In vivo evidence for the existence of autoreceptors on dopaminergic, serotonergic, and cholinergic neurons in the brain.
Intrastriatal infusions as well as systemic administration of the selective D-2 antagonist (-)-sulpiride caused similar increases in the dialysate levels of dopamine (DA) to about 180% of controls. A similar conclusion was drawn when the selective D-2 agonist (-)-N-0437 was infused intrastriatally or administered systemically: both routes of administration caused a decrease in the release of DA to about 40-50% of controls. In order to evaluate the properties of synthesis-modulating autoreceptors on dopaminergic and serotonergic neurons we have estimated the synthesis rate of serotonin (5-HT) or DA by monitoring the 5-HTP or DOPA formation in the dialysates during infusion of a decarboxylase inhibitor. Infusion of (-)-N-0437 decreased the DOPA formation, whereas infusion of (-)-sulpiride increased the dialysate levels of DOPA; these results indicate that the D-2 receptors controlling the synthesis of DA are localized on nerve terminals. Administration of the selective 5-HT-IA agonist 8-hydroxy-dipropyl-aminotetraline (8-OH-DPAT) resulted in a decrease in the synthesis rate of 5-HT. When 8-OH-DPAT was infused via the dialysis membrane, the agonist was unable to modify the release of 5-HT. The effects of infusion of the muscarinic agonist oxotremorine and the muscarinic antagonist atropine were dependent on the presence of the esterase inhibitor neostigmine in the perfusion fluid. In the absence of neostigmine, oxotremorine caused a pronounced decrease in the output of acetylcholine (ACh), whereas atropine was without effect. In the presence of neostigmine oxotremorine was without effect but infusion of atropine or other anticholinergics caused a pronounced increase in the dialysate levels of ACh. It is concluded that the autoreceptor controlling the release of ACh is of the M3-type and that the receptor is not fully occupied during normal conditions. In conclusion, microdialysis of neurotransmitters is a valuable tool for the study of autoreceptors in vivo. The presented studies provided evidence for the existence of autoreceptors controlling the synthesis and/or release of DA, 5-HT, as well as ACh in the striatum.
Westerink
B H
BH
Department of Medicinal Chemistry, University of Groningen, The Netherlands.
De Boer
P
P
Timmerman
W
W
De Vries
J B
JB
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003956:Dialysis / Q000379:methods; D004298:Dopamine / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology; D006706:Homeostasis; D008297:Male; D009388:Neostigmine / Q000494:pharmacology; D009474:Neurons / Q000502:physiology; D010275:Parasympathetic Nervous System / Q000166:cytology / Q000502:physiology*; D010277:Parasympathomimetics / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D012701:Serotonin / Q000502:physiology*; D013237:Stereoisomerism; D013469:Sulpiride / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
D015259:Dopamine Agents; D010277:Parasympathomimetics; D017981:Receptors, Neurotransmitter; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D012701:Serotonin; D009388:Neostigmine; D013469:Sulpiride; C047508:rotigotine; D000109:Acetylcholine; D004298:Dopamine