conditions. Compared with baseline, LAAM treatment increased the ED(50) values for the rate-decreasing effects of nalbuphine, morphine, and alfentanil by 7-, 7-, and 2-fold, respectively, in monkeys responding under a fixed ratio 10 schedule of food presentation. Similarly, LAAM treatment increased ED(50) values for the antinociceptive effects of morphine and alfentanil by 5- and 3-fold, respectively. LAAM treatment also increased the ED(50) values for the antinociceptive effects of the kappa-agonist enadoline by 5-fold and not those of U-50,488. That tolerance developed differentially to the ventilatory, rate, and antinociceptive effects of mu-agonists in LAAM-treated monkeys suggests that cross-tolerance might not be a safe therapeutic approach for the treatment of some opioid abusers.

Analgesics, Opioid↗

PubMed2000

Antagonism of the discriminative stimulus effects of positive gamma-aminobutyric acid(A) modulators in rhesus monkeys discriminating midazolam.

The extent to which individual subtypes of benzodiazepine receptors are functionally independent has not been elucidated in vivo. This study used apparent pA(2) analysis to test the hypothesis that a single receptor subtype mediates the discriminative stimulus effects of midazolam, triazolam, and diazepam, three positive gamma-aminobutyric acid(A) (GABA(A)) modulators. Four rhesus monkeys discriminated 0.56 mg/kg midazolam from vehicle under a fixed-ratio 5 schedule of stimulus-shock termination. Midazolam, triazolam, and diazepam increased responding on the midazolam-appropriate lever. The neutral GABA(A) modulator flumazenil shifted dose-effect curves for triazolam and diazepam to the right, and the negative GABA(A) modulators Ro 15-4513 and ethyl beta-carboline-3-carboxylate (beta-CCE) shifted dose-effect curves for midazolam and triazolam to the right. Slopes of Schild plots for flumazenil and Ro 15-4513 conformed to unity. The apparent pA(2) values were 7.41 and 7.69 for flumazenil in combination with triazolam and diazepam, respectively, and 7.53 and 6.88 for Ro 15-4513 in combination with midazolam and triazolam, respectively. The slope of the Schild plot for beta-CCE in combination with midazolam deviated from unity. Slopes of Schild plots obtained with flumazenil and Ro 15-4513 support the notion that a single benzodiazepine receptor subtype mediates the effects of midazolam, triazolam, or diazepam. The similarity in apparent pA(2) values for flumazenil in combination with triazolam and diazepam or for Ro 15-4513 in combination with midazolam and triazolam suggests that the same subtype mediates the effects of these positive modulators. In contrast, beta-CCE and midazolam do not appear to interact in a simple, competitive manner.

Animals↗

PubMed1999

Inhibitors of cytochrome P450 differentially modify discriminative-stimulus and antinociceptive effects of hydrocodone and hydromorphone in rhesus monkeys.

The present study was conducted to investigate the role of cytochrome P450 in the discriminative-stimulus and antinociceptive effects of hydrocodone (HC) and hydromorphone (HM) in rhesus monkeys. In morphine-deprived monkeys, morphine dose-dependently reversed naltrexone-lever responding, an effect also produced by HC and HM. HC and HM also produced antinociception in a warm-water tail withdrawal procedure. Budipine and naltrexone shifted the dose-effect curves for the discriminative-stimulus effects of HC and HM to the right. In contrast, naltrexone, but not budipine (10.0 mg/kg) or quinidine (10.0 mg/kg), dose-dependently antagonized the antinociceptive effects of HC. Budipine and quinidine decreased the concentration of HM in plasma without significantly affecting the levels of HC, suggesting that these CYP2D6 inhibitors decreased the conversion of HC HM. Thus, some behavioral effects of HC are not modified by a marked inhibition of CYP2D6, suggesting that these effects of HC are not due to its conversion to HM but, rather, that both HC and HM act directly on mu receptors.

Analgesics, Opioid↗

PubMed1999

Evaluation of the reinforcing and discriminative stimulus effects of gamma-hydroxybutyrate in rhesus monkeys.

Gamma-hydroxybutyrate (GHB) is a metabolite of GABA that is present in the CNS and fulfils at least some of the criteria for a neurotransmitter. Its effects are generally similar to those of CNS depressants and include ataxia, sleep and anesthesia. It has also been suggested that GHB is a drug of abuse. The present experiment was designed to evaluate GHB in procedures predictive of abuse and dependence potential in rhesus monkeys. Three monkeys were surgically prepared with indwelling silicone venous catheters and allowed to self-administer methohexital or saline in twice-daily experimental sessions. Other groups of monkeys were trained in drug discrimination paradigms to discriminate D-amphetamine (AMPH; n = 4), pentobarbital (PB; n = 3) or triazolam (n = 3) from saline. Another group was maintained on diazepam daily and trained to discriminate flumazenil from saline (n = 2). GHB (0.01-10 mg/kg per injection) maintained self-administration marginally above saline levels at one dose (3.2 or 10 mg/kg) in two of the three monkeys tested. GHB (1.0-178 mg/kg, subcutaneously (s.c.) or intragastrically (i.g.)) did not reliably substitute as a discriminative stimulus for any of the training conditions. Taken together with previous results, the present experiment suggests that GHB has, at most, low potential for abuse.

Anesthetics, Intravenous↗