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G Winger

Publications and source records attributed to G Winger.

At least 19 recordsLinked to original sources
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↗
PubMed1999

Effects of self-administered cocaine on plasma adrenocorticotropic hormone and cortisol in male rhesus monkeys.

This study was designed to examine the effects of self-administered cocaine on hypothalamic-pituitary-adrenal (HPA) axis activity in rhesus monkeys. Initially, basal release of cortisol and adrenocorticotropic hormone (ACTH) was measured in singly housed male and female monkeys (n = 9) over a 24-h period using plasma samples obtained from indwelling venous catheters. Basal cortisol and ACTH levels in both male and female rhesus monkeys demonstrated a circadian pattern of release, with peak levels for cortisol (19.60 +/- 2.16 microgram/dl) and ACTH (19.63 +/- 2.56 pg/ml) measured at 6:00 AM. The nadir for ACTH (6.27 +/- 0.62 pg/ml) occurred at 6:00 PM, preceding the cortisol nadir (5.55 +/- 1.21 microgram/dl) at 9:00 PM. The reinforcing effects of saline, 0.01, 0.03, 0.1, and 0.3 mg/kg/injection cocaine were then evaluated using a fixed-ratio 30, time-out 10-min schedule of reinforcement in seven male monkeys. Blood was sampled before, during, and after self-administration sessions. Self-administration of cocaine produced dose-dependent increases in cortisol and ACTH. One dose of cocaine (0.03 mg/kg/injection), although reliably self-administered, did not produce a significant increase in HPA axis activity. These results indicate that although cocaine dose-dependently increases HPA axis activity, the HPA effect is more likely a consequence of overall cocaine intake than it is an indicator of cocaine doses that are sufficient to maintain self-administration behavior.

Adrenocorticotropic Hormone↗
PubMed1999

Effects of response contingent and noncontingent cocaine injection on hypothalamic-pituitary-adrenal activity in rhesus monkeys.

Earlier studies of cocaine's effects on the hypothalamic-pituitary-adrenal (HPA) axis used nonresponse-contingent designs in which the investigator determined dose, timing, and route of administration. It is important to evaluate whether "control" over cocaine delivery is a significant determinant of cocaine's HPA axis effect. This study measured cocaine's effects on plasma adrenocorticotropic hormone and cortisol, using nonresponse-contingent injections followed later by response-contingent cocaine delivery. In addition, the effects of cocaine history on the HPA response to a noncontingent injection of 1 mg/kg of cocaine were measured. HPA effects of corticotropin-releasing hormone (CRF) were also measured. Male and female rhesus monkeys, with surgically placed venous catheters, were tested in their home cages. Up to 13 injections of saline and cocaine (0.01-, 0.03-, 0.1-, and 0.3-mg/kg/injection) were administered at 10-min intervals (nonresponse-contingent condition) and on a fixed ratio 30, time out 10-min schedule of reinforcement. Overall, cocaine delivered response contingently produced larger, more dose-dependent HPA responses than did noncontingent delivery. The HPA response to a 1 mg/kg cocaine infusion in cocaine-naive monkeys was not predictive of the HPA effect of this dose subsequent to acquisition of cocaine self-administration. Overall, male monkeys had larger HPA responses to cocaine than did female monkeys. Finally, the HPA effects of CRF were significantly correlated with those of large cocaine doses delivered nonresponse contingently, but not with response-contingent administration.

Adrenocorticotropic Hormone↗
PubMed1998

A catalytic antibody against cocaine prevents cocaine's reinforcing and toxic effects in rats.

Cocaine addiction and overdose have long defied specific treatment. To provide a new approach, the high-activity catalytic antibody mAb 15A10 was elicited using a transition-state analog for the hydrolysis of cocaine to nontoxic, nonaddictive products. In a model of cocaine overdose, mAb 15A10 protected rats from cocaine-induced seizures and sudden death in a dose-dependent fashion; a noncatalytic anticocaine antibody did not reduce toxicity. Consistent with accelerated catalysis, the hydrolysis product ecgonine methyl ester was increased >10-fold in plasma of rats receiving mAb 15A10 and lethal amounts of cocaine. In a model of cocaine addiction, mAb 15A10 blocked completely the reinforcing effect of cocaine in rats. mAb 15A10 blocked cocaine specifically and did not affect behavior maintained by milk or by the dopamine reuptake inhibitor bupropion. This artificial cocaine esterase is a rationally designed cocaine antagonist and a catalytic antibody with potential for medicinal use.

Animals↗
PubMed1998

Naltrexone reduces ethanol- and sucrose-reinforced responding in rhesus monkeys.

