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The Journal of Neuroscience, June 15, 2003, 23(12):5272-5282

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Activation of 1-Adrenoceptors Excites Striatal Cholinergic Interneurons through a cAMP-Dependent, Protein Kinase-Independent Pathway

A. Pisani,^1,3 P. Bonsi,³ D. Centonze,^1,3 A. Martorana,¹ F. Fusco,³ G. Sancesario,¹ C. De Persis,² G. Bernardi,^1,3 and P. Calabresi^1,3

¹Clinica Neurologica and ²Clinica Psichiatrica, Dipartimento di Neuroscienze, Università di Roma "Tor Vergata," 00133 Rome, Italy, and ³Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, 00179 Rome, Italy

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 µM) 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 -adrenoceptor antagonists, whereas it was mimicked by the -adrenoceptor agonist isoproterenol and blocked by the 1 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 I_h, the effects of ZD7288, a selective inhibitor of I_h 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 1-adrenoceptor and choline acetyltransferase immunocytochemistry by means of confocal microscopy revealed a strong1-adrenoceptor labeling on cholinergic interneurons. We conclude that NA depolarizes striatal cholinergic interneurons via 1-adrenoceptor activation, through a cAMP-dependent but PKA-independent mechanism.

Key words: striatum; slices; noradrenaline; cAMP; TANs; electrophysiology

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Received Dec. 27, 2002; revised Apr. 9, 2003; accepted Apr. 9, 2003.

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