Serotonergic lesions of the dorsal hippocampus differentially modulate locomotor hyperactivity induced by drugs of abuse in rats: implications for schizophrenia.
BACKGROUND
Psychotomimetic drug-induced locomotor hyperactivity is a widely used animal model of psychotic states, such as in schizophrenia. We previously found that serotonergic lesions of the dorsal, but not ventral, hippocampus in rats result in enhanced phencyclidine-induced locomotor hyperactivity.


OBJECTIVE
The objective of this study was to investigate the effect of serotonin depletion in the dorsal and ventral hippocampus on hyperlocomotion induced by ketamine, cocaine, 3,4-methylenedioxymethampethamine (MDMA), methamphetamine, and D: -amphetamine.


METHODS
Male Sprague-Dawley rats were bilaterally microinjected with vehicle or the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the dorsal or ventral hippocampus using a stereotaxic approach. Separate cohorts of rats were used for each drug of abuse; each rat received saline and a low, medium, and high dose of the drug in a random-sequence, repeated-measures protocol. Locomotor hyperactivity following treatment was measured using automated photocell cages.


RESULTS
Similar to phencyclidine, 5,7-DHT-induced lesions of the dorsal hippocampus enhanced ketamine-induced hyperlocomotion at all doses. They also reduced methamphetamine-induced hyperlocomotion at the high dose only and caused a minor, biphasic modulation of responses to cocaine. Locomotor responses to D: -amphetamine and MDMA were unchanged by lesions of the dorsal hippocampus. Serotonergic lesions of the ventral hippocampus did not significantly alter locomotor hyperactivity induced by any of the drugs investigated.


CONCLUSIONS
These findings further implicate a role for serotonin in the dorsal hippocampus in modulating the behavioral effects of dissociative anesthetics, such as ketamine, with more subtle effects on psychostimulant drugs of abuse. The dorsal hippocampus may be a site of serotonergic dysfunction in aspects of schizophrenia.
Adams
Wendy
W
Behavioural Neuroscience Laboratory, Mental Health Research Institute of Victoria, 155 Oak Street, Parkville, VIC 3052, Australia.
Ayton
Scott
S
van den Buuse
Maarten
M
D015116:5,7-Dihydroxytryptamine / Q000633:toxicity; D000662:Amphetamines / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D006948:Hyperkinesis / Q000139:chemically induced*; D007649:Ketamine / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D010622:Phencyclidine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000503:physiopathology*; D012701:Serotonin / Q000378:metabolism*
D000662:Amphetamines; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D007649:Ketamine; D003042:Cocaine; D010622:Phencyclidine