α1-Adrenoceptor antagonists differentially control serotonin release in the hippocampus and striatum: a microdialysis study

doi:10.1016/0014-2999(94)90300-X

European Journal of Pharmacology

Volume 261, Issues 1–2, 11 August 1994, Pages 59-64

https://doi.org/10.1016/0014-2999(94)90300-X Get rights and content

Abstract

Using the in vivo microdialysis technique, we have studied the effect of the systemic administration of several α₁-adrenoceptor antagonists on the extracellular levels of serotonin (5-HT) in the rat hippocampus. Prazosin, and to a lesser extent, terazosin, decreased these levels by 50–65% for 0.03–0.4 mg/kg, i.v. and by 30–40% for 0.1–0.4 mg/kg, i.v., respectively. In contrast, alfuzosin, an α₁-adrenoceptor antagonist with poor brain penetration, did not significantly affect these levels even at the high dose of 0.4 mg/kg, i.v. When perfused into the hippocampus through the dialysis probe, prazosin (1–10 μM) induced a more limited (20–30%) and delayed decrease in 5-HT outflow. These results support the existence of a central noradrenergic facilitatory influence, mediated by α₁-adrenoceptors, on serotonergic neurons projecting to the hippocampus. In the striatum prazosin (0.4 mg/kg, i.v.) decreased 5-HT levels to a smaller extent (−35%) than in the hippocampus (−65%), suggesting the existence of differences in the degree of noradrenergic influence on median and dorsal raphé nuclei, which preferentially project to the hippocampus and striatum, respectively.