These experiments evaluated the ability of naltrexone (NTX) to reduce selectively oral and i.v. ethanol-reinforced responding, and examined the ethanol-NTX interaction in terms of the competitive opioid antagonist property of NTX. Five rhesus monkeys self-administered ethanol or sucrose and concurrently available water. Ethanol concentration was varied from 0.25% to 8% (w/v). Naltrexone (0.032-0.32 mg/kg) or saline was given i.m. 30 min prior to some drinking sessions. NTX (0.32 mg/kg) reduced ethanol-reinforced responding at the concentration that maintained the most responding (1% or 2%). NTX (0.1 mg/kg) reduced ethanol-reinforced responding, both at a low ethanol concentration (0.25%) that produced little ethanol intake (g/kg), and at a higher concentration (4%) with an appreciable intake. Thus, NTX (0.1 mg/kg) shifted the ethanol concentration-consumption curve down, in an insurmountable manner. NTX (0.1 and 0.32 mg/kg) also reduced reinforced responding for sucrose 100 g/l. In another experiment, three rhesus monkeys were given opportunities to self-administer ethanol i.v. NTX (0.1 mg/kg) reduced the number of ethanol injections obtained by the monkeys at all ethanol doses tested (0.01, 0.032, and 0.1 g/kg per injection). The dose-effect curve was also shifted down. These results showed that NTX reduced behavior maintained by either ethanol or sucrose non-selectively. Furthermore, the ability of NTX to suppress ethanol-reinforced responding did not depend on the route of ethanol administration and was not overcome by increasing the concentration or dose per injection of ethanol.

Administration, Oral↗
PubMed1997

Ethanol effects on self-administration of alfentanil, cocaine, and nomifensine in rhesus monkeys.

A common form of polydrug use is that of cocaine and ethanol. The identification of an ethanol-cocaine combination product, cocaethylene, with properties in common with cocaine, has led to speculation that this metabolite may contribute to the co-abuse of cocaine and ethanol. In order to determine whether ethanol pretreatments selectively altered cocaine's reinforcing potency, ethanol pretreatments were given to monkeys trained to press levers and receive IV infusions of several doses of cocaine or alfentanil. In addition, nomifensine, a drug which has a mechanism of action similar to cocaine's, was evaluated in the presence and absence of ethanol in monkeys with the cocaine baseline history. Ethanol, in doses ranging from 100 to 1780 mg/kg, given 10 min before the 130-min session, had no effect on responding maintained by alfentanil. These doses also had no significant effect on cocaine-maintained responding, although the potency of cocaine as a reinforcer was increased following administration of 1000 mg/kg ethanol in two of the four subjects. The potency of nomifensine as a reinforcer was significantly increased by 1000 mg/kg ethanol, but again, this enhancement was limited to the same two subjects. These data indicate that, in this paradigm, cocaethylene did not selectively modify cocaine's reinforcing potency, but there appear to be individual differences with respect to ethanol's ability to stimulate rates of drug-maintained responding.

Alfentanil↗
PubMed1997

Abuse liability of flunitrazepam.

Flunitrazepam is among the most frequently prescribed hypnotics in many countries. Although it was never marketed in the United States, flunitrazepam, in recent years, has been smuggled into the country, and reports of abuse--including alleged use of the drug to facilitate "date rape"--have attracted a great deal of scrutiny. It has been suggested that flunitrazepam may have greater liability for abuse than other benzodiazepines; such suggestions are supported by surveys of opioid abusers, many of whom report a distinct preference for flunitrazepam over other benzodiazepines. Experimental studies of animals and normal human subjects indicate that, although flunitrazepam has high efficacy and is very potent, it is pharmacologically similar to most other benzodiazepines. Although the studies are limited in number and scope, the data show no apparent differences between flunitrazepam and other benzodiazepines in ability to produce drug-taking or drug-seeking behavior, in capacity to produce physiologic dependence, nor in the characteristics of withdrawal after administration of an antagonist or discontinuation of treatment. Similar to other benzodiazepines, flunitrazepam produces dose-dependent effects on psychomotor performance and recall. Flunitrazepam does not seem to be involved in medical emergencies more often than other benzodiazepines, and there is no indication that flunitrazepam is more toxic than other benzodiazepines when taken in overdose by drug abusers or other individuals. Survey research among typical patient populations suggests that flunitrazepam is characteristic of benzodiazepines in that it is used appropriately and conservatively, with low liability for abuse. Thus the reported preference for flunitrazepam among opioid abusers seems to be the only way in which flunitrazepam is distinguished from other benzodiazepines; it is unclear what characteristics of the drug may be responsible for this reported preference. The evidence considered in this review indicates that abuse of flunitrazepam in this special population is not associated with any distinctive threats to the health of the general public.

