Enhancement of spatial reversal learning by 5-HT2C receptor antagonism is neuroanatomically specific.
We have recently demonstrated that systemic administration of 5-HT(2C) and 5-HT(2A) receptor antagonists significantly enhanced and impaired spatial reversal learning, respectively. In this study, the role of 5-HT(2C) and 5-HT(2A) receptor subtypes in the mediation of these opposing effects was further investigated with respect to neuroanatomical specificity. The roles of 5-HT(2C) and 5-HT(2A) receptors were examined within some of the brain regions implicated in cognitive flexibility, namely the orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and nucleus accumbens (NAc), by means of targeted infusions of selective 5-HT(2C) and 5-HT(2A) receptor antagonists (SB 242084 and M100907, respectively). Intra-OFC 5-HT(2C) receptor antagonism produced dose-dependent effects similar to those of systemic administration, i.e., improved spatial reversal learning by reducing the number of trials (all doses: 0.1, 0.3, and 1.0 microg) and perseverative errors to criterion (0.3 and 1.0 microg) compared with controls. However, the highest dose (1.0 microg) showed a nonselective effect, as it also affected retention preceding the reversal phase and decreased learning errors. Intracerebral infusions of SB 242084 into the mPFC or NAc produced no significant effects on any behavioral measures. Similarly, no significant differences were observed with intra-OFC, -mPFC, or -NAc infusions of M100907. These data suggest that the improved performance in reversal learning observed after 5-HT(2C) receptor antagonism is mediated within the OFC. These data also bear on the issue of whether 5-HT(2C) receptor antagonism within the OFC might help elucidate the biological substrate of obsessive-compulsive disorder, offering the potential for therapeutic application.
Boulougouris
Vasileios
V
Behavioural and Clinical Neuroscience Institute and Department of Experimental Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom. vboulougouris@googlemail.com
Robbins
Trevor W
TW
D000631:Aminopyridines / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D001931:Brain Mapping; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D012055:Reinforcement Schedule; D012193:Reversal Learning / Q000187:drug effects*; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013028:Space Perception / Q000187:drug effects*; D013997:Time Factors
C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D005464:Fluorobenzenes; D007211:Indoles; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; C079049:volinanserin