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.
King
M V
MV
Institute of Neuroscience, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG72UH, UK. madeleine.king@nottingham.ac.uk
Spicer
C H
CH
Sleight
A J
AJ
Marsden
C A
CA
Fone
K C F
KC
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