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

Abstract

Given that norepinephrine (NE) and serotonin (5-HT) neurons are implicated in the mechanisms of action of antidepressant drugs and both project to the hippocampus, the impact of acute and long-term administration of the selective NE inhibitor reboxetine was assessed on CA 3 pyramidal neuron firing in this postsynaptic structure. Cumulative injections of reboxetine (1-4 mg/kg, i.v.) The major classes of antidepressant drugs, including the tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRIs), modify serotonin (5-HT) and/or norepinephrine (NE) neurotransmission through which they likely exert their therapeutic effects in anxiety and affective disorders (see Blier and de Montigny 1999). It has been postulated that antidepressant drugs selective for either the 5-HT or NE system act via independent mechanisms. Furthermore, these "selective" drugs display side effect profiles indicative of their neurotransmitter specificity. This, however, does not preclude that antidepressant agents specific for one monoaminergic From the Neurobiological Psychiatry Unit, McGill University, Montréal, Canada H3A 1A1(STS) and Department of Psychiatry, Brain Institute, University of Florida, Gainesville, Florida (PB).Address correspondence to: Department of Psychiatry, Brain Institute, University of Florida, Gainesville, FL 32610-0256, Tel.: 352-392-3681; Fax: 352-392-2579; E-mail: blier@psych.med.ufl.edu Received February 12, 2001; revised April 24, 2001; accepted May 3, 2001.Online publication: 5/7/01 at www.acnp.org/citations/Npp 05070117 846 S. T. Szabo et al. N EUROPSYCHOPHARMACOLOGY 2001 -VOL . 25 , NO . 6 transporter, or receptor subtype, may exert their therapeutic action through interactions between the 5-HT and NE systems. For example, SSRIs induce a gradual decrease in the spontaneous firing activity of NE neurons after long-term administration (Szabo et al. 1999, via a complex neuronal circuitry (Szabo and Blier 2000a), which may contribute to their beneficial and/or side effects depending on the symptomatic profile of the patients (Blier 2000). On the other hand, the selective NE reuptake inhibitor desipramine increases the synaptic availability of NE but also alters 5-HT parameters after long-term administration, such as enhancing extracellular 5-HT concentrations and the responsiveness of 5-HT receptors in postsynaptic structures (de Montigny and Aghajanian 1978;Wang and Aghajanian 1980;Menkes and Aghajanian 1981;Yoshioka et al. 1995). This enhanced synaptic availability of 5-HT may be due to a decreased sensitivity of ␣ 2 -adrenergic heteroreceptors located on 5-HT terminals that normally induce a negative feedback regulation on 5-HT release (Mongeau et al. 1993;Yoshioka et al. 1995). Interestingly, all TCA drugs, independent of their capacity to inhibit the reuptake of 5-HT and/or NE, progressively enhance the responsiveness of postsynaptic 5-HT 1A receptors with a time-course congruent to the delayed onset of action of these drugs in major...

Genetic Deletion of Fatty Acid Amide Hydrolase Alters Emotional Behavior and Serotonergic Transmission in the Dorsal Raphe, Prefrontal Cortex, and Hippocampus

“…The similarity of effects of genetic and pharmacological FAAH deactivation and the fact that both were blocked by prolonged co-application with rimonabant strengthen the notion that postsynaptic 5-HT receptor adaptations are due to the common mechanism of increased anandamide-CB 1 R signaling, and that the effects observed in FAAH À/À mice are not merely because of non-specific compensatory mechanisms resulting from a life-long condition of increased anandamide levels. These data are reminiscent of the hallmark enhancement in hippocampal 5-HT 1A tonus that follows long-term administration of different classes of antidepressant treatments, including electroconvulsive shock (Haddjeri et al, 1998;Besson et al, 2000;Szabo and Blier, 2001b). This similar observation made in FAAH À/À mice may be explained by the increase in the depolarizationinduced efflux of 5-HT in this structure, which has been shown in this transgenic mouse .…”

“…The delay in therapeutic onset of antidepressants has been attributed to gradual neuroplastic adaptations at the presynaptic and postsynaptic levels that result from the progressive augmentation in 5-HT activity. These modifications include desensitization of auto-inhibitory 5-HT 1A receptors, sensitization or increased tonic activation of postsynaptic 5-HT 1A receptors (Haddjeri et al, 1998;Besson et al, 2000;Szabo and Blier, 2001b), and downregulation of cortical 5-HT 2A/2C receptors (Hollander et al, 1991a;Kennett et al, 1994a, c;Quested et al, 1997). The receptor subtypes involved have been extensively explored for their roles in emotion and mood regulation, and for their modulatory impact on neurotrophic factor synthesis and neurogenesis, which are considered downstream biological signatures of antidepressant activity (Holmes, 2008;Bambico and Gobbi, 2008;Bambico et al, 2009a).…”

Sustained Administration of Pramipexole Modifies the Spontaneous Firing of Dopamine, Norepinephrine, and Serotonin Neurons in the Rat Brain

“…Furthermore, reciprocal interactions between these two neuronal entities are now well established (Blier, 2001;Szabo and Blier, 2001;Guiard et al, 2008a). However, during the last decade substantial data suggesting participation of dopaminergic system in this neuronal network of interactions have emerged (Aman et al, 2007;Esposito, 2006;Haj-Dahmane, 2001).…”

Possible role of more positive social behaviour in the clinical effect of antidepressant drugs

“…However, preclinical studies suggest that reboxetine also increases serotonin function. 27 Therefore, serotonin may have been a mediator of the effects of all the antidepressants.…”