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G Winger

Publications and source records attributed to G Winger.

At least 37 records · Page 2Linked to original sources
PubMed1992

Opioid and non-opioid effects of novel butyrophenone analogues.

Haloperidol, haloperidol propionate, and a haloperidol analogue N-3-(p-fluorobenzoyl) propyl-4-phenyl-4-propionyl-oxypiperidine (NIH 10495) were evaluated in several in vitro and in vivo tests of opioid effects. Haloperidol bound to opioid receptors with very low affinity and had no opioid agonist effects in the other test systems. Haloperidol propionate was 10 times less potent than NIH 10495 in the binding assay and in the smooth-muscle assay. Both of these haloperidol analogues decreased the rate and volume of respiration in air and in 5% CO2 with NIH 10495 being approximately 50 times more potent than haloperidol propionate. The NIH 10495, but not the haloperidol propionate, attenuated naltrexone-like discriminative stimulus effects in morphine-dependent withdrawn rhesus monkeys. Intravenously delivered NIH 10495 maintained higher rates of responding than did haloperidol propionate when evaluated for reinforcing effects. These drugs appear to have novel spectra of action that suggest possible value for this synthetic approach to the development of clinically useful analgesics and to the development of novel neuroleptics.

Animals↗
PubMed1992

Effects of buprenorphine and other opioid agonists and antagonists on alfentanil- and cocaine-reinforced responding in rhesus monkeys.

Rhesus monkeys self-administered a range of doses of either cocaine or alfentanil under a fixed-ratio 30, time out 45 sec schedule of i.v. drug delivery. Buprenorphine suppressed responding maintained by both cocaine and alfentanil; however, much larger doses of buprenorphine were required to suppress cocaine-reinforced as opposed to alfentanil-reinforced responding. Neither cocaine nor alfentanil dose-effect curves were shifted to the right by buprenorphine, but were simply shifted downward. Opioid agonists heroin and nalbuphine produced similar downward shifts in both alfentanil and cocaine dose-effect curves; unlike buprenorphine, similar doses of heroin and nalbuphine suppressed behavior maintained by both cocaine and alfentanil. Increasing doses of the pure opioid antagonist quadazocine produced shifts to the right in the alfentanil rate-maintaining dose-effect curves but had no dose-related effect on behavior maintained by cocaine. The data suggest that buprenorphine suppresses drug-maintained responding through an agonist action but that alfentanil-maintained responding is uniquely sensitive to buprenorphine's effects.

Alfentanil↗
PubMed1991

Discriminative and reinforcing effects of brotizolam in rhesus monkeys.

The reinforcing and discriminative stimulus effects of brotizolam, a benzodiazepine-hypnotic, were evaluated in rhesus monkeys. In one experiment, separate groups of monkeys (N = 3 group) were trained to discriminate pentobarbital (10 mg/kg, IG) or d-amphetamine. (0.56-1.0 mg/kg, IG) from saline, in a discrete-trials avoidance/escape paradigm. Pentobarbital (5.6-10 mg/kg), diazepam (1.0-1.7 mg/kg), and brotizolam (0.3-1.7 mg/kg) resulted in 100% drug-lever responding in all three pentobarbital-trained monkeys. In d-amphetamine-trained monkeys brotizolam administration resulted only in saline-lever responding. In another experiment, monkeys were surgically prepared with indwelling intravenous catheters and lever pressing resulted in an injection of 0.1 mg/kg/injection sodium methohexital under a fixed-ratio 10 (FR 10) schedule. Pentobarbital (0.01-0.3 mg/kg/injection) and diazepam (0.003-0.10 mg/kg/injection) maintained responding above saline control levels when substituted for methohexital. Brotizolam (0.001-0.01 mg/kg/injection) resulted in more injections received compared to saline, but fewer injections compared to pentobarbital or diazepam. Thus, results from the present experiment suggest that brotizolam would have pentobarbital-like subjective effects. However, the abuse liability of brotizolam may be lower than that for diazepam.

Animals↗
PubMed1991

Cocaethylene: a neuropharmacologically active metabolite associated with concurrent cocaine-ethanol ingestion.

High concentrations of cocaethylene (EC), the ethyl ester of benzoylecgonine, were measured in the blood of individuals who had concurrently used cocaine and ethanol. Since the powerful reinforcing effects of cocaine appear to be dependent on inhibition of dopamine reuptake in brain, we compared the effects of EC on the dopamine uptake system and its behavioral effects with those of cocaine. EC was equipotent to cocaine with respect to inhibition of binding of [3H]GBR 12935 to the dopamine reuptake complex, inhibition of [3H]dopamine uptake into synaptosomes and in its ability to increase extracellular dopamine concentration in the nucleus accumbens following its systemic administration to rats. Moreover, in rats, EC and cocaine each increased locomotor activity and rearing to the same extent following i.p. administration. In self-administration studies in primates, EC was approximately equipotent to cocaine in maintaining responding. The in vivo formation of this active, transesterified ethyl homolog of cocaine may contribute to the effects and consequences of combined cocaine and ethanol abuse.

Analysis of Variance↗
PubMed1991

Analysis of fixed-ratio behavior maintained by drug reinforcers.

