S33005, a novel ligand at both serotonin and norepinephrine transporters: II. Behavioral profile in comparison with Venlafaxine ( Effexor ), reboxetine, Citalopram ( Celexa ), and clomipramine.

Reflecting its potent inhibition of serotonin (5-HT) reuptake (accompanying paper), S33005 blocked spontaneous tail-flicks induced by parachloroamphetamine in rats. This action was mimicked by the 5-HT reuptake inhibitor, Citalopram ( Celexa ), and the 5-HT/norepinephrine (NE) reuptake inhibitor, Venlafaxine ( Effexor ), whereas the preferential NE reuptake inhibitor, reboxetine, was inactive. Consistent with its less potent interaction with NE transporters, higher doses of S33005 attenuated induction of hypothermia by reserpine, an action mimicked by reboxetine and Venlafaxine ( Effexor ), whereas Citalopram ( Celexa ) was ineffective. In mice, S33005 reduced immobility in forced-swim and tail-suspension procedures. It also inhibited marble-burying behavior and suppressed aggressive behavior between resident and intruder animals. In rats, S33005 generalized to a discriminative stimulus elicited by Citalopram ( Celexa ) and attenuated hypnotic-sedative actions of the alpha2-adrenoceptor agonist, S18616. For these parameters, S33005 was a more potent agent (median, 1.2 mg/kg, s.c.) than Venlafaxine ( Effexor ), Citalopram ( Celexa ), reboxetine, or the tricyclic agent, clomipramine. Even at markedly higher doses (40.0-80.0 mg/kg, s.c.), S33005 little affected motor behavior. S33005 (10.0 mg/kg, s.c.) also increased responses in a learned helplessness paradigm in rats, whereas Venlafaxine ( Effexor ) was ineffective. Finally, in a rat chronic mild-stress model, S33005 dose- (2.5-40.0 mg/kg) and time- (2-5 weeks) dependently enhanced sucrose consumption. Venlafaxine ( Effexor ) was likewise active in this procedure. In conclusion, in line with its inhibition of 5-HT and (less potently) NE reuptake, S33005 is active in a broad range of models suggestive of antidepressant activity. It exerts its actions more potently than Venlafaxine ( Effexor ) and clomipramine, and its overall profile is distinct from those of Citalopram ( Celexa ) and reboxetine.

Receptors control the firing of serotoninergic neurons in the dorsal raphe nucleus of the mouse: studies in 5-HT1B knock-out mice.

The characteristics of the spontaneous firing of serotoninergic neurons in the dorsal raphe nucleus and its control by serotonin (5-hydroxytryptamine, 5-HT) receptors were investigated in wild-type and 5-HT1B knock-out (5-HT1B-/-) mice of the 129/Sv strain, anaesthetized with chloral hydrate. In both groups of mice, 5-HT neurons exhibited a regular activity with an identical firing rate of 0.5-4.5 spikes/s. Intravenous administration of the 5-HT reuptake inhibitor Citalopram ( Celexa ) or the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) induced a dose-dependent inhibition of 5-HT neuronal firing which could be reversed by the selective 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xane carboxamide (WAY 100635). Both strains were equally sensitive to 8-OH-DPAT (ED50 approximately 6.3 microgram/kg i.v.), but the mutants were less sensitive than wild-type animals to Citalopram ( Celexa ) (ED50 = 0.49 +/- 0.02 and 0.28 +/- 0.01 mg/kg i.v., respectively, P < 0.05). This difference could be reduced by pre-treatment of wild-type mice with the 5-HT1B/1D antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carbox yli c acid [4-methoxy-3-(4-methyl-piperazine-1-yl)-phenyl]amide (GR 127935), and might be accounted for by the lack of 5-HT1B receptors and a higher density of 5-HT reuptake sites (specifically labelled by Citalopram ( Celexa )) in 5-HT1B-/- mice. In wild-type but not 5-HT1B-/- mice, the 5-HT1B agonists 3-(1,2,5, 6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94253, 3 mg/kg i.v.) and 5-methoxy-3-(1,2,3, 6-tetrahydropyridin-4-yl)-1H-indole (RU 24969, 0.6 mg/kg i.v.) increased the firing rate of 5-HT neurons (+22.4 +/- 2.8% and +13.7 +/- 6.0%, respectively, P < 0.05), and this effect could be prevented by the 5-HT1B antagonist GR 127935 (1 mg/kg i.v.). Altogether, these data indicate that in the mouse, the firing of 5-HT neurons in the dorsal raphe nucleus is under both an inhibitory control through 5-HT1A receptors and an excitatory influence through 5-HT1B receptors.

Citalopram ( Celexa ) combined with WAY 100635 inhibits ejaculation and ejaculation-related Fos immunoreactivity.

The role of 5-HT (5-hydroxytryptamine, 5-HT)(1A) receptor activation in the sexual side-effects, in particular delayed ejaculation, of selective serotonin reuptake inhibitors (SSRIs) was studied. Male Wistar rats were treated for 15 days with vehicle, the SSRI Citalopram ( Celexa ) (10 mg/kg/day p.o.), the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide 3HCL (WAY 100635, 0.1 mg/kg/ day s.c.), or both drugs combined. Sexual behavior was assessed weekly. One h after the last sexual behavior test, rat brains were processed for Fos-immunohistochemistry. Acute and chronic Citalopram ( Celexa ) mildly inhibited ejaculation, which was strongly augmented by co-administration of WAY 100635. WAY 100635 alone did not alter sexual behavior. Brain sites associated with ejaculation showed reduced Fos-immunoreactivity in rats treated with both Citalopram ( Celexa ) and WAY 100635. Citalopram ( Celexa ) reduced Fos-immunoreactivity in the arcuate hypothalamic nucleus, an area that might link serotonergic neurotransmission to ejaculation.

Protective effects of serotonin reuptake inhibitors, Citalopram ( Celexa ) and clomipramine, against hippocampal CA1 neuronal damage following transient ischemia in the gerbil.

To clarify the role of serotonin in cerebral ischemia, we examined the effects of selective serotonin reuptake inhibitors, Citalopram ( Celexa ) and clomipramine, on ischemic neuronal damage in the gerbil. Pretreatment with Citalopram ( Celexa ) (40 mg/kg i.p.) and clomipramine (20 mg/kg i.p.) protected against neuronal destruction of hippocampal CA1 pyramidal cells following 5 min of forebrain ischemia. Furthermore, microdialysis assays showed that a striking increase in extracellular excitatory amino acid levels during ischemia was significantly inhibited by pretreatment with Citalopram ( Celexa ) and clomipramine. However, Citalopram ( Celexa ) (40 mg/kg i.p.) did not alter the extracellular amino acid concentrations in normal gerbils. Thus, serotonin reuptake inhibitors have a protective effect against ischemic neuronal damage. Furthermore, the present result suggests that the protective effect is mediated through prevention of the accumulation of extracellular excitatory amino acids during and after ischemia.