A crucial aspect of pacemaker current (I_h) function is the regulation by cyclic nucleotides. To assess the endogenous mechanisms controlling cAMP levels in the vicinity of pacemaker channels, I_h regulation by G-protein-coupled neurotransmitter receptors was studied in mouse thalamocortical neurons. Activation of -adrenergic receptors with (-)-isoproterenol (Iso) led to a small steady enhancement of I_h amplitude, whereas activation of GABA_B receptors with (±)-Baclofen (Bac) reduced I_h, consistent with an up- and downregulation of basal cAMP levels, respectively. In contrast, a transient (_decay200 s), supralinear upregulation of I_h was observed upon co-application of Iso and Bac that was larger than that observed with Iso alone. This upregulation appeared to involve a cAMP synthesis pathway distinct from that recruited by Iso, as it was associated with a reversible acceleration in I_h activation kinetics and an occlusion of modulation by photolytically released cAMP, yet showed an 11 mV as opposed to a 6 mV positive shift in the activation curve and an at least seven-fold increase in duration. GABA, in the presence of the GABA_A antagonist picrotoxin, mimicked, whereas N-ethylmaleimide, an inhibitor of G_i-proteins, blocked the upregulation, supporting a requirement for GABA_B receptor activation in the potentiation. Activation of synaptic GABA_B responses via stimulation of inhibitory afferents from the nucleus reticularis potentiated Iso-induced increments in I_h, suggesting that synaptically located receptors couple positively to cAMP synthesis induced by -adrenergic receptors. These findings indicate that distinct pathways of cAMP synthesis target the pacemaker current and the recruitment of these may be controlled by GABAergic activity within thalamic networks.