venlafaxine (Effexor)
Pharmacological actions of the antidepressant venlafaxine beyond aminergic receptors.

Rossby SP, Manier DH, Liang S, Nalepa I, Sulser F.

Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232.

The present study examines the effects of the antidepressant venlafaxine, a dual amine reuptake inhibitor, on (a) in vivo regulation of the densities of high- and low-affinity dihydroalprenolol (DHA) binding sites in the cortex of normal and reserpinized Sprague-Dawley rats and (b) targets beyond the beta adrenoceptor. While venlafaxine (30 mg/kg i.p. b.i.d.) administered for 4 d did not alter the DHA-binding parameters in the cortex of normal rats, it significantly reduced, in reserpinized animals, the number of up-regulated low-affinity sites (R(L)) which have been tentatively identified as serotonin(1B) sites. The drug did not influence the up-regulated high-affinity (R(H)) DHA-binding sites (beta-adrenoceptor sites). Venlafaxine failed to alter the up-regulated R(L) sites in brains of rats depleted of serotonin (5-HT) by p-chlorophenylalanine (PCPA) indicating that the normalization by venlafaxine of the up-regulated R(L) receptor population is mediated by increased synaptic 5-HT. Venlafaxine, given for a short period of time, thus mimicked the action of fluoxetine. While venlafaxine (20 mg/kg i.p. b.i.d.) given for 10 d did not change protein kinase A activity as assessed by the phosphorylation of kemptide in the 900 g supernatant or particulate fractions, the drug significantly reduced phosphorylated cAMP response-element binding protein (CREB-P) in nuclear lysates of cortex after chronic but not acute administration. Depletion of 5-HT by PCPA did not alter the venlafaxine-induced change in nuclear CREB-P. Lastly, analysis of reverse transcribed cortical CREB mRNA by competitive PCR indicated that the mean steady-state levels of CREB mRNA in venlafaxine vs. saline-treated animals were not significantly different. Therefore, since the phosphorylation status of CREB determines its transcriptional activity the reduction of nuclear CREB-P may be venlafaxine's most relevant action beyond the adrenoceptor.

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Effexor, Effexor XR

venlafaxine (Effexor)
Sustained administration of the antidepressant venlafaxine in rats: pharmacokinetic and pharmacodynamic findings.

Wikell C, Hjorth S, Apelqvist G, Kullingsjo J, Lundmark J, Bergqvist PB, Bengtsson F.

Department of Clinical Pharmacology, Lund University, Sweden.

Rats were administered venlafaxine (10 mg/kg per day) for 14 days by using subcutaneously implanted osmotic minipumps. The present study assessed the distribution of VEN in different compartments, whether the VEN concentration in the compartments correlated, the effect of VEN on dialysate monoamine levels and on the spontaneous open-field behavior, and possible relations between the pharmacokinetic and pharmacodynamic parameters. The venlafaxine level in serum after sustained treatment was about 25% of the concentration in brain parenchyma and much higher than in brain dialysate. There was a clear correlation between venlafaxine concentrations in blood and brain compartments. The sustained venlafaxine challenge resulted in higher neocortical concentration of serotonin and noradrenaline, lower 5-hydroxyindole-3-acetic acid levels and increased locomotor activity in the central part of the test arena as compared to controls. No correlations were found between the venlafaxine concentration and brain monoamine parameters or the open-field behaviors. We conclude that, although species differences in pharmacokinetic properties for venlafaxine between rat and man exist, the pharmacokinetic correlations found after sustained treatment add information to the in vivo nature of the drug. Also, more studies like the present need to be performed to find the pharmacokinetic/pharmacodynamic interrelations for drugs like VEN.

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Effexor, Effexor XR

venlafaxine (Effexor)
Short-term administration of fluoxetine and venlafaxine decreases corticosteroid receptor mRNA expression in the rat hippocampus.

Yau JL, Noble J, Hibberd C, Seckl JR.

Molecular Endocrinology Laboratory, Molecular Medicine Centre, Western General Hospital, Edinburgh EH4 2XU, UK. Joyce.Lau ed.ac.uk

Chronic treatment with antidepressant drugs (2 weeks or longer) increases corticosteroid receptor mRNA expression in the hippocampus and reduces hypothalamic-pituitary-adrenal axis activity in parallel with improving mood and neuroendocrine function. Earlier effects are less well documented. We examined the effects of short term (9 days) treatment with fluoxetine (10 mg/kg) and venlafaxine (10 mg/kg) on hippocampal mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA expression and spatial memory in adult rats. In situ hybridization histochemistry showed that the antidepressants decreased MR mRNA expression in all hippocampal subregions (e.g. 45% decrease in CA1 with venlafaxine, P<0.001), while GR mRNA expression was selectively reduced in the CA3 subregion. There was a trend for decreased plasma corticosterone levels following fluoxetine (50% fall, P=0.07) and venlafaxine (30% fall, P=0.18) but neither antidepressants affected spatial memory in the watermaze. Thus antidepressants can have complex and opposing actions on hippocampal corticosteroid receptor expression depending on the duration of treatment.

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Effexor, Effexor XR

venlafaxine (Effexor)
Attenuation of morphine dependence and withdrawal in rats by venlafaxine, a serotonin and noradrenaline reuptake inhibitor.

Lu L, Su WJ, Yue W, Ge X, Su F, Pei G, Ma L.

National Laboratory of Medical Neurobiology, Fudan University Medical Center, Shanghai, People's Republic of China.

The effects of venlafaxine, a novel serotonin and adrenaline reuptake inhibitor, on the morphine withdrawal and activation of morphine conditioned place preference (CPP), were investigated in rats. Our results showed that the most morphine withdrawal signs, including jumping, writhing, shakes, exploring, lacrimation, piloerection, irritability, and diarrhea, were attenuated by pretreatment with 10 or 20 mg/kg venlafaxine. To investigate the effects of venlafaxine on relapse to opiate dependence, the morphine CPP was used and a dopamine D2 antagonist sulpiride was selected as a control drug. The morphine CPP disappeared following a 28-day drug-free period and appeared again after given a single injection of 1 mg/kg morphine. Acute treatment with sulpiride (25 or 50 mg/kg, i.p.) 30 min prior to 1 mg/kg morphine injection significantly blocked the reacquisition of CPP, while venlafaxine (10 or 20 mg/kg, i.p.) did not show significant effect. However, chronic treatment with venlafaxine (5 or 10 mg/kg, i.p. twice, daily, for seven consecutive days) significantly attenuated the reacquisition of morphine CPP, whereas chronic treatment with sulpiride (10 or 20 mg/kg, i.p.) have no significant effect. Our results demonstrated for the first time that venlafaxine strongly attenuates morphine withdrawal and morphine-induced reaquisition of

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Effexor, Effexor XR

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

Millan MJ, Dekeyne A, Papp M, La Rochelle CD, MacSweeny C, Peglion JL, Brocco M.

Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, Paris, France. mark.millan fr.netgrs.com

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, and the 5-HT/norepinephrine (NE) reuptake inhibitor, venlafaxine, 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, whereas citalopram 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 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, citalopram, 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 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 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 and clomipramine, and its overall profile is distinct from those of citalopram and reboxetine.

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Effexor, Effexor XR