Normand Lavoie

Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters.

In vitro radioligand binding studies were carried out in rat brain membranes to assess the affinity of various reuptake inhibitors for the serotonin (5-hydroxytryptamine, 5-HT) and the norepinephrine transporters using the selective ligands [3H]cyanoimipramine and [3H]nisoxetine, respectively. The selective 5-HT reuptake inhibitors paroxetine, indalpine and fluvoxamine displayed a high affinity for the 5-HT transporter, whereas the norepinephrine reuptake inhibitor desipramine had a high affinity for the norepinephrine transporter. Duloxetine, a dual 5-HT and norepinephrine reuptake inhibitor, displayed a high affinity for both the 5-HT and the norepinephrine transporters. Interestingly, venlafaxine, a dual 5-HT and norepinephrine reuptake inhibitor, displayed only a moderate affinity for the 5-HT transporter (Ki = 74 nM) and a very low affinity for the norepinephrine transporter (Ki = 1.26 microM). The relatively low affinities of venlafaxine contrast with its potent in vivo 5-HT and norepinephrine reuptake blocking properties. These results raise the possibility that the in vivo effects on the 5-HT and norepinephrine reuptake observed with venlafaxine may not be mediated solely by its binding to the [3H]cyanoimipramine and [3H]nisoxetine binding sites.

Differential physiological effects of a low dose and high doses of venlafaxine in major depression

Venlafaxine is an antidepressant drug with demonstrated serotonin (5-HT) and norepinephrine (NE) reuptake blockade properties in electrophysiological and microdialysis experiments in laboratory animals. In healthy volunteers, its 5-HT reuptake-inhibiting potential has also been clearly documented, but not its NE reuptake blockade action. This double-blind study compared the effects of a low dose (75 mg) and of a forced titration of high (up to 375 mg in 1 wk) daily doses of venlafaxine. Forty-four patients with major depression according to DSM-IV criteria were assessed bi-weekly for the first 2 wk and weekly for the next 2 wk. Inhibition of 5-HT reuptake was estimated using the depletion of whole-blood 5-HT, while that of NE was assessed using the attenuation of the systolic blood-pressure elevations produced by intravenous injections of tyramine. Forty-two patients completed the study. Both the low and the high doses of venlafaxine decreased the levels of 5-HT to the same extent: the reduction was of about 55% after 1 wk and of 75% after 4 wk. The 75 mg/d dose of venlafaxine did not alter the tyramine pressor response, whereas, in patients receiving the higher regimens of venlafaxine, there was a significant attenuation of the pressor effect of tyramine. There was no significant difference between the two treatment arms regarding the modifications of the depression scores. The present data showed that, at its minimal effective dose in depression (75 mg/d), venlafaxine acted as a selective 5-HT reuptake inhibitor, whereas when administered at higher doses (225 and 375 mg/d), it acted as a dual 5-HT and NE reuptake inhibitor.

Electrophysiological Evidence for the Tonic Activation of 5-HT 1A Autoreceptors in the Rat Dorsal Raphe Nucleus

Serotonin (5-hydroxytryptamine, 5-HT) and norepinephine (NE) neurons have reciprocal connections. These may thus interfere with anticipated effects of selective pharmacological agents targeting these neurons. The main goal of the present study was to assess whether the somatodendritic 5-HT1A autoreceptor is tonically activated by endogenous 5-HT in anesthetised rats, using in vivo extracellular unitary recordings. In rats with their NE neurons lesioned using 6-hydroxydopamine (6-OHDA) and in controls administered the NE reuptake inhibitor desipramine to suppress NE neuronal firing, the α2-adrenoceptor agonist clonidine no longer inhibited 5-HT neuron firing, therefore indicating the important modulation of the firing activity of 5-HT neurons by NE neurons. In control rats, the administration of the potent and selective 5-HT1A receptor antagonist WAY 100,635 ((N-{2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide trihydroxychloride) (100 μg/kg, i.v.) did not modify the spontaneous firing activity of 5-HT neurons, but in NE-lesioned rats using either 6-OHDA or DSP-4, WAY 100,635 produced a mean firing increase of 80 and 69%, respectively. When desipramine and D-amphetamine were used in control rats to prevent alterations in the availability of NE in the dorsal raphe, again WAY 100,635 produced a significant disinhibition of the firing of 5-HT neurons (83 and 53%, respectively). These data support the notion that the NE system tonically activates the firing activity of 5-HT neurons. When the fluctuations of the function of NE neurons normally produced by WAY 100,635 were prevented, a tonic activation of 5-HT1A autoreceptors by endogenous 5-HT was unmasked.

