Evaluation of nefazodone self-administration in rhesus monkeys

doi:10.1016/0376-8716(91)90057-6

Drug and Alcohol Dependence

Volume 28, Issue 3, October 1991, Pages 241-247

https://doi.org/10.1016/0376-8716(91)90057-6 Get rights and content

Abstract

Intravenous self-administration of nefazodone, a potential new antidepressant medication, was evaluated using a substitution procedure in rhesus monkeys. Subjects had established stable rates of responding for cocaine (0.033 mg/kg per infusion) under a fixed-ratio 10 schedule during 60-min sessions each day. Various doses of nefazodone hydrochloride (0.03–0.3 mg/kg per infusion) were substituted for cocaine for four consecutive daily self-administration sessions. Compared to rates of responding obtained during saline substitutions, nefazodone failed to function as a reinforcer when substituted for cocaine. In only one monkey, at one dose, did the rate of responding exceed the range of saline responding; an effect not observed in two subsequent replications in that subject. In all three monkeys, the total number of infusions tended to decrease during the 4-day nefazodone substitution and the majority of nefazodone infusions occurred during the first quarter of each session, with few infusions occurring in the latter three-quarters. Overall intake of nefazodone increased as a function of dose per infusion. Such a result is expected when response rates do not vary with dose, which is more likely to occur when a test drug is not a reinforcer. In summary, the present results provide no evidence of reinforcing effects with nefazodone and suggest that it would possess little or no abuse liability.

References (20)

N.A. Ator et al.
Self-administration of barbiturates and benzodiazepines: A review
Pharmacol. Biochem. Behav.
(1987)
R.L. Balster et al.
A comparison of damphetamine, l-amphetamine and methamphetamine self-administration in rhesus monkeys
Pharmacol. Biochem. Behav.
(1973)
D.C.S. Roberts et al.
On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine
Pharmacol. Biochem. Behav.
(1977)
G. Winger et al.
Comparison of fixedratio and progressive ratio schedules of maintenance of stimulant drug-reinforced responding
Drug Alcohol Depend.
(1985)
R.L. Balster et al.
Intravenous buspirone self-administration in rhesus monkeys
J. Clin. Psychiatry
(1982)
M.F. D'Amico et al.
Placebo-controlled dose-ranging trial designs in Phase II development of nefazodone
Psychopharmacol. Bull.
(1990)
G. Deneau et al.
Self-administration of psychoactive substances by the monkey
Psychopharmacologia
(1969)
A.S. Eison et al.
Nefazodone: Preclinical pharmacology of a new antidepressant
Psychopharmacol. Bull.
(1990)
J.P. Feighner et al.
A comparison of nefazodone, imipramine, and placebo in patients with moderate to severe depression
Psychopharmacol. Bull.
(1989)
R.M. Ferris et al.
Some neurochemical properties of a new antidepressant, bupropion hydrochloride (Wellbutrin)
Drug Dev. Res.
(1981)

There are more references available in the full text version of this article.

Cited by (13)

