Acute increases in monoamine release in the rat prefrontal cortex by the mGlu2/3 agonist LY379268 are similar in profile to risperidone, not locally mediated, and can be elicited in the presence of uptake blockade.
Our recent work (Cartmell et al., Journal of Neurochemistry, 75 (2000) 1147-1154) demonstrated that systemic injection of the potent, selective mGlu2/3 receptor agonist, LY379268, acutely increased extracellular levels of dopamine, its metabolites DOPAC and HVA, and the 5-HT metabolite, 5-HIAA, in rat medial prefrontal cortex (mPFC). Here, we compared the acute effects of LY379268 with those of clozapine and risperidone (atypical antipsychotics) on extracellular levels of both dopamine and 5-HT in the mPFC of freely-moving rats. Uptake blockers were included to minimize metabolism of monoamines near the probe area. One hour after injection, LY379268 (10 mg/kg s.c.), clozapine (10 mg/kg s.c.) or risperidone (1 mg/kg s.c.) maximally increased dopamine by 224, 257 and 234% of basal levels. These effects were followed by maximal increases in DOPAC and HVA levels 2 to 3.5 hours after administration. LY379268, at 3 and 10 mg/kg s.c., and risperidone (1 mg/kg s.c.) also increased dialysate 5-HT to 169, 179 and 140% of basal levels and 5-HIAA to 144, 154 and 121% of basal levels, respectively. These neurochemical changes in the mPFC could not be mimicked when LY379268 (3 or 30 microM) was administered locally via the microdialysis probe. These data demonstrate that increases in extracellular monoamines in the rat prefrontal cortex evoked acutely by the mGlu2/3 agonist, LY379268, are similar in profile to risperidone, not locally mediated, and can be elicited in the presence of uptake blockade.
Cartmell
J
J
Lilly Research Laboratories, Eli Lilly and Company, IN Indianapolis 46285, USA.
Perry
K W
KW
Salhoff
C R
CR
Monn
J A
JA
Schoepp
D D
DD
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*
D000596:Amino Acids; D015306:Biogenic Monoamines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018492:Dopamine Antagonists; D018690:Excitatory Amino Acid Agonists; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; D012702:Serotonin Antagonists; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D003024:Clozapine; D018967:Risperidone; D004298:Dopamine; D006719:Homovanillic Acid