TY - JOUR
T1 - Venlafaxine and its interaction with WAY 100635
T2 - Effects on serotonergic unit activity and behavior in cats
AU - Bjorvatn, Bjørn
AU - Fornal, Casimir A.
AU - Martı́n, Francisco J.
AU - Metzler, Christine W.
AU - Jacobs, Barry L.
N1 - Funding Information:
This work was supported in part by Grant MH-23433 from the National Institute of Mental Health, and by the Norwegian Research Council for Science and the Humanities. F.J.M. was a recipient of a FPI postdoctoral fellowship from the Spanish Government. B.B. was a visiting research scientist from the Department of Physiology, University of Bergen, Bergen, Norway.
PY - 2000/9/15
Y1 - 2000/9/15
N2 - The therapeutic efficacy of antidepressant drugs that inhibit the reuptake of serotonin (5-hydroxytryptamine, 5-HT) may be enhanced by blocking their indirect activation of 5-HT(1A) autoreceptors, which mediate feedback inhibition of serotonergic neuronal activity. In this study, we examined the effects of venlafaxine, a dual 5-HT/noradrenaline reuptake inhibitor, alone and in combination with the selective 5-HT(1A) receptor antagonist N-[2-[4- (2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY 100635), on the single-unit activity of serotonergic dorsal raphe neurons and concurrent behavior in freely moving cats. Systemic administration of venlafaxine (0.05-1.0 mg/kg, i.v.) produced a dose- dependent decrease in firing rate (ED50 = 0.19 mg/kg), with virtually complete inhibition of neuronal discharge at the highest dose tested. The subsequent administration of WAY 100635 (0.1 mg/kg, i.v.) rapidly reversed the neuronal suppression produced by venlafaxine and significantly elevated the firing rate above baseline levels. The overshoot in neuronal activity was associated with the onset of an adverse behavioral reaction resembling the 5- HT syndrome resulting from excessive levels of brain 5-HT. The intensity of this reaction paralleled the degree of neuronal restoration induced by WAY 100635, suggesting a causal relationship. Such behavioral responses were either not observed previously, or of a low intensity, when WAY 100635 was combined with selective 5-HT reuptake inhibitors. Overall, these results suggest that the risk of inducing adverse effects, such as the 5-HT syndrome, may be higher with dual 5-HT/noradrenaline reuptake inhibitors than with selective 5-HT reuptake inhibitors, when these agents are combined with a potent 5-HT(1A) autoreceptor antagonist. Possible mechanisms that might account for these differences in drug interaction are discussed. (C) 2000 Elsevier Science B.V.
AB - The therapeutic efficacy of antidepressant drugs that inhibit the reuptake of serotonin (5-hydroxytryptamine, 5-HT) may be enhanced by blocking their indirect activation of 5-HT(1A) autoreceptors, which mediate feedback inhibition of serotonergic neuronal activity. In this study, we examined the effects of venlafaxine, a dual 5-HT/noradrenaline reuptake inhibitor, alone and in combination with the selective 5-HT(1A) receptor antagonist N-[2-[4- (2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY 100635), on the single-unit activity of serotonergic dorsal raphe neurons and concurrent behavior in freely moving cats. Systemic administration of venlafaxine (0.05-1.0 mg/kg, i.v.) produced a dose- dependent decrease in firing rate (ED50 = 0.19 mg/kg), with virtually complete inhibition of neuronal discharge at the highest dose tested. The subsequent administration of WAY 100635 (0.1 mg/kg, i.v.) rapidly reversed the neuronal suppression produced by venlafaxine and significantly elevated the firing rate above baseline levels. The overshoot in neuronal activity was associated with the onset of an adverse behavioral reaction resembling the 5- HT syndrome resulting from excessive levels of brain 5-HT. The intensity of this reaction paralleled the degree of neuronal restoration induced by WAY 100635, suggesting a causal relationship. Such behavioral responses were either not observed previously, or of a low intensity, when WAY 100635 was combined with selective 5-HT reuptake inhibitors. Overall, these results suggest that the risk of inducing adverse effects, such as the 5-HT syndrome, may be higher with dual 5-HT/noradrenaline reuptake inhibitors than with selective 5-HT reuptake inhibitors, when these agents are combined with a potent 5-HT(1A) autoreceptor antagonist. Possible mechanisms that might account for these differences in drug interaction are discussed. (C) 2000 Elsevier Science B.V.
KW - (Cat)
KW - 5-HT syndrome
KW - 5-HT(1A) autoreceptor
KW - 5-HT(5-hydroxytryptamine, serotonin)
KW - Dorsal raphe nucleus
KW - Venlafaxine
KW - WAY 100635
UR - http://www.scopus.com/inward/record.url?scp=0034666602&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034666602&partnerID=8YFLogxK
U2 - 10.1016/S0014-2999(00)00622-1
DO - 10.1016/S0014-2999(00)00622-1
M3 - Article
C2 - 10980270
AN - SCOPUS:0034666602
SN - 0014-2999
VL - 404
SP - 121
EP - 132
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-2
ER -