Site-specific activation of dopamine and serotonin transmission by aniracetam in the mesocorticolimbic pathway of rats.
The effects of aniracetam on extracellular levels of dopamine (DA), serotonin (5-HT) and their metabolites were examined in five brain regions in freely moving stroke-prone spontaneously hypertensive rats (SHRSP) using in vivo microdialysis. Basal DA release in SHRSP was uniformly lower in all regions tested than that in age-matched control Wistar Kyoto rats. 3,4-Dihydroxyphenylacetic acid and homovanillic acid levels were altered in the basolateral amygdala, dorsal hippocampus and prefrontal cortex of SHRSP. While basal 5-HT release decreased in the striatum and increased in the basolateral amygdala, there was no associated change in 5-hydroxyindoleacetic acid levels. Systemic administration of aniracetam to SHRSP enhanced both DA and 5-HT release with partly associated change in their metabolite levels in the prefrontal cortex, basolateral amygdala and dorsal hippocampus, but not in the striatum and nucleus accumbens shell, in a dose-dependent manner (30 and/or 100 mg/kg p.o.). Microinjection (1 and 10 ng) of aniracetam or its metabolites (N-anisoyl-GABA and 2-pyrrolidinone) into the nucleus accumbens shell produced no turning behavior. These findings indicate that SHRSP have a dopaminergic hypofunction throughout the brain and that aniracetam elicits a site-specific activation in mesocorticolimbic dopaminergic and serotonergic pathways in SHRSP, possibly via nicotinic acetylcholine receptors in the ventral tegmental area and raphe nuclei. The physiological roles in the aniracetam-sensitive brain regions may closely link with their clinical efficacy towards emotional disturbances appearing after cerebral infarction.
Nakamura
K
K
CNS Supporting Laboratory, Nippon Roche Research Center, 200 Kajiwara, Kamakura, 247-8530, Kanagawa, Japan. kazuo.nakamura@roche.com
Shirane
M
M
Koshikawa
N
N
D000679:Amygdala / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009434:Neural Pathways / Q000378:metabolism; D018697:Nootropic Agents / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism; D017397:Prefrontal Cortex / Q000166:cytology / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012701:Serotonin / Q000378:metabolism*; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D018697:Nootropic Agents; D011760:Pyrrolidinones; D012701:Serotonin; C036466:aniracetam; D004298:Dopamine