title: Activation of beta1-adrenoceptors excites striatal cholinergic interneurons through a cAMP-dependent, protein kinase-independent pathway.
abstract: The role of noradrenergic neurotransmission was analyzed in striatal cholinergic interneurons. Conventional intracellular and whole-cell patch-clamp recordings were made of cholinergic interneurons in rat brain slice preparations. Bath-applied noradrenaline (NA) (1-300 microm) dose-dependently induced both an increase in the spontaneous firing activity and a membrane depolarization of the recorded cells. In voltage-clamped neurons, an inward current was induced by NA. This effect was not prevented by alpha-adrenoceptor antagonists, whereas it was mimicked by the beta-adrenoceptor agonist isoproterenol and blocked by the beta1 antagonists propranolol and betaxolol. Interestingly, forskolin, activator of adenylate cyclase, mimicked and occluded the membrane depolarization obtained at saturating doses of both dopamine and NA. Accordingly, SQ22,536, a selective adenylate cyclase inhibitor, reduced the response to NA. Analysis of the reversal potential of the NA-induced current did not provide homogeneous results, indicating the involvement of multiple membrane conductances. Because cAMP is known to modulate Ih, the effects of ZD7288, a selective inhibitor of Ih current, were examined on the NA-induced membrane depolarization/inward current. ZD7288 mostly reduced the response to NA. However, both KT-5720 and H-89, selective protein kinase A (PKA) blockers, failed to prevent the excitatory action of NA. Likewise, calphostin C, antagonist of PKC, genistein, inhibitor of tyrosine kinase, and 8-Bromo-cGMP, blocker of PKG, did not affect the response to NA. Finally, double-labeling experiments combining beta1-adrenoceptor and choline acetyltransferase immunocytochemistry by means of confocal microscopy revealed a strong beta1-adrenoceptor labeling on cholinergic interneurons. We conclude that NA depolarizes striatal cholinergic interneurons via beta1-adrenoceptor activation, through a cAMP-dependent but PKA-independent mechanism.
authors.affiliation: Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma Tor Vergata, Rome, Italy. pisani@uniroma2.it
authors.forename: A
authors.initials: A
authors.lastname: Pisani
authors.forename: P
authors.initials: P
authors.lastname: Bonsi
authors.forename: D
authors.initials: D
authors.lastname: Centonze
authors.forename: A
authors.initials: A
authors.lastname: Martorana
authors.forename: F
authors.initials: F
authors.lastname: Fusco
authors.forename: G
authors.initials: G
authors.lastname: Sancesario
authors.forename: C
authors.initials: C
authors.lastname: De Persis
authors.forename: G
authors.initials: G
authors.lastname: Bernardi
authors.forename: P
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology / Q000502:physiology; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D018342:Receptors, Adrenergic, beta-1; D000242:Cyclic AMP; D004299:Dopamine beta-Hydroxylase; D002795:Choline O-Acetyltransferase; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D011493:Protein Kinase C; D000262:Adenylyl Cyclases; D009638:Norepinephrine