Effects of 5-HT1A, 5-HT2A and 5-HT2C receptor agonists and antagonists on responding for a conditioned reinforcer and its enhancement by methylphenidate

Psychopharmacology (Berl). 2017 Mar;234(5):889-902. doi: 10.1007/s00213-017-4529-5. Epub 2017 Jan 18.

Abstract

Objectives: These experiments examined the effects of selective 5-HT1A, 5-HT2A and 5-HT2C receptor ligands on responding for a conditioned reinforcer (CRf). Effects of these ligands were measured under basal conditions and following elevated dopamine (DA) activity produced by the DA reuptake inhibitor methylphenidate.

Methods: Water-restricted rats learned to associate a conditioned stimulus (CS) with water in operant chambers. Subsequently, two response levers were made available; responding on one lever delivered the CS (now a CRf), while responding on the second lever had no consequences. The effects of agonist and antagonists of 5-HT1A (8-hydroxy-2(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT) and N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635)), 5-HT2A (DOI and M100907) and 5-HT2C (Ro60-0175 and SB242084) receptors on responding were examined alone, as well as in the presence of methylphenidate.

Results: Responding for a CRf was reduced by the agonists 8-OH-DPAT, DOI and Ro60-0175. 8-OH-DPAT also reduced responding for water and seemed to impair responding in a non-specific fashion. None of the receptor antagonists affected responding. Methylphenidate dose-dependently enhanced responding for a CRf, and this was attenuated by DOI and Ro60-0175. Conversely, the 5-HT2C receptor antagonist SB242084 potentiated the effect of methylphenidate.

Conclusions: No evidence was found for a behaviourally selective effect of 5-HT1A receptor ligands on responding for a CRf. Activation of 5-HT2A receptors selectively inhibits responding for a CRf. 5-HT2C receptor ligands exerted bidirectional modulation of responding for a CRf, especially when DA activity was increased. This indicates that 5-HT2C receptor activity is an important modulator of DA-dependent reward-related behaviours.

Keywords: 5-HT1A receptors; 5-HT2A receptors; 5-HT2C receptors; Conditioned reinforcer; Methylphenidate; Serotonin.

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Aminopyridines / pharmacology
  • Amphetamines / pharmacology
  • Animals
  • Conditioning, Operant / drug effects*
  • Fluorobenzenes / pharmacology
  • Indoles / pharmacology
  • Male
  • Methylphenidate / pharmacology*
  • Piperazines / pharmacology
  • Piperidines / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Receptor, Serotonin, 5-HT1A
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Reinforcement, Psychology
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Serotonin 5-HT1 Receptor Antagonists / pharmacology
  • Serotonin 5-HT2 Receptor Agonists / pharmacology
  • Serotonin 5-HT2 Receptor Antagonists / pharmacology
  • Serotonin Antagonists / pharmacology*
  • Serotonin Receptor Agonists / pharmacology*

Substances

  • 6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline
  • Aminopyridines
  • Amphetamines
  • Fluorobenzenes
  • Indoles
  • Piperazines
  • Piperidines
  • Pyridines
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • Methylphenidate
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • volinanserin
  • 4-iodo-2,5-dimethoxyphenylisopropylamine

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