Activation of the retrohippocampal region in the rat causes dopamine release in the nucleus accumbens: disruption by fornix section.
There is a well-described projection from the retrohippocampus (subiculum and entorhinal cortex) to the nucleus accumbens that is involved in the control of psychomotor behaviour, and is implicated in the aetiology of schizophrenia. Cortical abnormalities are widely reported in the brains of schizophrenic patients, but it is unclear whether they are the cause or consequence of those changes in subcortical systems that are treated with neuroleptic drugs. We have, therefore, conducted a series of microdialysis experiments in anaesthetized rats to determine whether infusion of the excitotoxin, N-methyl-D-aspartate, into the retrohippocampus increases mesolimbic dopamine release. We found a clear and reproducible increase in extracellular dopamine in the nucleus accumbens following N-methyl-D-aspartate (2.5 microg), that was abolished when we sectioned the fimbria-fornix. Furthermore, inhibition of gamma-aminobutyric acid receptors following retrohippocampus administration of bicuculline (4 microg), also increased dopamine in the nucleus accumbens. The dopamine response to bicuculline was accompanied by an increase in dopamine metabolism, was long lasting, and also reduced by fornix section.The response to both N-methyl-D-aspartate and bicuculline depends on the integrity of the projection from the retrohippocampus to the nucleus accumbens. The results provide an underlying mechanism whereby a primary insult in the temporal cortex, caused by excessive N-methyl-D-aspartate receptor stimulation, can produce a hyperdopaminergic state. In addition, an increase in subiculo-accumbens activity evoked by bicuculline may also explain why patients with limbic epilepsy can develop a psychosis.
Mitchell
S N
SN
Department of Psychology, Institute of Psychiatry, De Crespigny Park, Denmark Hill, SE5 8AF, London, UK. mitchell_stephen@lilly.com
Yee
B K
BK
Feldon
J
J
Gray
J A
JA
Rawlins
J N
JN
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018728:Entorhinal Cortex / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D020712:Fornix, Brain / Q000293:injuries; D018756:GABA Antagonists / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D016202:N-Methylaspartate; D004298:Dopamine; D001640:Bicuculline