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Effects of the Selective Norepinephrine Reuptake Inhibitor Reboxetine on Norepinephrine and Serotonin Transmission in the Rat Hippocampus Steven T

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Effects of the Selective Norepinephrine Reuptake Inhibitor Reboxetine on Norepinephrine and Serotonin Transmission in the Rat Hippocampus Steven T Effects of the Selective Norepinephrine Reuptake Inhibitor Reboxetine on Norepinephrine and Serotonin Transmission in the Rat Hippocampus Steven T. Szabo, B.Sc., and Pierre Blier, M.D., Ph.D. Given that norepinephrine (NE) and serotonin (5-HT) frequency-dependent decreases in pyramidal neuron firing neurons are implicated in the mechanisms of action of in both groups. However, after low and high doses of ␮ ␣ antidepressant drugs and both project to the hippocampus, clonidine (10 and 400 g/kg, i.v.), which assesses 2- the impact of acute and long-term administration of the adrenergic auto- and heteroreceptor sensitivity, respectively, selective NE inhibitor reboxetine was assessed on CA3 only the effect of the high dose of clonidine was attenuated. pyramidal neuron firing in this postsynaptic structure. Interestingly, administration of the selective 5-HT1A Cumulative injections of reboxetine (1–4 mg/kg, i.v.) dose- receptor antagonist WAY 100,635 induced a 140% increase dependently increased the recovery time of the firing of these in basal pyramidal neuron firing in reboxetine as compared neurons following iontophoretic applications of NE, but not to saline-treated rats. This increase in tonic activation of 5-HT. In rats treated with reboxetine for 2.5 mg/kg/day for postsynaptic 5-HT1A receptors might be attributable in part ␣ 21 days, a robust increase in the recovery time following NE to a desensitization of 2-adrenergic heteroreceptors, applications was observed, and a small but significant presumably resulting from sustained NE reuptake prolongation occurred following 5-HT applications. In inhibition. These results indicate that even a selective NE controls and reboxetine-treated rats, 1 and 5 Hz reuptake inhibitor can modulate 5-HT transmission. stimulations of the afferent 5-HT bundle to the [Neuropsychopharmacology 25:845–857, 2001 hippocampus, which allows determination of terminal © 2001 American College of Neuropsychopharmacology. 5-HT1B autoreceptor sensitivity, produced similar Published by Elsevier Science Inc. ␣ KEY WORDS: Antidepressants; 2-adrenoceptors; Clonidine; The major classes of antidepressant drugs, including 5-HT1A receptors; 5-HT1B receptors; Locus coeruleus the tricyclic antidepressants (TCAs), monoamine oxi- dase inhibitors (MAOIs), and selective serotonin re- uptake inhibitors (SSRIs), modify serotonin (5-HT) and/or norepinephrine (NE) neurotransmission through which From the Neurobiological Psychiatry Unit, McGill University, they likely exert their therapeutic effects in anxiety and Montréal, Canada H3A 1A1(STS) and Department of Psychiatry, affective disorders (see Blier and de Montigny 1999). It Brain Institute, University of Florida, Gainesville, Florida (PB). has been postulated that antidepressant drugs selective Address correspondence to: Department of Psychiatry, Brain Institute, University of Florida, Gainesville, FL 32610-0256, Tel.: 352- for either the 5-HT or NE system act via independent 392-3681; Fax: 352-392-2579; E-mail: [email protected] mechanisms. Furthermore, these “selective” drugs dis- Received February 12, 2001; revised April 24, 2001; accepted May play side effect profiles indicative of their neurotrans- 3, 2001. Online publication: 5/7/01 at www.acnp.org/citations/Npp mitter specificity. This, however, does not preclude that 05070117 antidepressant agents specific for one monoaminergic NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 6 © 2001 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/01/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(01)00284-6 846 S. T. Szabo et al. NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 6 ␣ transporter, or receptor subtype, may exert their thera- ment, -adrenergic heteroreceptor and 5-HT1B autore- peutic action through interactions between the 5-HT ceptor function was assessed using electrical stimula- and NE systems. For example, SSRIs induce a gradual tion of the afferent 5-HT bundle to this postsynaptic decrease in the spontaneous firing activity of NE neu- structure. rons after long-term administration (Szabo et al. 1999, 2000), via a complex neuronal circuitry (Szabo and Blier 2000a), which may contribute to their beneficial and/or MATERIALS AND METHODS side effects depending on the symptomatic profile of Animals and Treatments the patients (Blier 2000). On the other hand, the selec- tive NE reuptake inhibitor desipramine increases the The experiments were carried out in male Sprague synaptic availability of NE but also alters 5-HT parame- Dawley rats (Charles River, St. Constant, Québec, Can- ters after long-term administration, such as enhancing ada) weighing 300–325 g and were kept under standard extracellular 5-HT concentrations and the responsive- laboratory conditions (12:12 light-dark cycle with ac- ness of 5-HT receptors in postsynaptic structures (de cess to food and