Cholinergic modulation of basal and amphetamine-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens.
Behavioral evidence suggests that muscarinic/cholinergic inhibition of brain dopaminergic activity may be a useful principle for developing novel antipsychotic drugs (APDs). Thus, oxotremorine, a muscarinic agonist, attenuates amphetamine-induced locomotor activity in rodents, an effect also produced by a wide variety of proven APDs, whereas scopolamine, a muscarinic antagonist, has the opposite effect. Since atypical APDs such as clozapine, olanzapine, risperidone, ziprasidone and quetiapine, increase brain acetylcholine as well as dopamine (DA) release in a region-specific manner, their effects on cholinergic and dopaminergic neurotransmission may also contribute to various actions of these drugs. Oxotremorine (0.5-1.5 mg/kg) dose-dependently and preferentially increased DA release in rat medial prefrontal cortex (mPFC), compared to the nucleus accumbens (NAC). However, S-(-)-scopolamine (0.5-1.5 mg/kg) produced similar increases in DA release in the mPFC, but the effect was much less than that of oxotremorine. Whereas a dose of S-(-)-scopolamine of 0.5 mg/kg comparably increased DA release in the mPFC and NAC, 1.5 mg/kg had no effect on DA release in the NAC. Oxotremorine-M (0.5 mg/kg), a M(1/4)-preferring agonist, also increased DA release in the mPFC, but not the NAC, an effect completely abolished by telenzepine (3 mg/kg), a M(1/4)-preferring antagonist, which by itself had no effect on DA release in either region. Oxotremorine (0.5, but not 1.5, mg/kg) attenuated amphetamine (1 mg/kg)-induced DA release in the NAC, whereas S-(-)-scopolamine did not. Oxotremorine (1.5 mg/kg) and S-(-)-scopolamine (0.5 mg/kg) modestly but significantly potentiated amphetamine (1 mg/kg)-induced DA release in the mPFC. These results suggest that stimulation of muscarinic receptors, in particular M(1/4), as indicated by the effect of oxotremorine-M and telenzepine, may preferentially increase cortical DA release and inhibit amphetamine-induced DA release in the NAC.
Ichikawa
Junji
J
Division of Psychopharmacology, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37212, USA. ichkaj@ctrvax.vanderbilt.edu
Chung
Young Chul
YC
Li
Zhu
Z
Dai
Jin
J
Meltzer
Herbert Y
HY
D000109:Acetylcholine / Q000378:metabolism*; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010095:Oxotremorine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy*; D012601:Scopolamine / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D011976:Receptors, Muscarinic; C046338:telenzepine; D010890:Pirenzepine; D010095:Oxotremorine; C042743:oxotremorine M; D000661:Amphetamine; D012601:Scopolamine; D000109:Acetylcholine; D004298:Dopamine