Modulation of serotonergic neurotransmission by short‐ and long‐term treatments with sigma ligands

Modulation of serotonergic neurotransmission by short‐ and long‐term treatments with sigma... Sigma receptors were first described in 1976 as opiate receptors but were later determined to be a distinct class of receptors with two subtypes, sigma1 and sigma2. Although the endogenous ligand is yet to be elucidated, the sigma1 receptor has recently been cloned. Behavioural models used to test potential antidepressants have shown sigma ligands to produce antidepressant effects but their mechanism of action is unknown. The goal of the present study was to assess the effects of various sigma1 ligands on the firing activity of serotonin (5‐HT) neurons of the dorsal raphe nucleus (DRN) using extracellular in vivo recordings in anaesthetized rats. The sigma1 ligands (+)‐pentazocine and 4‐(N‐benzylpiperidin‐4‐yl)‐4‐iodobenzamide (4‐IBP) (2 mg kg−1 day−1) increased markedly 5‐HT firing activity after 2 days of treatment and maintained the same increased firing rate after long‐term (21 days) treatments. Furthermore, the increased firing rate produced by 2 and 21 day treatments with (+)‐pentazocine was prevented by the co‐administration of N,N‐dipropyl‐2‐(4‐methoxy‐3‐(2‐phenylethoxy)phenyl)‐thylamine (NE‐100) (10 mg kg−1 day−1) a selective sigma1 antagonist, confirming the sigma1 receptor's modulation of these effects. In contrast, the sigma1 ligands (+)‐N‐cyclopropylmethyl‐N‐methyl‐1,4‐diphenyl‐1‐1‐ethyl‐but‐3‐en‐1‐ylamine hydrochloride (JO‐1784) and 2‐(4‐morpholinoethyl 1‐phenyl‐cyclohexane‐1‐carboxylate hydrochloride (PRE‐084) had no effect. Following a 21‐day treatment with (+)‐pentazocine there was a marked reduction in the number of neurons found per track. This decrease was not seen after chronic treatment with 4‐IBP and may represent a depolarization block. These results suggest a modulation of serotonergic neurotransmission by some sigma receptors and provide a potential mechanism for the ‘antidepressant effects’ reported and provide evidence toward sigma1 ligands as potential antidepressants with a rapid onset of action. British Journal of Pharmacology (2001) 134, 691–699; doi:10.1038/sj.bjp.0704294 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Modulation of serotonergic neurotransmission by short‐ and long‐term treatments with sigma ligands

British Journal of Pharmacology, Volume 134 (3) – Oct 1, 2001

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Publisher
Wiley
Copyright
2001 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0704294
pmid
11588125
Publisher site
See Article on Publisher Site

Abstract

Sigma receptors were first described in 1976 as opiate receptors but were later determined to be a distinct class of receptors with two subtypes, sigma1 and sigma2. Although the endogenous ligand is yet to be elucidated, the sigma1 receptor has recently been cloned. Behavioural models used to test potential antidepressants have shown sigma ligands to produce antidepressant effects but their mechanism of action is unknown. The goal of the present study was to assess the effects of various sigma1 ligands on the firing activity of serotonin (5‐HT) neurons of the dorsal raphe nucleus (DRN) using extracellular in vivo recordings in anaesthetized rats. The sigma1 ligands (+)‐pentazocine and 4‐(N‐benzylpiperidin‐4‐yl)‐4‐iodobenzamide (4‐IBP) (2 mg kg−1 day−1) increased markedly 5‐HT firing activity after 2 days of treatment and maintained the same increased firing rate after long‐term (21 days) treatments. Furthermore, the increased firing rate produced by 2 and 21 day treatments with (+)‐pentazocine was prevented by the co‐administration of N,N‐dipropyl‐2‐(4‐methoxy‐3‐(2‐phenylethoxy)phenyl)‐thylamine (NE‐100) (10 mg kg−1 day−1) a selective sigma1 antagonist, confirming the sigma1 receptor's modulation of these effects. In contrast, the sigma1 ligands (+)‐N‐cyclopropylmethyl‐N‐methyl‐1,4‐diphenyl‐1‐1‐ethyl‐but‐3‐en‐1‐ylamine hydrochloride (JO‐1784) and 2‐(4‐morpholinoethyl 1‐phenyl‐cyclohexane‐1‐carboxylate hydrochloride (PRE‐084) had no effect. Following a 21‐day treatment with (+)‐pentazocine there was a marked reduction in the number of neurons found per track. This decrease was not seen after chronic treatment with 4‐IBP and may represent a depolarization block. These results suggest a modulation of serotonergic neurotransmission by some sigma receptors and provide a potential mechanism for the ‘antidepressant effects’ reported and provide evidence toward sigma1 ligands as potential antidepressants with a rapid onset of action. British Journal of Pharmacology (2001) 134, 691–699; doi:10.1038/sj.bjp.0704294

Journal

British Journal of PharmacologyWiley

Published: Oct 1, 2001

References

  • Dual control of dorsal raphe serotonergic neurons by GABA B receptors. Electrophysiological and microdialysis studies
    ABELLAN, ABELLAN; JOLAS, JOLAS; AGHAJANIAN, AGHAJANIAN; ARTIGAS, ARTIGAS
  • Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei
    BEL, BEL; ARTIGAS, ARTIGAS
  • Effects of the two antidepressant drugs mianserin and indalpine on the serotonergic system: Single‐cell studies in the rat
    BLIER, BLIER; DE MONTIGNY, DE MONTIGNY; TARDIF, TARDIF
  • Some of the effects of the selective sigma ligand (+)pentazocine are mediated via a naloxone‐sensitive receptor
    COUTURE, COUTURE; DEBONNEL, DEBONNEL
  • Role of the medial prefrontal cortex in 5‐HT 1A ‐induced inhibition of 5‐HT neuronal activity in the rat
    HAJOS, HAJOS; HAJOS‐KORCSOK, HAJOS‐KORCSOK; SHARP, SHARP
  • Beneficial effects of sigma agonists on the age‐related learning impairment in the senescence‐accelerated mouse (SAM)
    MAURICE, MAURICE; ROMAN, ROMAN; SU, SU; PRIVAT, PRIVAT
  • The effects of sigma ligands and of neuropeptide Y or N‐methyl‐D‐aspartate‐induced neuronal activation of CA 3 hippocampus neurones are differentially affected by pertussin toxin
    MONNET, MONNET; DEBONNEL, DEBONNEL; BERGERON, BERGERON; GRONIER, GRONIER; DE MONTIGNEY, DE MONTIGNEY

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