Effects of sustained administration of the serotonin and norepinephrine reuptake inhibitor venlafaxine: II. In vitro studies in the rat
Introduction
The monoaminergic systems are endowed with homeostatic mechanisms that subserve an important function in controlling neurotransmission. For instance, both serotonergic (5-HT) and noradrenergic (NE) terminal autoreceptors have been known for many years to tightly regulate the release of 5HT and NE, respectively, thereby regulating the synaptic availability of the neurotransmitter (Langer, 1980, Göthert, 1986, Starke et al., 1989). There is a substantial corpus of data suggesting that most antidepressant treatments exert their primary pharmacological effects on monoaminergic systems. However, given that these effects, for example the blockade of the reuptake of either 5-HT and/or NE, become apparent almost immediately upon initiating the treatment, they cannot per se be held responsible for the therapeutic response as it develops over the course of several weeks of treatment. On the basis of these contentions, particular attention was thus paid to the effects of long-term antidepressant treatments on specific target receptors which modulate monoaminergic neurotransmission. Out of this endeavour, relevant findings have emerged. For instance, the long-term administration of selective 5-HT reuptake inhibitors (SSRI's) was shown to induce a desensitization of the terminal 5-HT1B autoreceptors (Chaput et al., 1986, Moret and Briley, 1990, Chaput et al., 1991) thereby increasing the amount of 5-HT released per action potential. Moreover, the long-term administration of drugs that enhance the synaptic availability of NE was shown to induce the desensitization of the α2-adrenergic heteroreceptors located on 5-HT terminals (Mongeau et al., 1994, Yoshioka et al., 1995). Since the latter heteroreceptors inhibit the release of 5-HT (Göthert and Huth, 1980, Göthert et al., 1981, Maura et al., 1982, Mongeau et al., 1993), this also results in an enhanced release of 5-HT.
Venlafaxine (1-[2-(dimethylamino)-1-(4-methyoxyphenyl)-ethyl]cyclohexanol) is an antidepressant for which clinical studies have suggested a superior clinical efficacy as it would display an earlier onset of action and show efficacy in treatment-resistant depression (Schweizer et al., 1991, Guelfi et al., 1992, Nierenberg et al., 1994, Kelsey, 1996, Benkert et al., 1996, de Montigny et al., 1999). Its pharmacological profile is characterized by the inhibition of the reuptake of both 5-HT and NE with a potency greater for blocking the reuptake of 5-HT than that of NE (Muth et al., 1986, Bolden-Watson and Richelson, 1993, Béı̈que et al., 1998b, Béı̈que et al., 1999). In light of the different adaptative changes induced by either 5-HT or NE reuptake inhibitors, it was deemed important to determine whether the long-term administration of venlafaxine could induce some of the adaptative changes previously observed with either 5-HT and/or NE reuptake inhibitors. Thus, the sensitivity of the 5-HT1B autoreceptors and the α2-adrenergic heteroreceptors located on 5-HT terminals and of the α2-adrenergic autoreceptors located on NE terminals were assessed following the long-term administration of a low (10 mg/kg/day) and a high (40 mg/kg/day) dose of venlafaxine for 21 days. To this end, an in vitro approach in which hippocampal slices were preloaded with [3H]5-HT or [3H]NE was employed. Finally, the function of the 5-HT transporter was assessed in mesencephalic and in hippocampal slices following long-term administration of venlafaxine by determining the effects of a challenging concentration of paroxetine on [3H]5-HT release.
Parts of the present work have previously been published in abstract form (Béı̈que et al., 1998a)
Section snippets
Animals
Male Sprague Dawley rats (125–150 g; Charles River, St. Constant, Québec, Canada) were received one day before the implantation of minipumps and housed three to four per cage. They were kept on a 12:12 h light/dark cycle, with access to food and water ad libitium.
Treatments
Rats were anaesthetized with halothane and implanted with an osmotic minipump (Alza, Palo Alto, CA, USA) which delivered either 10 or 40 mg/kg/day of venlafaxine or vehicle for 21 days. The rationale for using these doses is based on
Effects of long-term administrations of venlafaxine on [3H]5-HT and [3H]NE overflow
Rats were treated for 21 days with either a low (10 mg/kg/day) or a high (40 mg/kg/day) dose of venlafaxine. Experiments were carried out 48 h after the removal of the minipumps. In the absence of any drugs in the perfusion medium, the electrically-evoked outflow of [3H]5-HT during the first electrical stimulation period (S1) was significantly enhanced in slices of rats treated with 40 mg/kg/day of venlafaxine (p<0.01, using the non-paired student t-test), but not in those from rats treated
Discussion
In the present study, a high (40 mg/kg/day), but not a low (10 mg/kg/day), dose of venlafaxine, administered for 21 days, elicited an increase of the electrically-evoked release (S1) of tritium from hippocampal slices preloaded with [3H]5-HT. The latter effect most probably stemmed from the desensitization of the terminal 5-HT1B autoreceptor as inferred from the reduced efficacy of the 5-HT1B agonist CP 93,129 to suppress the electrically-evoked release of [3H]5-HT from preloaded hippocampal
Acknowledgments
This work was supported by the Medical Research Council of Canada (MRC; grants MA 6444 and MT 11014) and by Wyeth-Ayerst Research. J.C.B. is in receipt of a Fonds de la Recherche en Sante du Quebec (FRSQ) Fellowship, P.B. of a MRC Scientist award and G.D. of a Scholarship from the FRSQ.
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