Antidepressant-induced modulation of GABAA receptors and β-adrenoceptors but not GABAB receptors in the frontal cortex of olfactory bulbectomised rats

The effects of prolonged administration of antidepressant drugs, belonging to three different classes, on high-affinity GABAA receptor, GABAB receptor and beta-adrenoceptor binding parameters were determined in the frontal cortex of olfactory bulbectomised rats. Clorgyline (1 mg/kg/day), paroxetine (10 mg/kg/day) or desipramine (10 mg/kg/day) were administered for 21 days via subcutaneous osmotic minipumps implanted in the scapular region 7 days after bulbectomy. Cortical GABAA receptor densities, defined with [3H]gamma-aminobutyric acid ([3H]GABA), were significantly increased following bulbectomy. This effect on Bmax values was reversed by all three antidepressant drugs. GABAB receptor densities decreased slightly after bulbectomy. Chronic antidepressant administration had no effect on GABAB receptor binding parameters. Olfactory bulbectomy did not induce any changes in cortical beta-adrenoceptor binding parameters determined with [3H]CGP-12177 ((-)-4-(3-t- butylamino-2-hydroxypropxy)- [5,7-3H]benzimidazol-2-one). However, prolonged administration of all three antidepressant drugs induced a downregulation of beta-adrenoceptors. The results of the present study confirm the involvement of cortical GABAA rather than GABAB receptors in the olfactory bulbectomy animal model of human depression. Moreover, the data further support the hypothesis that a decrease in function of the GABAA receptor complex could play a role in the therapeutic effects of antidepressant treatments.

Dimethylthiourea protects against chlorine induced changes in airway function in a murine model of irritant induced asthma.

BackgroundExposure to chlorine (Cl2) causes airway injury, characterized by oxidative damage, an influx of inflammatory cells and airway hyperresponsiveness. We hypothesized that Cl2-induced airway injury may be attenuated by antioxidant treatment, even after the initial injury.MethodsBalb/C mice were exposed to Cl2 gas (100 ppm) for 5 mins, an exposure that was established to alter airway function with minimal histological disruption of the epithelium. Twenty-four hours after exposure to Cl2, airway responsiveness to aerosolized methacholine (MCh) was measured. Bronchoalveolar lavage (BAL) was performed to determine inflammatory cell profiles, total protein, and glutathione levels. Dimethylthiourea (DMTU;100 mg/kg) was administered one hour before or one hour following Cl2 exposure.ResultsMice exposed to Cl2 had airway hyperresponsiveness to MCh compared to control animals pre-treated and post-treated with DMTU. Total cell counts in BAL fluid were elevated by Cl2 exposure and were not affected by DMTU treatment. However, DMTU-treated mice had lower protein levels in the BAL than the Cl2-only treated animals. 4-Hydroxynonenal analysis showed that DMTU given pre- or post-Cl2 prevented lipid peroxidation in the lung. Following Cl2 exposure glutathione (GSH) was elevated immediately following exposure both in BAL cells and in fluid and this change was prevented by DMTU. GSSG was depleted in Cl2 exposed mice at later time points. However, the GSH/GSSG ratio remained high in chlorine exposed mice, an effect attenuated by DMTU.ConclusionOur data show that the anti-oxidant DMTU is effective in attenuating Cl2 induced increase in airway responsiveness, inflammation and biomarkers of oxidative stress.

Effects of different doses of venlafaxine on serotonin and norepinephrine reuptake in healthy volunteers

Venlafaxine is generally considered to be a dual 5-HT and NE reuptake inhibitor when it is used at doses above 75 mg/d in humans. While its 5-HT reuptake-inhibiting property has been demonstrated, some controversy still exists regarding the doses of venlafaxine required to inhibit NE reuptake. Healthy male volunteers received, on a double-blind basis, paroxetine (20 mg/d), desipramine (100 mg/d), nefazodone (300 mg/d), or venlafaxine (150 or 300 mg/d) in the last 5 d of a 7-d period of administration. Inhibition of 5-HT reuptake was estimated by determining the degree of depletion of whole-blood 5-HT, while that of NE was assessed by measuring the attenuation of the systolic blood pressure increases produced by intravenous injections of tyramine. Paroxetine, both regimens of venlafaxine, and to a lesser extent desipramine significantly decreased whole-blood 5-HT content. Nefazodone failed to produce any significant change. Desipramine abolished the tyramine pressor response, whereas all other drug regimens left this parameter unaltered. Venlafaxine and paroxetine acted as potent 5-HT reuptake inhibitors in the present study. In contrast, neither the moderate nor the high dose of venlafaxine displayed any significant inhibiting activity in this model assessing NE reuptake in peripheral NE terminals. The validity of the model was confirmed by the potent inhibitory action of desipramine on NE reuptake. While the reasons for this unexpected lack of action remain unclear, venlafaxine appeared to be an effective NE reuptake agent in depressed patients using the same approach.

