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Psychopharmacological profile of the selective serotonin reuptake inhibitor, paroxetine: implication of noradrenergic and serotonergic mechanisms

GIS Médicament, JE 2027 Neurobiologie de l'anxieté, Faculté de Médecine BP 53508, 1 rue Gaston Veil, 44035 Nantes cedex, France

Michel Bourin

GIS Médicament, JE 2027 Neurobiologie de l'anxieté, Faculté de Médecine BP 53508, 1 rue Gaston Veil, 44035 Nantes cedex, France

Marie Claude Colombel

GIS Médicament, JE 2027 Neurobiologie de l'anxieté, Faculté de Médecine BP 53508, 1 rue Gaston Veil, 44035 Nantes cedex, France

Glen B. Baker

GIS Médicament, JE 2027 Neurobiologie de l'anxieté, Faculté de Médecine BP 53508, 1 rue Gaston Veil, 44035 Nantes cedex, France

The present study was designed to evaluate the psychopharmacological profile of the selective serotonin reuptake inhibitor paroxetine, and thus assess potential noradrenergic and/or serotonergic activity. Paroxetine dose-dependently increased mobility time in the mouse forced swimming test (8, 16, 32 and 64 mg/ kg, i.p.) and reduced spontaneous locomotor activity when administered at a high dose (64 mg/kg, i.p.). Prior administration of 8-hydroxy-2-(di-n-propylamino)tetralin (1 mg/kg, i.p.), (±) pindolol (32 mg/kg, i.p.) or 5- methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU 24969) (1 mg/kg, i.p.) potentiated the antidepressant- like effects of subactive doses of paroxetine (1, 2 and 4 mg/kg, i.p.) in the mouse forced swimming test. These effects were antagonized by prior administration of 1-(2-methoxyphenyl)-4-[-(2-phthalimido)butyl]piperazine) (0.5 mg/kg, i.p.). Complementary studies suggested that RU24969-induced anti-immobility effects were a result of an increase in locomotor activity; other interactions were without increase/decrease in locomotor activity. Acute administration of paroxetine (8,16, and 32 mg/kg, i.p.) antagonized the hypothermia induced by the D₂/D₁ receptor agonist, apomorphine (16 mg/kg, s.c.), while repeated treatment with paroxetine (32 mg/kg) attenuated clonidine-induced (0.5 mg/kg, i.p.) hypothermia. Pre-treatment with the serotonergic neurotoxin, para chlorophenylalanine attenuated the anti-immobility effects of low doses of paroxetine (8 and 16 mg/kg, i.p.) in the forced swimming test, whereas a higher dose of paroxetine remained active (32 mg/kg, i.p.). The results of the present study indicated that paroxetine displayed both noradrenergic-like and serotonergic-like activity in the pre-clinical psychopharmacological tests employed.

Key Words: apomorphine • clonidine • forced swimming test • noradrenaline • paroxetine • serotonin

Journal of Psychopharmacology, Vol. 12, No. 4, 348-355 (1998)
DOI: 10.1177/026988119801200404


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