Substitution and cross-tolerance profiles of anorectic drugs in rats trained to detect the discriminative stimulus properties of cocaine

Wood, Douglas M.; Emmett‐Oglesby, M. W.

doi:10.1007/bf00181948

Cited by 53 publications

(26 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Phenmetrazine is a schedule II stimulant that was once approved as an appetite suppressant, but its use was discontinued due to high abuse potential (Silverstone, 1992). Phenmetrazine substituted for the discriminative stimulus effects of cocaine in rats and amphetamine in monkeys, maintained self-administration in monkeys and humans, and produced prototypical stimulant-like subjective effects in humans (Griffiths et al, 1976;Chait et al, 1987;de la Garza and Johanson, 1987;Wood and Emmett-Oglesby, 1988). To our knowledge, this is the first report of the cocaine-like effects of 4-benzylpiperidine; however, its robust cocaine-like discriminative stimulus effects and rapid onset of action suggest that it too would have high abuse liability in humans.…”

Section: Discussionmentioning

confidence: 99%

Selective Suppression of Cocaine- versus Food-Maintained Responding by Monoamine Releasers in Rhesus Monkeys: Benzylpiperazine, (+)Phenmetrazine, and 4-Benzylpiperidine

Negus

Baumann²,

Rothman³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Monoamine releasers constitute one class of drugs currently under investigation as potential agonist medications for the treatment of cocaine dependence. The efficacy and safety of monoamine releasers as candidate medications may be influenced in part by their relative potency to release dopamine and serotonin, and we reported previously that releasers with approximately 30-fold selectivity for dopamine versus serotonin release may be especially promising. The present study examined the effects of the releasers benzylpiperazine, (ϩ)phenmetrazine, and 4-benzylpiperidine, which have 20-to 48-fold selectivity in vitro for releasing dopamine versus serotonin. In an assay of cocaine discrimination, rhesus monkeys were trained to discriminate 0.4 mg/kg i.m. cocaine from saline in a two-key, food-reinforced procedure. Each of the releasers produced a dose-and time-dependent substitution for cocaine. 4-Benzylpiperidine had the most rapid onset and shortest duration of action. Phenmetrazine and benzylpiperazine had slower onsets and longer durations of action. In an assay of cocaine self-administration, rhesus monkeys were trained to respond for cocaine injections and food pellets under a second order schedule. Treatment for 7 days with each of the releasers produced a dose-dependent and selective reduction in self-administration of cocaine (0.01 mg/kg/injection). The most selective effects were produced by phenmetrazine. Phenmetrazine also produced a downward shift in the cocaine self-administration dose effect curve, virtually eliminating responding maintained by a 30-fold range of cocaine doses (0.0032-0.1 mg/ kg/injection) while having only small and transient effects on foodmaintained responding. These findings support the potential utility of dopamine-selective releasers as candidate treatments for cocaine dependence.

show abstract

Section: Discussionmentioning

confidence: 99%

Selective Suppression of Cocaine- versus Food-Maintained Responding by Monoamine Releasers in Rhesus Monkeys: Benzylpiperazine, (+)Phenmetrazine, and 4-Benzylpiperidine

Negus

Baumann²,

Rothman³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…PHEN is self-administered by Rhesus monkeys (Gri¦ths et al 1976), whereas FEN is not self-administered (Woods and Tessel 1974;Gri¦ths et al 1976). In drug discrimination tests, PHEN substitutes for the cocaine discriminative stimulus whereas FEN does not (Wood and Emmett-Oglesby 1988). Evidence with amphetamine, a drug with a pharmacological proÞle similar to PHEN indirectly conÞrms the dissimilarity between these two class of drugs.…”

Section: Introductionmentioning

confidence: 93%

Behavioural and neurochemical characteristics of phentermine and fenfluramine administered separately and as a mixture in rats

et al. 1997

View full text Add to dashboard Cite

Clinical case studies suggest that combined administration of the serotonergic agent fenfluramine (FEN) and the weak amphetamine-like anorexic agent phentermine (PHEN) may be useful in the treatment of alcohol and cocaine addictions. The present experiment examined the nature of the interaction between the two agonists using the drug discrimination paradigm. In vivo microdialysis served to examine the neurochemical profile of dopamine and serotonin release in the nucleus accumbens. In conscious rats, acute injections of FEN (1.0-2.0 mg/kg i.p.) or PHEN (1.0-2.0 mg/kg i.p.) selectively elevated levels of serotonin and dopamine in the nucleus accumbens, respectively. A mixture (1 mg/kg of each) increased levels of both amines by similar magnitudes to those observed with each individually. Three groups of Sprague-Dawley rats were trained to discriminate (1) FEN (1.0 mg/kg i.p.) alone, (2) PHEN (1.0 mg/kg i.p.) alone or a mixture (3) PHEN+FEN (1 mg/kg of each, i.p.) from saline under a fixed ratio (FR-10) schedule of food reinforcement. Rats acquired the mixture discrimination rapidly, while for the other groups the training dose had to be increased to 2.0 mg/kg to attain stimulus control. The individual components of the mixture at the training dose generalized partially to the mixture, and complete generalisation was observed following 3.0 mg/kg FEN or PHEN. Rats trained to discriminate the individual components showed respective cross-generalisation profiles. Generalisation to cocaine (0.3-10.0 mg/kg i.p.), amphetamine (0.1-3.0 mg/kg i.p.) and nicotine (0.1-0.8 mg/kg s.c.) was greatest in the MIX-trained rats, while partial or no generalisation was observed in rats trained to discriminate the individual compounds. From the present results, it may be concluded that the two drugs given as a mixture do not produce a novel cue. Rather, these aminergics appear to interact additively. Furthermore, the dual stimulation of the amines by the mixture may be the basis for the cueing effects of the FEN+PHEN drug mixture, and its effectiveness in treating drug addictions.