Use of in vitro models in drug development and issue resolution
2018, Advanced Issue Resolution in Safety Pharmacology
It has been a goal of the pharmaceutical industry to provide drugs with as few side effects as possible. In vitro off-target pharmacology assay, which includes receptors, enzymes, and ion channels, is a cost-effective way to increase efficiency in the drug discovery process to achieve that goal. Early in a project, the chemical scaffolds of interest are subjected to a panel of assays. The panel includes not only closely related targets but also targets that are known to have adverse or intolerable side effect in the patient population. The number of assays to include in the panel can get quite extensive and cost-prohibitive, but scientific expertise and experience can help limit the panel to targets that have been shown to be more promiscuous. In addition, the development of in silico modeling using 3-D structures of targets and chemical similarity searches can be used to identify targets of concern. Once the panel for a particular project is identified, the typical approach is to screen the targets using receptor binding. To verify the interactions are truly pharmacological, the hit need to be followed-up with full concentration response curves and functional assays to eliminate false positives. Early in the development process, the prudent use of in vitro pharmacology assays is of significant value to identify selective compounds for the intended target-limiting potential adverse side effects.
The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse?
2006, Neuroscience and Biobehavioral Reviews
In this review we will critically assess the hypothesis that the reinforcing effect of virtually all drugs of abuse is primarily dependent on activation of the mesolimbic dopamine system. The focus is on five classes of abused drugs: psychostimulants, opiates, ethanol, cannabinoids and nicotine. For each of these drug classes, the pharmacological and physiological mechanisms underlying the direct or indirect influence on mesolimbic dopamine transmission will be reviewed. Next, we evaluate behavioral pharmacological experiments that specifically assess the influence of activation of the mesolimbic dopamine system on drug reinforcement, with particular emphasis on animal experiments using drug self-administration paradigms. There is overwhelming evidence that all five classes of abused drugs increase dopamine transmission in limbic regions of the brain through interactions with a variety of transporters, ionotropic receptors and metabotropic receptors. Behavioral pharmacological experiments indicate that increased dopamine transmission is clearly both necessary and sufficient to promote psychostimulant reinforcement. For the other four classes of abused substances, self-administration experiments suggest that although increasing mesolimbic dopamine transmission plays an important role in the reinforcing effects of opiates, ethanol, cannabinoids and nicotine, there are also dopamine-independent processes that contribute significantly to the reinforcing effects of these compounds.
A comparison of the reinforcing efficacy of 3,4- methylenedioxymethamphetamine (MDMA, "ecstasy") with cocaine in rhesus monkeys
2005, Drug and Alcohol Dependence
The purpose of the present study was to compare the reinforcing efficacy of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) to cocaine. Rhesus monkeys (n = 4) responded under a within-session, exponentially increasing, progressive-ratio (PR) schedule of cocaine reinforcement. Breaking point (BP) for the PR schedule was defined as the final response requirement completed before 2 h had elapsed without an injection delivered. Saline and doses of cocaine (0.003–0.3 mg/kg/injection) and MDMA (0.01–0.56 mg/kg/injection) were substituted for the training dose of cocaine for at least five consecutive sessions. Both cocaine and MDMA functioned as reinforcers, but self-administration of MDMA occurred at fewer doses and a significantly lower peak BP was obtained for MDMA. These data demonstrate that MDMA functions as a reinforcer, although its reinforcing efficacy appears to be less than that of cocaine.
Evaluation of the reinforcing effects of the cannabinoid CB<inf>1</inf> receptor antagonist, SR141716, in rhesus monkeys
2002, European Journal of Pharmacology
The abuse liability of a selective cannabinoid CB₁ receptor antagonist, SR141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide hydrochloride), was evaluated in rhesus monkeys. Four rhesus monkeys with chronically indwelling venous catheters were initially trained to self-administer cocaine (30 μg/kg/injection) during daily 1-h sessions under a fixed ratio 50 (FR50) schedule of reinforcement. SR141716 was subsequently substituted for cocaine, and SR141716 dose was varied from 1 to 100 μg/kg/injection. Each dose of SR141716 was tested for four consecutive sessions and each unit dose was separated by at least three sessions of cocaine self-administration. Substitution of SR141716 for cocaine resulted in rapid extinction of lever pressing and none of the doses of SR141716 tested was self-administered above the vehicle levels. When the highest dose of SR141716 (100 μg/kg/injection) was evaluated, self-administration behavior was suppressed below vehicle levels suggesting that behaviorally active doses were evaluated. Since positive results in self-administration tests are generally predictive of abuse potential, the negative results with SR141716 suggest that this drug would likely have low abuse liability.
Nefazodone attenuates the behavioral and neurochemical effects of ethanol
1998, Alcohol
This study evaluated the influence of nefazodone, a combined 5-HT_2A receptor antagonist and 5-HT reuptake inhibitor, on the behavioral and neurochemical effects of ethanol in nonselected male Wistar rats. In microdialysis experiments, ethanol (2.5 g/kg, IP) increased extracellular accumbal dopamine levels by 36% (p = 0.0073) compared to baseline levels, and elevated the maximal DOPAC and HVA levels by 26% (p = 0.0093) and 52% (p = 0.0010), respectively. Nefazodone (50 mg/kg, SC) per se increased accumbal dopamine levels by 28% (p = 0.0199), but, when injected 40 min before ethanol, reduced the ethanol-induced elevation of accumbal dopamine overflow (p = 0.0132) and decreased the ethanol-induced HVA levels (p = 0.0159). In an ethanol(6% v/v)/water free-choice paradigm, nefazodone (50 mg/kg, SC) decreased ethanol intake by 51% (p = 0.0251) and preference by 22% (p = 0.0251) in high- but not low-preferring rats from a nonselected Wistar strain. These results show that nefazodone modulates the mesolimbic dopamine system in a dopamine activity-dependent manner, and influences the neurochemical and behavioral effects of ethanol in the rat.
Repeated MDMA administration increases MDMA-produced locomotor activity and facilitates the acquisition of MDMA self-administration: role of dopamine D<inf>2</inf> receptor mechanisms.
2017, Psychopharmacology

View all citing articles on Scopus

View full text

Evaluation of nefazodone self-administration in rhesus monkeys

Abstract

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Drug Alcohol Depend.

Intravenous buspirone self-administration in rhesus monkeys

J. Clin. Psychiatry

Placebo-controlled dose-ranging trial designs in Phase II development of nefazodone

Psychopharmacol. Bull.

Self-administration of psychoactive substances by the monkey

Psychopharmacologia

Nefazodone: Preclinical pharmacology of a new antidepressant

Psychopharmacol. Bull.

A comparison of nefazodone, imipramine, and placebo in patients with moderate to severe depression

Psychopharmacol. Bull.

Some neurochemical properties of a new antidepressant, bupropion hydrochloride (Wellbutrin)

Drug Dev. Res.