water ad libitum, at a room temperature Montigny and Aghajanian 1978; Wang and Aghajanian of 21 Ϯ 2°C). Rats were anesthetized with chloral hy- 1980; Menkes and Aghajanian 1981; Yoshioka et al. drate (400 mg/kg, i.p.) and mounted in a stereotaxic ap- 1995). This enhanced synaptic availability of 5-HT may paratus (David Kopf Instruments). Supplemental doses ␣ be due to a decreased sensitivity of 2-adrenergic heter- (100 mg/kg, i.p.) were given to prevent any nociceptive oreceptors located on 5-HT terminals that normally in- reaction to pinching of the hind paw. Body temperature duce a negative feedback regulation on 5-HT release was maintained at 37°C throughout the experiments (Mongeau et al. 1993; Yoshioka et al. 1995). Interest- utilizing a thermistor-controlled heating pad (Seabrook ingly, all TCA drugs, independent of their capacity to Medical Instruments, Inc.). Prior to electrophysiological inhibit the reuptake of 5-HT and/or NE, progressively recording, a catheter was inserted in a lateral tail vein enhance the responsiveness of postsynaptic 5-HT1A re- for systemic i.v. injection of drugs. All experiments ceptors with a time-course congruent to the delayed on- were performed in compliance with NIH guidelines set of action of these drugs in major depression (de and the Canadian Council on Animal Care. Montigny and Aghajanian 1978; Heninger et al. 1984; In sustained treatment regimens, rats were anesthe- Chaput et al. 1991). Due to the lack of effective antide- tized with halothane containing a 2:1 O2/N2O mixture pressant drugs selective for the NE transporter not be- for subcutaneous implantation of osmotic Alzet 2ML4 longing to the TCA family, it has been difficult to assess minipumps (ALZA, Palo Alto, CA). The rats were tested whether the effects of desipramine on 5-HT transmis- with the minipumps in place in order to mimic the clini- sion is attributable to its TCA moiety (because at least cal condition whereby patients present an antidepres- one of these drugs does not block NE reuptake) or to sant response while taking their medication. Rats were NE blockade per se. treated with reboxetine (2.5 mg/kg/day) or the saline Reboxetine is not a TCA and it is a selective NE re- vehicle for 21 days delivered by osmotic minipumps. uptake inhibitor. It is currently the only antidepressant This dose was chosen because it produced a similar de- agent of its kind in clinical use in Europe. Given that gree of attenuation of LC neuronal firing after a two-day NE and 5-HT monoaminergic brainstem nuclei project treatment to that obtained with regimens of de- to the hippocampus, the impact of acute and long-term sipramine and MAOIs examined in long-term studies administration of reboxetine was assessed on CA3 py- (Szabo and Blier 2001; Blier and de Montigny 1985). ramidal neuron firing in this brain region generally thought to be implicated in at least some aspects of de- Recording from Dorsal Hippocampus CA pression. It is not currently known whether atrophy in 3 Pyramidal Neurons the hippocampus represents a depressive state or trait (Sheline et al. 1999; Bremner et al. 2000), however anti- Extracellular unitary recordings and microiontophore- depressant treatments have been shown to induce sis of drugs onto pyramidal neurons in the CA3 region adaptive changes in this structure (see Malberg et al. of the dorsal hippocampus were conducted with five- 2000 for review). The effect of reboxetine on NE trans- barreled micropipettes, pulled conventionally with the mission in this manuscript was not directly assessed as tips broken to a diameter of 9 to 12 ␮m under a micro- Sacchetti et al. (1999) already concluded that acute and scopic control. The central barrel, used for recording, sustained treatment with reboxetine leads to similar in- was filled with a 2 M NaCl solution. The side barrels creases in extracellular levels of NE without producing contained the following solutions: 5-HT creatinine sul- ␣ any adaptive changes in 2-autoreceptor sensitivity in fate (5 mM in 200 mM NaCl, pH 4), NE bitartrate (20 the hippocampus. However, given the importance of mM in 200 mM NaCl, pH 4), quisqualate (1.5 mM in 200 receptors on 5-HT terminals in the hippocampus, which mM NaCl, pH8), and a 2 M NaCl solution used for au- become altered after long-term antidepressant treat- tomatic current balancing. All drug solutions were in- NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 6 Reboxetine on NE and 5-HT Transmission 847 jected as cations and retained with a Ϫ10nA current be- tors, two series of stimulations (1 and 5 Hz) were car- tween injections. Pyramidal neurons were identified by ried out, while recording the same neurons. Since it has their large amplitude (0.5 mV to 1.2 mV) and long- been previously demonstrated that the activation of the duration (0.8 msec to 1.2 msec) simple spike alternating terminal 5-HT autoreceptors decreases the release of with complex spike discharges (Kandel and Spencer 5-HT, thus increasing the frequency of stimulation from 1961). These characteristics readily allow the on-line 1 to 5 Hz results in a greater activation of terminal 5-HT differentiation of pyramidal neurons from interneu- autoreceptors (Blier et al.
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