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

• Published in: Psychopharmacology Vol. 234; no. 5; pp. 889 - 902
• Main Authors: Fletcher, Paul J., Zeeb, Fiona D., Browne, Caleb J., Higgins, Guy A., Soko, Ashlie D.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-03-2017
• Subjects: Biomedical and Life Sciences; Biomedicine; Neurosciences; Original Investigation; Pharmacology/Toxicology; Psychiatry; Conditioned reinforcer; Serotonin; receptors; 5-HT; Methylphenidate
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-017-4529-5

Objectives
These experiments examined the effects of selective 5-HT
1A
, 5-HT
2A
and 5-HT
2C
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-HT
1A
(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-HT
2A
(DOI and M100907) and 5-HT
2C
(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-HT
2C
receptor antagonist SB242084 potentiated the effect of methylphenidate.
Conclusions
No evidence was found for a behaviourally selective effect of 5-HT
1A
receptor ligands on responding for a CRf. Activation of 5-HT
2A
receptors selectively inhibits responding for a CRf. 5-HT
2C
receptor ligands exerted bidirectional modulation of responding for a CRf, especially when DA activity was increased. This indicates that 5-HT
2C
receptor activity is an important modulator of DA-dependent reward-related behaviours.