Blockade of 5-HT 1B receptors facilitates contextual aversive learning in mice by disinhibition of cholinergic and glutamatergic neurotransmission

Neuropharmacology. 2008 Jun;54(7):1041-50. doi: 10.1016/j.neuropharm.2008.02.007. Epub 2008 Apr 3.

Abstract

Serotonergic (5-HT) neurotransmission plays a role in learning and memory processes, but the physiological role of various receptor subtypes is not well characterised. Among these, 5-HT(1B) receptors are located as autoreceptors on 5-HT axons and heteroreceptors on non-serotonergic terminals. This study examined the role of the 5-HT(1B) receptor in one-trial aversive contextual learning using the passive avoidance (PA) task in NMRI mice. Subcutaneous administration of the 5-HT(1B) receptor agonist anpirtoline (0.1-1.0mg/kg) before PA training impaired retention performance 24h later. Combined administration of anpirtoline with the selective 5-HT(1B) receptor antagonist NAS-181 (0.1-1.0mg/kg) fully blocked the impairments. Administration of NAS-181 alone dose-dependently improved PA retention performance. This facilitatory effect was blocked by subthreshold doses of both the muscarinic antagonist scopolamine (0.03 mg/kg) and the NMDA receptor antagonist MK-801 (0.03 mg/kg). NAS-181 also fully blocked the PA impairments induced by an amnesic dose of scopolamine (0.1mg/kg), when administered prior to, but not after, scopolamine. In addition, NAS-181 attenuated PA impairments induced by MK-801 (0.3mg/kg). These findings indicate that 5-HT(1B) receptors are activated at basal levels of 5-HT transmission. The facilitatory effect of NAS-181 involved alleviation of an inhibitory 5-HT tone mediated via 5-HT(1B) receptors on cholinergic and glutamatergic transmission. This disinhibition is expected to occur in neuronal circuits involved in contextual learning including the hippocampus and interconnected cortico-limbic regions. Blockade of brain 5-HT(1B) heteroreceptors may represent a novel therapeutic strategy for restoration of deficient cholinergic and glutamatergic neurotransmission contributing to memory disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism*
  • Analysis of Variance
  • Animals
  • Avoidance Learning / drug effects
  • Avoidance Learning / physiology*
  • Behavior, Animal / drug effects
  • Benzopyrans / pharmacology
  • Cholinergic Antagonists / pharmacology
  • Dizocilpine Maleate / pharmacology
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glutamic Acid / metabolism*
  • Male
  • Mice
  • Morpholines / pharmacology
  • Piperidines / pharmacology
  • Pyridines / pharmacology
  • Reaction Time / drug effects
  • Receptor, Serotonin, 5-HT1B / physiology*
  • Scopolamine / pharmacology
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / pharmacology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*

Substances

  • 2-(((3-(morpholinylmethyl)-2H-chromen-8-yl)oxy)methyl)morpholine
  • Benzopyrans
  • Cholinergic Antagonists
  • Excitatory Amino Acid Antagonists
  • Morpholines
  • Piperidines
  • Pyridines
  • Receptor, Serotonin, 5-HT1B
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • anpirtolin
  • Glutamic Acid
  • Dizocilpine Maleate
  • Scopolamine
  • Acetylcholine