Preclinical evaluation of the reinforcing and discriminative stimulus effects of agomelatine (S-20098), a melatonin agonist

Wiley, Jenny L.; Dance, Mario E.; Balster, Robert L.

doi:10.1007/s002130050795

Cited by 16 publications

(9 citation statements)

References 25 publications

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“…However, increasing doses of melatonin were unable to modify the penile erections induced by mCPP and Ro 60-0175. The differences between the results observed with melatonin and agomelatine on penile erections induced mCPP and Ro 60-0175 do not seem to reflect different activities at melatonin receptors since both compounds display very close affinities in the picomolar range at melatonin receptor subtypes, and behave as agonist of melatonin receptors (Grassi-Zucconi et al 1996;Martinet et al 1996;Ying et al 1996;Wiley et al 1998;Conway et al 2000;Weibel et al 2000). The effects of melatonin and agomelatine at MT1/MT2 receptors were observed at low doses with a maximal effect at 5 mg/kg (IP) (Ying et al 1996), whereas the complete inhibition of penile erections induced by 5-HT 2C agonists was observed only at 40 mg/kg agomelatine (IP).…”

Section: Discussioncontrasting

confidence: 49%

Agomelatine(S 20098) antagonizes the penile erections induced by the stimulation of 5-HT 2C receptors in Wistar rats

Chagraoui¹,

Protais²,

Filloux³

et al. 2003

Psychopharmacology

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Agomelatine, an antidepressant with melatonin agonist and 5-HT(2C) antagonist properties, as well as two of its main metabolites, S 21517 (N-[2-(7-hydroxy-1-naphtyl)ethyl]acetamide) and S21540 (N-[2-(3-hydroxy-7-methoxynaphtalen-1-yl)ethyl]acetamide), have been assessed in vitro on pig choroid plexus preparations to determine their affinities for 5-HT(2C) receptors and their effects on inositol phosphate production. These compounds were also tested for their ability to inhibit the penile erections induced by the 5-HT(2C) receptor agonists, m-(chlorophenyl)piperazine (mCPP, 0.75 mg/kg, SC) and Ro 60-0175 (2.5 mg/kg, SC) in Wistar rats. These in vivo effects were compared to those of melatonin and the 5-HT antagonists pizotifen and SB 206,553. Agomelatine and S 21517 had moderate affinity for 5-HT(2C) receptors and behaved in vitro as weak antagonists at this receptor subtype. S 21540 had a 10-fold lower affinity. Pizotifen and SB 206,553 antagonized mCPP- and Ro 60-0175-induced penile erections, suggesting that penile erections induced by mCPP or Ro 60-0175 resulted from the stimulation of 5-HT(2C) receptors. Whereas increasing doses (from 1.25 to 40 mg/kg, IP) of melatonin were unable to modify the penile erections induced by mCPP and Ro 60-0175, agomelatine (from 1.25 to 40 mg/kg, IP) dose-dependently decreased mCPP- as well Ro 60-0175-induced penile erections. Furthermore, increasing doses (from 1.25 to 40 mg/kg, IP) of S 21517 and S 21540, the two main metabolites of agomelatine, did not affect the penile erections induced by mCPP and Ro 60-0175. Considering the similar activity of melatonin and agomelatine at melatonin receptors, these data suggested that the reported effects were not due to the stimulation of melatonin receptors and that, contrary to melatonin, agomelatine exerted 5-HT(2C) receptor antagonist properties in addition to its agonist activity at melatonin receptors. Finally, neither S 21517 nor S 21540 seemed to participate to the observed inhibition of penile erections by agomelatine.

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Section: Discussioncontrasting

confidence: 49%

Agomelatine(S 20098) antagonizes the penile erections induced by the stimulation of 5-HT 2C receptors in Wistar rats

Chagraoui¹,

Protais²,

Filloux³

et al. 2003

Psychopharmacology

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“…In distinction to BZPs, then, modulation of 5-HT release is not involved in the anxiolytic properties of agomelatine (Table 1). In light of evidence that mechanisms underlying the anxiolytic profile of agomelatine differ to those harnessed by clorazepate, it is of interest that agomelatine does not generalize to a discriminative stimulus elicited by a further BZP, diazepam, in rats (Wiley et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade

Millan¹,

Brocco²,

Gobert³

et al. 2004

Psychopharmacology

216

144

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“…They were trained to discriminate 2.5 mg/kg diazepam from an equal volume of vehicle (1:4:5 mixture of ethanol, propylene glycol, and distilled water). A standard two-lever drug discrimination procedure, as used previously [Wiley et al, 1998], was employed. Rats were trained during daily (MondayFriday), 15-min sessions.…”

Section: Materials and Methods Drug Discrimination In Ratsmentioning

confidence: 99%

Preclinical abuse potential assessment of the anticonvulsant zonisamide

Wiley

Patrick

Dance

et al. 2001

Drug Development Research

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Zonisamide (Zonegran ® ) is a broad-spectrum antiepileptic agent that shares some pharmacological properties with other anticonvulsants, including phenytoin, carbamazepine, and valproic acid, but is differentiated from these agents by the ability to significantly block T-type calcium channels. Zonisamide interacts with the γ-amino-butyric acid (GABA) receptor in an allosteric manner, and thus does not modulate GABA receptor effects. However, given the potential of drugs within the latter class for drug abuse in humans, an evaluation of zonisamide for abuse potential is an important component of its potential sideeffect profile. In the present study, zonisamide was tested in animal models of the subjective and reinforcing effects of central nervous system (CNS) depressant drugs, e.g., diazepam discrimination in rats and intravenous self-administration in rhesus monkeys, respectively. In addition, zonisamide was evaluated for physical dependence liability in a chronic infusion model using rats. Zonisamide did not substitute for diazepam in rats trained to discriminate 2.5-mg/kg diazepam from vehicle nor was it self-administered by rhesus monkeys experienced in methohexital-reinforced responding. Continuous infusion of zonisamide (400 or 600 mg/kg/day) did not prevent the loss of body weight associated with discontinued pentobarbital infusion. These doses of zonisamide did produce some incomplete attenuation of observable signs of pentobarbital withdrawal, likely due to direct sedative or depressant effects of these high doses. These results suggest that zonisamide would not produce diazepam-like intoxication in humans nor would it likely be subject to abuse when made more widely available. Further, when administered chronically, zonisamide would not be expected to produce physical dependence of the CNS depressant type. Taken together, these results support the prediction that zonisamide would have low abuse liability. Drug Dev. Res. 54:66-74, 2001.

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Preclinical evaluation of the reinforcing and discriminative stimulus effects of agomelatine (S-20098), a melatonin agonist

Cited by 16 publications

References 25 publications

Agomelatine(S 20098) antagonizes the penile erections induced by the stimulation of 5-HT 2C receptors in Wistar rats

Agomelatine(S 20098) antagonizes the penile erections induced by the stimulation of 5-HT 2C receptors in Wistar rats

Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade

Preclinical abuse potential assessment of the anticonvulsant zonisamide

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