Animals↗
PubMed1996

Zipeprol: preclinical assessment of abuse potential.

Zipeprol was evaluated in a number of in vitro and in vivo assays predictive of stimulant, depressant, or opioid abuse potential. Zipeprol had affinity for mu and kappa opioid binding sites as well as sigma binding sites. However, it failed to exert opioid-like agonist actions in rodents, and did not attenuate withdrawal signs in morphine- or pentobarbital-dependent rats. Zipeprol did not substitute for either amphetamine or pentobarbital in drug discrimination assays in rhesus monkeys. On the other hand, it suppressed morphine withdrawal signs in rhesus monkeys in two assays, and it acted as a quadazocine-sensitive reinforcer in monkeys trained to self-inject alfentanil. Zipeprol also acted as a reinforcer in monkeys trained to self-inject methohexital. In a dose range of 10-18 mg/kg, zipeprol induced convulsions in monkeys. Zipeprol appears to have abuse potential and a novel spectrum of action involving both opioid and non-opioid effects.

Animals↗
PubMed1995

Current benzodiazepine issues.

This article deals with some of the recent evidence bearing on the issues of the liability of benzodiazepines to lead to abuse, dependence, and adverse behavioral effects. Reviews of epidemiological, clinical and experimental literature indicated that the previous conclusion about abuse of these drugs still holds: the vast majority of the use of benzodiazepines is appropriate. Problems of nonmedical use arise nearly exclusively among people who abuse other drugs. Nevertheless, there are reasons for concern about patients who take benzodiazepines regularly for long periods of time. These drugs can produce physiological dependence when taken chronically, and although this does not appear to result in dose escalation or other evidence of "psychological dependence," physiological dependence can result in patient discomfort if drug use is abruptly discontinued. Also, physicians are currently prescribing shorter-acting benzodiazepines in preference to longer-acting benzodiazepines. The shorter-acting drugs can produce a more intense withdrawal syndrome following chronic administration. Furthermore, rates of use of benzodiazepines increase with age, and elderly patients are more likely than younger ones to take the drug chronically. The clearest adverse effect of benzodiazepines is impairment of memory. This, too, may be particular concern in older patients whose recall in the absence of drug is typically impaired relative to younger individuals, and who are more compromised following drug administration.

Age Factors↗
PubMed1995

Normalized demand for drugs and other reinforcers.

The concepts of behavioral economics have proven to be useful for understanding the environmental control of overall levels of responding for a variety of commodities, including reinforcement by drug self-administration. These general concepts have implications for the assessment of abuse liability and drug abuse intervention and the formulation of public policy on drug abuse. An essential requirement is the ability to compare the demand for different drugs directly in order to assess relative abuse liability, and to compare demand for the same drug under different environmental and biological interventions to assess their ability to reduce demand. Until now, such comparisons were hampered by the confounding effect of varying drug doses and potencies that prevent quantitative comparisons of demand elasticity--sensitivity of consumption and responding to the constraint of price (effort). In this paper we describe a procedure to normalize demand-curve analysis that permits dose- and potency-independent comparisons of demand across drugs. The procedure is shown to be effective for comparing drug demand within and across the drug classes. The technique permits a quantitative ordering of demand that is consistent with the peak levels of responding maintained by the drugs. The same technique is generalized for the comparison of other types of reinforcers under different biological conditions.

Alfentanil↗
PubMed1995

Butorphanol: characterization of agonist and antagonist effects in rhesus monkeys.

The effects of butorphanol were studied in assays of antinociception, respiratory depression, sedation, diuresis and reinforcing effects in rhesus monkeys, and opioid binding in monkey brain. Butorphanol (0.003-0.1 mg/kg s.c.) was effective in the warm-water tail withdrawal assay in 50 degrees C water but not in 55 degrees C. Over a similar dose range, butorphanol caused substantial respiratory depression, without an obvious plateau. Constrained quadazocine apparent pA2 analysis on the respiratory depressant and antinociceptive effects of butorphanol yielded different values between the two assays (respiratory depression pA2 = 6.61; antinociception pA2 = 8.26). Butorphanol (0.1 mg/kg) antagonized the antinociceptive effects of etonitazene in 55 degrees C water, but caused a nonparallel leftward shift in the U50,488 dose-effect curve; both effects were probably due to butorphanol's intermediate efficacy at mu receptors. Butorphanol (0.0001-0.003 mg/kg per injection i.v.) was self-administered; unlike other mu opioid agonists, its maximum effect was depressed after pretreatment with quadazocine (0.01-1.0 mg/kg). Butorphanol (0.003-0.32 mg/kg) was devoid of substantial sedative or muscle relaxant effects, as measured by observational rating scales. Butorphanol (0.01-0.1 mg/kg s.c.), unlike U50,488 (0.01-0.32 mg/kg) did not cause diuresis. Kappa agonist or antagonist effects of butorphanol were not detected in the present studies. This profile is consistent with butorphanol's binding characteristics in rhesus monkey brain which indicated 12-fold mu:kappa selectively and 34-fold mu:delta selectivity.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

Evaluation of the abuse liability of aminorex.