Behavior maintained by intravenously delivered alfentanil, cocaine, or ketamine was assessed using a fixed-ratio schedule of reinforcement. As the dose of each drug was increased, rate of responding also increased up to a maximum. Further increases in dose resulted in decreased response rates (inverted U-shaped curve). An analysis of postreinforcement-pause-time and run-time measures for the ascending limb of the inverted U-shaped functions revealed that behavior was characterized by systematic decreases in both pause time and run time as dose and rate increased. An examination of the descending limb of the dose-response functions revealed that lowered response rates for cocaine and ketamine were correlated with increases in run time and small and inconsistent effects on postreinforcement pause time. Behavior maintained by rate-reducing doses of alfentanil was characterized by lengthened postreinforcement pauses with small increases in run time. These data suggest that at larger doses, drug reinforcers may have unconditioned or direct effects on the behavior that the drug is maintaining, and more important, that the nature of these unconditioned effects depends on the drug that is maintaining behavior.

Alfentanil↗
PubMed1991

Mirfentanil: pharmacological profile of a novel fentanyl derivative with opioid and nonopioid effects.

Mirfentanil [N-(2-pyrazinyl)-N-(1-phenethyl-4-piperidinyl)-2-furamide] was studied for its binding affinity in isolated neuronal membranes, and for its effects in vivo. In binding to opioid receptors in monkey brain membranes, mirfentanil was much more selective for mu sites (7.99 nM) than for either kappa (1428 nM) or delta (480 nM) sites as measured by displacement of [3H]DAMGO. [3H]U-69.593 or [3H]DPDPE, respectively. In morphine-treated pigeons discriminating among naltrexone, saline and morphine, mirfentanil failed to substitute for either training drug; in morphine-abstinent pigeons, mirfentanil reversed responding on the naltrexone key (i.e., reversed withdrawal). In morphine-treated monkeys discriminating between saline and naltrexone, mirfentanil substituted completely for naltrexone, and this effect was attenuated by an acute injection of morphine; mirfentanil also attenuated the withdrawal-reversing effects of alfentanil in morphine-abstinent monkeys. Administered i.v., mirfentanil maintained rates of self-administration responding only slightly below rates maintained by alfentanil, and this effect of mirfentanil was antagonized by quadazocine. Small doses of mirfentanil (0.032-0.32 mg/kg) antagonized the analgesic effects of alfentanil; larger doses of mirfentanil both antagonized the analgesic effects of alfentanil and produced analgesic effects when administered alone. The analgesic effects of mirfentanil were not attenuated by large doses of opioid antagonists. Mirfentanil had modest respiratory depressant effects that were not altered by quadazocine; however, mirfentanil antagonized the respiratory depressant effects of large doses of alfentanil. Both in vivo and in vitro, mirfentanil appears to have selectivity for opioid mu receptors. Moreover, at doses larger than those which exert opioid effects, mirfentanil has nonopioid analgesic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Alfentanil↗
PubMed1989

Drug-reinforced responding: rapid determination of dose-response functions.

Rhesus monkeys were conditioned to press on levers and receive intravenous infusions of cocaine or ketamine. Experimental conditions provided several different doses of drug during each of two daily 130 min sessions; as a result, a dose-response curve relating rate of responding to dose/injection for self-administered drug was obtained within each session. Relative rate-maintaining effects of nomifensine and cocaine in monkeys on baseline conditions of cocaine self-administration, and rate-maintaining effects of ketamine, phencyclidine and MK-801 in monkeys on baseline conditions of ketamine self-administration, compared favorably with relative rate-maintaining effects of these substances obtained in more traditional paradigms.

Animals↗
PubMed1988

Receptor mechanisms of opioid drug discrimination.

Receptor theory of opioid action has provided an extremely useful interpretive framework for the discriminative stimulus effects of opioids. By and large, receptor theory has been applied to opioid actions as they are measured in in vitro and reflex systems. It is clear, however, that it can also assist in interpreting data from experiments addressing operantly conditioned behavior, and provide a link between these data and those obtained using other procedures. The current paper describes the criteria that can be used to determine whether a drug effect is receptor mediated and applies these criteria to the effects of mu and kappa opioids in drug-discrimination studies. Criteria for distinguishing between drug effects occurring through one, as opposed to two, receptor systems are described and again applied to the discriminative stimulus effects of mu and kappa opioids. The potential difficulties that can be caused by postreceptor variability and the presence of multiple receptor systems are noted, since they can modify the effects predicted from simple receptor theory, and are likely to play an important role when studies of opioid action are made in the whole animal. In discrimination studies, complicating variables include dose of the training drug, subject species, nature of the training drug, and context of the discrimination. Finally, the ability of receptor theory to guide future investigation of the phenomenon of partial generalization is explored.

Animals↗
PubMed1988

Effects of ethanol withdrawal on ethanol-reinforced responding in rhesus monkeys.

Rhesus monkeys self-administered ethanol intravenously during daily, 3-h sessions. When ethanol-reinforced responding was stable and ethanol intake was in the range of 2.6-3.6 g/kg/3 h, physiological dependence to ethanol was induced by daily passive infusions of additional ethanol. In less than 1 week, mild to moderate withdrawal signs were observed prior to daily sessions. Ethanol intake was suppressed in the presence of these withdrawal signs and returned to normal only after withdrawal signs had subsided.

Animals↗
PubMed1987

Behavioral characterization of opioid mixed agonist-antagonists.

The effects of agonists and partial agonists of both mu and kappa receptor systems are described in several behavioral tests in rhesus monkeys. Procedures measuring drug discrimination, drug self-administration, drug dependence, and drug-induced analgesia are differentially sensitive to the agonist and antagonist effects of various opioids. The sensitivity of each of the procedures may be modified by altering behavioral parameters or dose of drug used to establish the behavioral effect.

Analgesia↗