Activation of nicotinic acetylcholine receptors (nAChRs) can elicit neurotransmitter release from presynaptic nerve terminals. Mechanisms contributing to cell-and-terminal specific regulation of nAChR-mediated neurotransmitter exocytosis are not fully understood. The experiments discussed here examine how activation of GABA B auto- and hetero-receptors suppress nAChR-mediated release of [ 3 H]-GABA and [ 3 H]-dopamine ( 3 H-DA) from mouse striatal synaptosomes. Activation of presynaptic GABA B receptors with (R)-baclofen decreased both [ 3 H]-GABA and [ 3 H]-DA release evoked by potassium depolarization. However, when nAChRs were activated with ACh to evoke neurotransmitter release, (R)-baclofen had no effect on [ 3 H]-DA release, but potently inhibited ACh-evoked [ 3 H]-GABA release. Inhibition of nAChR-evoked [ 3 H]-GABA release by (R)-baclofen was time sensitive and the effect was lost after prolonged exposure to the GABA B agonist. The early inhibitory effect of GABA B activation on ACh-evoked [ 3 H]-GABA release was partially attenuated by antagonists of the phosphatase, calcineurin. Furthermore, antagonists of protein kinase C (PKC) prevented the time-dependent loss of the inhibitory (R)-baclofen effect on [ 3 H]-GABA release. These results suggest that α4β2*-nAChRs present on GABAergic nerve terminals in the striatum are subject to functional regulation by GABA B autoreceptors that is apparently cell-type specific, since it is absent from DAergic striatal nerve terminals. In addition, the functional modulation of α4β2*-type nAChRs on striatal GABAergic nerve terminals by GABA B autoreceptor activation is time-sensitive and appears to involve opposing actions of calcineurin and PKC.