Aminorex is a cyclic phenylisopropylamine that has been marketed as an anorectic. Despite obvious pharmacological similarities to the amphetamines, little is known about its liability for abuse. In the present study, one group of rhesus monkeys (n = 3) was prepared with intravenous catheters and allowed to self-administer either methohexital or saline in daily experimental sessions. When methohexital and saline self-administration were stable and clearly different, various doses of aminorex (0.001-0.1 mg/kg/injection) were made available for self-administration. Aminorex maintained self-administration above that maintained by saline and slightly lower than that maintained by methohexital in all monkeys. The discriminative stimulus effects of aminorex were evaluated in rhesus monkeys trained to discriminate d-amphetamine (n = 3) or pentobarbital (n = 4) from saline. Aminorex substituted completely for d-amphetamine as a discriminative stimulus but engendered little or no pentobarbital-appropriate responding. Aminorex stimulated locomotor activity in mice and exacerbated the withdrawal syndrome in rats that were dependent upon pentobarbital. These findings indicate that aminorex is a psychomotor stimulant that would be predicted to have significant d-amphetamine-like abuse liability in humans.

Aminorex↗
PubMed1994

Behavioral effects of the systemically active delta opioid agonist BW373U86 in rhesus monkeys.

The behavioral effects of (+-)-4-((alpha R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3- hydroxybenzyl)-N,N-diethylbenzamide dihydrochloride (BW373U86), a nonpeptidic, systemically active, delta opioid agonist, were examined in rhesus monkeys. BW373U86, the mu agonist alfentanil and the kappa agonist U69,593 [(5 alpha,7 alpha,8 beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro- (4,5)dec-8-yl)benzeneacetamide] all produced a dose-dependent suppression of response rates maintained under a fixed ratio 30 schedule of food presentation. The rate-suppressing effects of BW373U86 lasted 1 to 2 hr and were no longer apparent after 4 hr. The selective delta antagonist naltrindole (NTI) antagonized the effects of BW373U86 with relatively high potency (pKB = 6.5) and the antagonist effects of NTI against BW373U86 lasted approximately 4 hr. NTI was less potent in antagonizing alfentanil (pKB = 5.1) and the highest dose of NTI examined (10.0 mg/kg) did not antagonize U69,593. BW373U86 did not generalize to the discriminative stimulus effects of the mu agonist alfentanil or the kappa agonist ethylketocyclazocine. BW373U86 also did not produce antinociceptive effects in the warm-water tail-withdrawal procedure, significant respiratory depressant effects in monkeys breathing either air or 5% CO2 or reinforcing effects in a self-administration procedure. The highest dose of BW373U86 examined (1.78 mg/kg) produced convulsions in one monkey. The high relative potency of NTI to antagonize the rate-suppressing effects of BW373U86 was consistent with the characterization of BW373U86 as a systemically active, delta-selective agonist in rhesus monkeys. Under the conditions evaluated in the present study, the delta receptors to which BW373U86 binds do not appear to mediate antinociceptive, respiratory depressant or reinforcing effects in monkeys.

Analgesics↗
PubMed1993

Effects of GBR 12909 and cocaine on cocaine-maintained behavior in rhesus monkeys.

The reinforcing effect of the high affinity dopamine reuptake inhibitor GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl)-4(3- phenylpropyl)piperazine) was compared with that of cocaine, and the effects of both GBR 12909 and cocaine pretreatments were evaluated on behaviour maintained by cocaine in rhesus monkeys. Increasing dose per injection of intravenously-delivered GBR 12909 or cocaine led to increased rates of lever-press responding. Maximum cocaine-maintained rates were higher and occurred at a smaller dose than maximum rates of GBR 12909-maintained responding. Presession intravenous administration of either GBR 12909 or cocaine (0.32, 1.0 or 3.2 mg/kg) resulted in dose-dependent decreases in rates of cocaine-maintained responding when high doses of cocaine, which engendered high response rates, were available early in the session. Under these conditions, the decrease in response rates was associated primarily with decreases in running rate rather than with a lengthening in post-reinforcement pause times. The decreases in running rate produced by both cocaine and GBR 12909 probably reflect an unconditioned rate-disruptive effect of these drugs on cocaine-reinforced responding rather than a reduction in the reinforcing efficacy of cocaine.

Animals↗