Electrical sensitization of the meso-limbic dopaminergic system in rats: a pathogenetic model for schizophrenia.
To study whether it was possible to modify mesolimbic dopaminergic activity by intermittent electrical stimulations (IES), 44 rats were either electrically stimulated or sham-stimulated in the ventral tegmental area (VTA) once daily for 70 days. This was done through chronically implanted intracranial electrodes. The intensity of electrical stimulation was determined by the lowest current that elicited a definite motor response. Stimulated rats demonstrated a significantly potentiated behavioral response after 70 stimulations. Seven months after IES rats still demonstrated an increased sensitivity to electrical stimulations in the VTA. A new stimulation period only resulted in a modest additional fall in threshold values. There was a highly significant difference between the current needed to provoke a given response in sensitized rats and in sham-stimulated rats. The behavioral response to stimulation was suppressed both by the dopamine (DA) D2 receptor antagonists haloperidol and raclopride and by the DA D1 receptor antagonist SCH 23390. Furthermore, stimulated rats showed an enhanced response to stimulation with amphetamine and to a lesser extent with apomorphine. Between stimulation periods sensitized animals demonstrated a reduced social interaction. In conclusion intermittent electrical stimulations of the VTA resulted in a syndrome characterized by a hypersensitive response to electrical and pharmacological DA provocation combined with abnormal social interaction. This animal model has points of resemblance with recent interpretations of the DA hypothesis for schizophrenia.
Department of Psychiatry, University of Copenhagen, Rigshospitalet, Denmark.
B
B
Glenthøj
J
J
Mogensen
H
H
Laursen
S
S
Holm
R
R
Hemmingsen
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D004195:Disease Models, Animal; D065127:Dopamine D2 Receptor Antagonists; D004558:Electric Stimulation; D004569:Electroencephalography; D006185:Habituation, Psychophysiologic; D006220:Haloperidol / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D008297:Male; D008959:Models, Neurological; D009043:Motor Activity / Q000187:drug effects; D020891:Raclopride; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D012457:Salicylamides / Q000494:pharmacology; D012559:Schizophrenia / Q000503:physiopathology*; D012640:Seizures / Q000503:physiopathology; D013239:Stereotyped Behavior / Q000187:drug effects; D013681:Tegmentum Mesencephali / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D013997:Time Factors
D001552:Benzazepines; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D012457:Salicylamides; D020891:Raclopride; D000661:Amphetamine; D006220:Haloperidol; D001058:Apomorphine