Evidence that 5‐HT₂receptor activation decreases noradrenaline release in rat hippocampusin vivo

Abstract

1 Recent electrophysiological studies have shown that 5-HT215-HTlc receptor agonists inhibit the electrical activity of noradrenergic neurones in the rat locus coeruleus. Here we examine the effect of various agonists and antagonists of 5-HT2/5-HT,c receptors on noradrenaline release in hippocampus of anaesthetized rats using microdialysis.2 Subcutaneous administration of the 5-HT2/5-HTc receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl) -2-aminopropane (DOI: 0.2 and 0.5 mg kg-'), caused a marked decrease (50% of pre-drug levels 60 min after injection) of noradrenaline in hippocampal dialysates which was long-lasting (>120 min). Noradrenaline output also decreased in response to administration of the structural analogue of DOI, 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB: 1 mg kg-', s.c.). 3 The effect of DOI on noradrenaline output was prevented by pretreatment with the 5-HT2/5-HTc receptor antagonist, ritanserin (0.4 mg kg-1, s.c.). Spiperone (0.2 and 1 mg kg-', s.c.), a 5-HT2/dopamine D2 receptor antagonist which has low affinity for 5-HTc receptors, also antagonized the effect of DOI (0.5 mg kg-', s.c.). Sulpiride (50mg kg-', s.c.), a dopamine D2 receptor antagonist did not alter the response to DOI (0.5 mg kg-', s.c.).4 Both the non-selective 5-HT receptor agonist, quipazine (1 mg kg-', s.c.), and the 5-HT-releasing agent, p-chloroamphetamine (2 mg kg-', s.c.), decreased noradrenaline release in hippocampus and these effects were antagonized by pretreatment with ritanserin (0.4 mg kg', s.c.).5 Our data suggest that in vivo, noradrenaline release in hippocampus is inhibited by 5-HT2 receptor activation. This effect is probably associated with a decrease in noradrenergic neuronal activity.

5-HT Receptor Regulation of Neurotransmitter Release

“…For the 5-HT 2 receptor modulating NA release in the rat hippocampus, this effect is indirect as well and the location of the receptor is also by no means clear (Done and Sharp, 1992). These restrictions are valid because the respective microdialysis study in anesthetized rats was almost exclusively based on subcutaneous injection of nonselective 5-HT 2 receptor ligands.…”

“…In awake rats, the 5-HT 2 receptor antagonists ritanserin and ICI 170,809 given alone increased NA release, suggesting tonic activation of the 5-HT 2 receptors (Done and Sharp, 1994). The inhibition of NA release in the hippocampus (Done and Sharp, 1992) was suggested to be directly related to a decrease in the firing rate of noradrenergic neurons in the locus coeruleus in response to systemic administration of DOB, DOM, and quipazine, an effect sensitive to blockade by 5-HT 2 receptor antagonists Gorea and Adrien, 1988). A direct inhibitory action of the 5-HT 2 receptor ligands on the noradrenergic nerve terminals of the hippocampus was excluded in preliminary experiments by the failure of DOI, applied locally via the dialysis probe, to modify NA release.…”

Inhibitory 5‐hydroxytryptamine receptors involved in pressor effects obtained by stimulation of sympathetic outflow from spinal cord in pithed rats

“…The participation of 5-HT in the control of blood pressure (Cohen, 1984;Grading et al, 1985;Saxena et al, 1987; Dabire, 1990) and the modulation of cardiac and vascular sympathetic transmission has also been demonstrated. For this modulation, potentiating and inhibitory actions have been proposed, however in both cases there is a disparity between mechanisms postulated to account for such actions (Fozard & Mwaluko, 1976;Fozard, 1984b;Coote et al, 1987;Docherty, 1988;Bom et al, 1989;Shepheard et al, 1991;Done & Sharp, 1992).…”

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“…They reported the inhibitory infl uence of the 5-HT agonists on the NA synthesis in this nucleus [ 13 ] . In addition, the latter study suggested that the 5-HT 2 receptors mediate the 5-HT inhibitory eff ect on the NA synthesis [ 13 ] . Duloxetine is also a 5-HT and NA reuptake inhibitor [ 14 ] that inhibits the 5-HT reuptake 5-fold greater than the NA [ 15 ] .…”

“…Besides, Done, et. al. reported that the 5-HT induces the inhibitory eff ect on the LC hyperactivity that is mediated by the 5-HT 2 receptors [ 13 ] . Moreover, antidepressant drugs with the 5-HT and/or the NA reuptake inhibition activity are frequently used for the treatment of pains related to postherpetic neuralgia, diabetic neuropathy, and fi bromyalgia [ 43 , 44 ] .…”