show abstract

“…The results of the present study agree with previous findings that dopamine/norepinephrineselective releasers substitute more effectively than serotonin-selective releasers for a cocaine training stimulus in drug discrimination studies. For example, amphetamine substituted for cocaine in rats and rhesus monkeys trained to discriminate cocaine from saline, whereas fenfluramine did not (D 'Mello and Stolerman, 1977;Schuster and Johanson, 1985;Wood and Emmett-Oglesby, 1988). Likewise, cocaine and amphetamine produced relatively similar profiles of discriminative and subjective effects in humans, whereas fenfluramine did not produce stimulant-like subjective effects (Chait et al, 1986;Oliveto et al, 1998).…”

Section: Drugmentioning

confidence: 99%

Monoamine Releasers with Varying Selectivity for Dopamine/Norepinephrine versus Serotonin Release as Candidate “Agonist” Medications for Cocaine Dependence: Studies in Assays of Cocaine Discrimination and Cocaine Self-Administration in Rhesus Monkeys

Negus¹,

Mello²,

Blough³

et al. 2006

J Pharmacol Exp Ther

114

View full text Add to dashboard Cite

Monoamine releasers constitute one class of drugs under investigation as candidate medications for the treatment of cocaine abuse. Promising preclinical and clinical results have been obtained with amphetamine, which has high selectivity for releasing dopamine/norepinephrine versus serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that nonselective monoamine releasers or serotoninselective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine. To address this issue, the present study evaluated the effects of five monoamine releasers in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. The releasers varied along a continuum from dopamine/norepinephrine-selective to serotonin-selective [m-fluoroamphetamine (PAL-353), methamphetamine, m-methylamphetamine (PAL-314), 1-napthyl-2-aminopropane (PAL-287), fenfluramine]. In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine (0.4 mg/kg i.m.) in a two-key, foodreinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/norepinephrine versus serotonin release. In drug selfadministration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/injection) and food (1-g pellets) under a second-order fixed-ratio 2 (variable-ratio 16:S) schedule. In general, monoamine releasers produced dose-dependent and sustained decreases in cocaine self-administration. However, the dopamine/norepinephrine-selective releasers decreased cocaine self-administration with minimal effects on foodmaintained responding, whereas the more serotonin-selective releasers produced nonselective reductions in both cocaineand food-maintained responding. These results are consistent with the conclusion that dopamine/norepinephrine-selective releasers retain cocaine-like abuse-related effects but may also be capable of producing relatively selective reductions in the reinforcing effects of cocaine.Cocaine abuse and dependence constitute a significant public health problem, and reliable pharmacotherapies are not yet available (Mendelson and Mello, 2004;Vocci et al., 2005). One potential approach to the treatment of cocaine dependence has been suggested by the effective treatment of opioid dependence with opioid agonists such as methadone and of tobacco dependence with formulations of nicotine. These medications share pharmacological mechanisms of action with the abused drug and produce some effects in common with the abused drug, and they have been referred to as "agonist" medications (Rothman and Glowa, 1995). Cocaine blocks the reuptake of dopamine, serotonin, and norepinephrine, and the abuse-related effects of cocaine are thought to be mediated primarily by its dopaminergic effects (

show abstract

Substitution and cross-tolerance profiles of anorectic drugs in rats trained to detect the discriminative stimulus properties of cocaine

Cited by 53 publications

References 19 publications

Selective Suppression of Cocaine- versus Food-Maintained Responding by Monoamine Releasers in Rhesus Monkeys: Benzylpiperazine, (+)Phenmetrazine, and 4-Benzylpiperidine

Selective Suppression of Cocaine- versus Food-Maintained Responding by Monoamine Releasers in Rhesus Monkeys: Benzylpiperazine, (+)Phenmetrazine, and 4-Benzylpiperidine

Behavioural and neurochemical characteristics of phentermine and fenfluramine administered separately and as a mixture in rats

Monoamine Releasers with Varying Selectivity for Dopamine/Norepinephrine versus Serotonin Release as Candidate “Agonist” Medications for Cocaine Dependence: Studies in Assays of Cocaine Discrimination and Cocaine Self-Administration in Rhesus Monkeys

Contact Info

Product

Resources

About