Differential effects of olfactory bulbectomy on GABAA and GABAB receptors in the rat brain.

GABAergic mechanisms have been implicated in the bilateral olfactory bulbectomy (OBX) animal model of depression, where GABAB receptor binding sites have been shown to decrease markedly at specific time points after OBX. However, as no detailed time course of events has been determined, the present study investigated the effects of OBX on high-affinity GABAA, GABAB, beta-adrenergic, and benzodiazepine receptor binding parameters in membrane preparations from rat brain regions at weekly intervals (1-4 weeks) after OBX. Persistent significant increases (40-60%) in Bmax values of high affinity GABAA receptors were observed in the frontal cortex throughout the period investigated following OBX. Bmax values in the hippocampus increased significantly after 1 week (53%) but were not statistically significant thereafter. No changes in GABAA binding parameters were observed in the hypothalamus or cerebellum. Conversely, GABAB receptor densities were significantly decreased in the frontal cortex after 1 (-38%) and 2 (-41%) weeks and moderately decreased 3 and 4 weeks (-27 and -23%, respectively) after OBX, while in the cerebellum they were significantly increased after 1 week (96%) and returned to sham-operated levels by 3 weeks. No changes in GABAB receptor binding parameters were observed in the hippocampus or hypothalamus. Binding parameters for benzodiazepine receptor binding sites or beta-adrenoceptors were not modified throughout the time course. GABAergic transmission, reflected by changes in GABAA and GABAB receptor density in the frontal cortex, may be altered in OBX rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative autoradiographic studies of the effects of bilateral olfactory bulbectomy in the rat brain: central- and peripheral-type benzodiazepine receptors.

We investigated the discrete regional effects of bilateral olfactory bulbectomy on central- and peripheral-type benzodiazepine receptors in rat brains at weekly intervals until one month after bulb ablation. Persistent increases in [3H]flunitrazepam binding to central benzodiazepine receptors were observed in the cingulum (27%) and in the frontal (15%) and parietal (14%) cortices. Progressive increases in central benzodiazepine receptors, reaching statistical significance four weeks after olfactory bulbectomy, were observed in the ventromedial thalamic nucleus (35%), the lateral hypothalamic region (22%), the basolateral amygdaloid nucleus (23%) and substantia nigra (25%). Persistent major increases (between four- and six-fold) in [3H]PK-11195 [eH]1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide binding to peripheral-type benzodiazepine receptors were observed in all anterior olfactory nuclei. Similarly, throughout the time period studied, [3H]PK-11195 binding densities were increased two- to three-fold in the piriform cortex and lateral olfactory tract. These observations confirm the usefulness of [3H]PK-11195 binding as a marker of neuronal insult in the brain. Moreover, the persistent regional increases in [3H]flunitrazepam binding to central-type benzodiazepine receptors suggest that GABAergic transmission is altered following olfactory bulb ablation.

Antidepressants reverse the olfactory bulbectomy-induced decreases in splenic peripheral-type benzodiazepine receptors in rats

The present study investigated the effects of 21-day administration of clorgyline (1 mg/kg/day), desipramine (10 mg/kg/day) or paroxetine (10 mg/kg/day) on peripheral-type benzodiazepine receptors in rat peripheral tissues following bilateral olfactory bulbectomy. Thymus and spleen weights decreased as a result of bulbectomy. Subsequent antidepressant drug administration had no further effects on the weights of thymus glands but increased those of spleens. In thymus glands, higher densities of peripheral-type benzodiazepine receptors were observed in medulla than in cortex; no significant variations were observed following bulbectomy or antidepressant drug administration. In spleen, higher densities were observed in white pulp than in red pulp. The bulbectomy-induced decreases in binding densities observed in both regions were reversed following administration of antidepressants. Adrenal peripheral-type benzodiazepine receptors were not altered by bulbectomy or subsequent treatment with clorgyline or desipramine while paroxetine upregulated these receptors. No changes in kidney peripheral-type benzodiazepine receptors were observed. The present study confirms that cell lines of the rat immune system possess high densities of peripheral-type benzodiazepine receptor binding sites and further support the contention that, following olfactory bulbectomy, rats may present an antidepressant-reversible immunitary dysfunction.