Impact of regional 5-HT depletion on the cognitive enhancing effects of a typical 5-ht(6) receptor antagonist, Ro 04-6790, in the Novel Object Discrimination task.
BACKGROUND
Selective 5-ht(6) receptor antagonists like Ro 04-6790 prolong memory in many rodent preclinical paradigms, possibly by blocking tonic 5-HT-evoked GABA release and allowing disinhibition of cortico-limbic glutamatergic and cholinergic neurones. If this is the case, behavioural responses to Ro 04-6790 should be abolished by depletion of endogenous 5-HT, and selective lesions of dorsal raphé (DR) or median raphé (MR) 5-HT pathways would allow the neuroanatomical substrates underlying the cognitive effects of 5-ht(6) receptor antagonists to be elucidated.


OBJECTIVE
This study compared the effect of Ro 04-6790 on novel object discrimination (NOD) before and after sham or 5,7-dihydroxytryptamine (5,7-DHT)-induced lesions produced by injection into the lateral ventricles (LV), DR or MR.


METHODS
NOD tests used a 4 h inter-trial interval (ITI) and Ro 04-6790 (10 mg kg(-1) i.p.) was administered 20 min before the familiarization trial. Brain region-specific 5-HT depletion was assessed by high performance liquid chromatography with electrochemical detection (HPLC-ED).


RESULTS
Widespread LV or selective MR, but not DR lesions, abolished the ability of Ro 04-6790 to delay natural forgetting. Successful performance of all lesioned rats in subsequent 'drug-free' NOD tests using a 1 h ITI excluded the possibility of any confounding effects on visual acuity or motivation.


CONCLUSIONS
The ability of Ro 04-6790 to prolong object recognition memory requires blockade of MR 5-HT function. Because DR lesions did not produce the expected depletion of striatal 5-HT an additional contribution of DR inputs to this region cannot be completely excluded.
Institute of Neuroscience, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG72UH, UK. madeleine.king@nottingham.ac.uk
M V
MV
King
C H
CH
Spicer
A J
AJ
Sleight
C A
CA
Marsden
K C F
KC
Fone
D015116:5,7-Dihydroxytryptamine / Q000008:administration & dosage / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D007276:Injections, Intraventricular; D008297:Male; D011597:Psychomotor Performance / Q000187:drug effects*; D011619:Psychotropic Drugs / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000502:physiology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000502:physiology*; D018490:Serotonin Agents / Q000008:administration & dosage / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D015116:5,7-Dihydroxytryptamine; D011619:Psychotropic Drugs; D011743:Pyrimidines; D011985:Receptors, Serotonin; D012701:Serotonin; D018490:Serotonin Agents; D012702:Serotonin Antagonists; C114163:Ro 4-6790; D000096926:Benzenesulfonamides; C097216:serotonin 6 receptor