Evaluation of nefazodone self-administration in rhesus monkeys

Gold, Lisa; Balster, Robert L.

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

Cited by 12 publications

(6 citation statements)

References 11 publications

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“…Furthermore, drugs that increase synaptic 5-HT typically do not maintain self-administration (Gold and Balster, 1991;Vanover et al, 1992). The data from those studies imply that increased extracellular 5-HT can have a negative impact on the reinforcing efficacy of psychostimulants.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the 5-HTT-selective cocaine analog HD-60 functioned robustly as a reinforcer in monkeys, but did not maintain self-administration at any dose in rats. Because earlier studies demonstrated that drugs acting preferentially at 5-HTT typically do not maintain responding in nonhuman primates (Gold and Balster, 1991;Vanover et al, 1992), the selectivity of HD-60 for the three monoamine transporter types was assessed in vitro using monkey brain tissue (experiment 3). The results from that experiment confirm that the monoamine transporter selectivity of the cocaine analogs (including HD-60) in monkey brain is in agreement with the data from in vitro binding studies in rodent tissue (Bennett et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…However, there are few data concerning the reinforcing efficacy of compounds selective for 5-HTT. In general, drugs that increase synaptic 5-HT do not maintain selfadministration (Gold and Balster, 1991;Vanover et al, 1992;Roberts et al, 1999), although there may be exceptions (Fantegrossi et al, 2002). There is even less information available on the interactions of psychostimulants with the norepinephrine system.…”

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confidence: 99%

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The Reinforcing Efficacy of Psychostimulants in Rhesus Monkeys: The Role of Pharmacokinetics and Pharmacodynamics

Lile

Wang²,

Woolverton³

et al. 2003

J Pharmacol Exp Ther

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This study was undertaken to investigate pharmacological variables that influence the reinforcing efficacy of psychostimulants. Rhesus monkeys (n ϭ 9) responded under a withinsession, exponentially increasing, progressive ratio schedule of cocaine reinforcement. Doses of cocaine, methylphenidate (MP), cocaine analogs [(Ϯ)-2␤-propanoyl-3␤-(2-naphthyl)-tropane (WF-23), HD-23; (Ϯ)-2␤-propanoyl-3␤-(2-isopropenyl)-tropane (WF-60), HD-60; and 2␤-propanoyl-3␤-(4-tolyl)-tropane (HD-11, WF-11), and 2␤-propanoyl-3␤-(4-tolyl)-tropane (HD-11, WF-11), PTT], and MP analogs [(␣R,2R)-␣-(2-naphthalenyl)-2-piperidineacetic acid methyl ester, HDMP-28; and (␣R,2S)-␣-(2-naphthalenyl)-2-pyrrolideneacetic acid methyl ester, HDMP-29] that varied in their pharmacokinetic and pharmacodynamic properties were substituted for cocaine. These drugs were chosen according to their selectivity for dopamine transporters (DAT) and 5-hydroxytryptamine (serotonin) transporters (5-HTT) as assessed in rodents and their duration of action. In addition, data pertaining to the rate of onset at DAT were collected for the cocaine analogs using an ex vivo binding assay in rodent tissue. Finally, the pharmacodynamic profile of select drugs was confirmed in primate brain tissue. All drugs had reinforcing effects except HDMP-29. The rank ordering of the peak breaking points (BPs) was cocaine ϭ MP ϭ HDMP-28 Ն HD-60 Ն PTT Ն HD-23 Ͼ HDMP-29. The time to peak DAT occupancy for the cocaine analogs was greater than 30 min. The potency to maintain peak BP was significantly correlated with DAT affinity. There was not a linear relationship between monoamine transporter affinity and reinforcing efficacy, but it appeared that in nonhuman primates there is a range of DAT affinity under which maximal responding is maintained. Interestingly, the 5-HTT-selective cocaine analog HD-60 functioned robustly as a reinforcer at several doses in all monkeys tested. These data question the dogma regarding the role of pharmacokinetic factors and the relative influence of DAT and 5-HTT in stimulant reinforcement.Although the use of psychomotor stimulants such as cocaine and various amphetamine derivatives has remained stable over the past several years (SAMHSA, 2001), an effective pharmacotherapy has yet to be developed. An understanding of the pharmacological properties that mediate the abuse liability of these drugs will assist in the design of treatments for psychostimulant abuse and dependence and result in a better understanding of addiction. Animal models of drug self-administration have allowed for the systematic investigation of drug-reinforced behavior; however, the variables that influence the reinforcing efficacy of psychostimulants are still not fully understood.One pharmacological attribute common to psychostimu-