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Citation Excerpt :
However, high-dose prazosin (0.5 mg/kg) attenuated the anxiolytic effect of high-dose citalopram (10 mg/kg) (Fig. 2). Rouquier et al. (1994) showed that systemic administration of prazosin at doses of 0.03, 0.1 and 0.4 mg/kg [intravenous injection (i.v.)] decreased the extracellular serotonin levels in the rat hippocampus in a dose-dependent manner (50%, 60% and 65%, respectively, 60 min after drug administration). They also showed that the systemic administration of 0.4 mg/kg (i.v.) prazosin decreased the extracellular serotonin levels (a 35% decrease 60 min after administration) in the striatum, although 0.03 mg/kg prazosin did not affect serotonin release.
Several studies have shown that the α₁-adrenoreceptor is involved in controlling extracellular serotonin levels. The administration of the α₁-adrenoreceptor antagonist prazosin was shown to decrease extracellular serotonin levels in the hippocampus, the prefrontal cortex and the raphe nucleus, while the administration of the α₁-adrenoreceptor agonist cirazoline was shown to increase serotonin levels. Furthermore, the elevation of serotonin levels induced by the selective serotonin reuptake inhibitor (SSRI) citalopram was attenuated by prazosin. Thus, α₁-adrenoreceptor antagonists may affect SSRI-induced increases in extracellular serotonin levels and their antidepressive and anxiolytic effects. However, little is known about the influence of α₁-adrenoreceptor antagonists on the behavioral pharmacological effects of SSRIs. The conditioned fear stress-induced freezing behavior is an animal model of anxiety and can detect the anxiolytic effect of SSRIs. To clarify whether an α₁-adrenoreceptor antagonist affects the anxiolytic action of SSRIs, we examined the effects of the co-administration of the α₁-adrenoreceptor antagonist prazosin and the SSRI citalopram using the contextual conditioned fear stress model. Low-dose prazosin (0.03 mg/kg) significantly attenuated the citalopram (3 mg/kg)-induced decrease in conditioned freezing. Moreover, high-dose (0.5 mg/kg), but not low-dose (0.03 mg/kg), prazosin significantly attenuated citalopram (10 mg/kg)-induced decreases in conditioned freezing. These drugs did not affect the spontaneous motor activity of the rats. Therefore, these results suggest that blocking the α₁-adrenoreceptor decreases the anxiolytic effect of citalopram.
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Previous studies suggest that noradrenaline may regulate serotonergic (5-HT) neurotransmission at the serotonin cell body and noradrenaline nerve terminal. Using microdialysis coupled to HPLC, we investigated the effects of α1-adrenoceptor manipulation on extracellular serotonin levels – in the ventral hippocampus, prefrontal cortex, and raphe nuclei – in the presence or absence of the serotonin reuptake inhibitor (SSRI), citalopram. Extracellular 5-HT levels from prefrontal cortex, ventral hippocampus and raphe nuclei were markedly increased following citalopram administration (3.0 mg/kg s.c.). In the prefrontal cortex and ventral hippocampus, local blockade of the α1-adrenoceptor (3.0 μM prazosin infusion) significantly decreased this citalopram-induced increase in serotonin, while cirazoline (α1-adrenoceptor agonist) and reboxetine (noradrenaline reuptake inhibitor) further increased extracellular serotonin levels when administered systemically (0.02 mg/kg i.p. and 5.0 mg/kg s.c. respectively) or locally infused (10.0 μM and 1.0 μM respectively). Moreover, prazosin pre-infusion into terminal areas prevented the increase in citalopram-induced increase in serotonin levels with systemic cirazoline or reboxetine administration. Prazosin also decreased the citalopram-induced increase in serotonin levels in the raphe nuclei; however no enhancement of the SSRI response was observed with systemic or local administration of cirazoline or reboxetine, suggesting that α1-adrenoceptors may already be maximally activated under these conditions. These data provide strong evidence that after acute citalopram administration, the α1-adrenoceptor exerts a modulatory role on serotonin levels.
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Serotonergic fibers in the brain originate from a small number of cell bodies confined to the raphe nuclei of the brainstem and spread profusely, giving rise to an extensive arborization of axons in terminal fields. For this reason, it is not surprising that the brain serotonergic system is involved in several physiological as well as pathological conditions, and the regulation of serotonergic transmission at the level of raphe nuclei is of crucial importance in terms of serotonin (5-HT) action in nerve endings. The mechanisms that are responsible for the regulation of serotonergic transmission can be divided into intrinsic, i.e. those circumscribed to the internal function of 5-HT cells, and extrinsic, i.e. those that depend fundamentally on the interaction between other transmitter systems. The afferent connections of the raphe nuclei provide the neuroanatomical substrate for the interaction between different brain areas and serotonergic neurons. However, it is worth noting that these interactions are reciprocal. In this chapter we summarize the mutual interactions between serotonin and noradrenaline, dopamine, acetylcholine, GABA and glutamate. The considerable amount of interest in those interactions is due to the critical role they appear to play in mental functions. Special attention has been paid to the reciprocal control of the prefrontal cortex (PFC) and the midbrain raphe nuclei, which are involved in psychiatric diseases like major depression and schizophrenia.
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Mirtazapine is an antidepressant with a unique mechanism of action and has been categorized as a Noradrenergic and Specific Serotonergic Antidepressant (NaSSA). Although numerous clinical trials suggested the usefulness of mirtazapine for not only major depressive disorders but also a variety of anxiety disorders, efficacy studies in animal anxiety models have been rarely reported. The present study investigated a potential anxiolytic-like profile of mirtazapine in rat conditioned fear stress model. A 5-hydroxytryptamine (5-HT) 1A receptor partial agonist, buspirone (1–5 mg/kg) exhibited a significant reduction in freezing time, and its maximal effect was reversed by a selective 5-HT_1A antagonist, WAY-100635 (1 mg/kg). Mirtazapine (1–10 mg/kg) also reduced the freezing time in a dose-related fashion, a substantial proportion (approx. 50%) of which was likewise antagonized by WAY-100635 (1 mg/kg). Mianserin (1–30 mg/kg), a structural analogue for mirtazapine, was ineffective. Furthermore, co-administration of α1 adrenoceptor antagonist, prazosin (0.03 mg/kg) completely reversed mirtazapine (10 mg/kg)-induced reduction of freezing time. These findings represent the first demonstration that the anxiolytic-like action of mirtazapine involves activation of 5-HT_1A receptor and α1 adrenoceptor to different extents, and are compatible with one aspect of mirtazapine's pharmacological profile as NaSSA.
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Citation Excerpt :
Prolonged stimulation of these receptors leads to their desensitization [7,26], and desensitization is mediated by G-protein uncoupling from the receptors [43], which reduces the binding capacity. Firing of raphe 5-HT neurons is, in part, regulated by the α-1A adrenergic heteroreceptors and this action is suggested to be stimulatory [63]. The adrenergic influence on the firing rate is more pronounced in the dorsal raphe, rather than the median raphe, areas [36].
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α1-Adrenoceptor antagonists differentially control serotonin release in the hippocampus and striatum: a microdialysis study

Abstract

Neuropharmacology

Neuropharmacology

Neurosci. Lett.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Dev. Brain Res.

Brain Res. Rev.

Neurochem. Int.

Neurosci. Lett.

An autoradiographic analysis of the differential ascending projections of the dorsal and median raphé nuclei in the rat

J. Comp. Neurol.

Modification of 5-HT neuron properties by sustained administration of the 5-HT1A agonist gepirone: electrophysiological studies in the rat brain

Synapse

α₁-Adrenoceptor antagonists differentially control serotonin release in the hippocampus and striatum: a microdialysis study

Modification of 5-HT neuron properties by sustained administration of the 5-HT_1A agonist gepirone: electrophysiological studies in the rat brain