Alterations in local cerebral glucose utilization produced by D3 dopamine receptor-selective doses of 7-OH-DPAT and nafadotride.
The D3 dopamine receptor, localized primarily in limbic brain areas, is a potential antipsychotic site. The effects of D3 receptor stimulation or blockade on neuronal activity were determined using the [14C]-2-deoxyglucose method. Freely-moving, adult, male, Sprague-Dawley rats were injected s.c. with saline, agonist 7-hydroxy-diphenylaminotetralin (7-OH-DPAT) (0.1 mg/kg), or antagonist l-nafadotride (1 mg/kg). These doses of 7-OH-DPAT and l-nafadotride are behaviorally active and are 10-fold lower than a dose producing significant in vivo occupancy of D2 receptors. The [14C]-2-deoxyglucose procedure was initiated 30 min after the administration of the test compound. The rate of local cerebral glucose utilization (LCGU) was determined by quantitative autoradiography. 7-OH-DPAT produced a significant increase in LCGU in the substantia nigra. l-Nafadotride produced significant increases in LCGU in several brain areas including the lateral preoptic area, lateral habenula, caudate, septal area, entorhinal cortex, and some thalamic and hypothalamic areas. These observations indicate that stimulation or blockade of D3 receptors alters LCGU and that produces a unique pattern of alterations in LCGU suggestive of potential antipsychotic activity.
Levant
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Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7147, USA. blevant@kumc.edu
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Pazdernik
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D000818:Animals; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D009281:Naphthalenes; D011759:Pyrrolidines; D013764:Tetrahydronaphthalenes; D005947:Glucose; C097285:nafadotride; C031349:7-hydroxy-2-N,N-dipropylaminotetralin