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Reinforcing Efficacy of Psychostimulants in Rhesus Monkeys: The Role of Pharmacokinetics and Pharmacodynamics

Lile

Wang²,

Woolverton³

et al. 2003

J Pharmacol Exp Ther

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“…Findings from CPP studies with the 5-HTT inhibitor fluoxetine, were equally inconsistent; fluoxetine facilitated the acquisition of CPP in 3 out of the 4 studies that it was tested [171,170,172,173]. In a preliminary study, fluoxetine did not function as a reinforcer in monkeys [169], consistent with what has been found with other inhibitors of 5-HT transport that have been made available for SA [199,200,201]. In contrast, 3,4methylenedioxymethamphetamine (MDMA; ecstasy) and the methylenedioxy analogues 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxy-N-ethylamphetamine (MDE) are believed to act primarily at 5-HTT and 5-HT receptors, but maintain responding when made available for self-administration [202,203,77,204].…”

Section: Vd 5-ht Involvementmentioning

confidence: 59%

The Abuse Liability and Therapeutic Potential of Drugs Evaluated for Cocaine Addiction as Predicted by Animal Models

Lile¹,

Nader²

2003

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One strategy in the search for a pharmacotherapy for cocaine abuse and dependence has been to use drugs with a similar mechanism of action as cocaine, or agonist substitution therapy. Research has indicated that cocaine's behavioral effects are primarily a result of its blockade of the dopamine (DA), serotonin (5-HT) and norepinephrine (NE) transporters. Therefore, drugs that act either directly or indirectly at these monoamine systems have been investigated for their potential as replacement medications for cocaine addiction. The intent of this review was to present data from animal models that assessed the reinforcing effects of these monoamine agonists using drug self-administration, and the rewarding effects, using the conditioned place preference paradigm. Those data were then compared to the abuse liability of the selected drugs in humans and to their efficacy as therapeutics for treating cocaine addiction to determine if animal models of reinforcing and rewarding effects were predictive of these drugs' effects in humans. Fourteen drugs with a primary mechanism of action at either the DA, 5-HT or NE systems were identified that had been tested as potential treatments for cocaine addiction and had also been evaluated in either the self-administration or conditioned place preference paradigms in animals. From these comparisons, it was concluded that the animal models were, in general, predictive of the abuse liability of these monoamine agonists in humans. However, monoamine agonists with reinforcing or rewarding effects did not affect the desired treatment outcomes for cocaine addiction.

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“…sertraline Ð Zawertailo et al, 1995) and in animal models (e.g. nefazodone Ð Gold and Balster, 1991). SSRIs often cause anxiety early in treatment (Lipinski et al, 1989) and in normal controls imipramine has been shown to cause transient dysphoria (Oswald et al, 1972).…”

Section: Pharmacological Issuesmentioning

confidence: 99%

Do antidepressants have any potential to cause addiction?

Haddad

1999

J Psychopharmacol

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Addiction/dependence is a syndrome in which the hallmark is a compulsive pattern of drug use. Most authorities do not regard antidepressants as causing addiction but this has been challenged. This debate is explored drawing on case reports and related clinical and pharmacological data. An extensive literature review identified 21 English language case reports of antidepressant addiction (DSM-IV 'substance dependence' criteria) published since 1963. Sixteen involved tranylcypromine or amineptine and may reflect their dopaminergic and stimulant properties. Subject characteristics included male sex (14/21), personality problems (10/21) and prior substance misuse (14/21). Withdrawal or discontinuation symptoms have long been recognized with antidepressants but other features of addiction such as tolerance and compulsive use are exceptionally rare. Common clinical problems are patients taking subtherapeutic dosages and prematurely stopping antidepressants. The pharmacodynamic profiles of most antidepressants and the absence of acute 'desirable' effects make addiction theoretically unlikely. It is concluded that, with the exception of tranylcypromine and amineptine, antidepressants do not have a clinically significant liability to cause addiction. Tranylcypromine and amineptine should be avoided in those with a history of substance misuse. Patients prescribed other antidepressants should be told that they are not addictive.

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Evaluation of nefazodone self-administration in rhesus monkeys

Cited by 12 publications

References 11 publications

The Reinforcing Efficacy of Psychostimulants in Rhesus Monkeys: The Role of Pharmacokinetics and Pharmacodynamics

The Reinforcing Efficacy of Psychostimulants in Rhesus Monkeys: The Role of Pharmacokinetics and Pharmacodynamics

The Abuse Liability and Therapeutic Potential of Drugs Evaluated for Cocaine Addiction as Predicted by Animal Models

Do antidepressants have any potential to cause addiction?

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