Cholecystokinin inhibits evoked inhibitory postsynaptic currents in the rat nucleus accumbens indirectly through γ‐aminobutyric acid and γ‐aminobutyric acid type B receptors

Abstract

We recently reported that cholecystokinin (CCK) excited nucleus accumbens (NAc) cells and depressed excitatory synaptic transmission indirectly through γ-aminobutyric acid (GABA), acting on presynaptic GABA_B receptors (Kombian et al. [ 2004 ] J. Physiol. 555:71–84). The present study tested the hypothesis that CCK modulates inhibitory synaptic transmission in the NAc. Using in vitro forebrain slices containing the NAc and whole-cell patch recording, we examined the effects of CCK on evoked inhibitory postsynaptic currents (IPSCs) recorded at a holding potential of −80 mV throughout CCK-8S caused a reversible inward current accompanied by a concentration-dependent decrease in evoked IPSC amplitude. Maximum IPSC depression was ∼25% at 10 μM, with an estimated EC₅₀ of 0.1 μM. At 1 μM, CCK-8S induced an inward current of 28.3 ± 4.8 pA (n = 6) accompanied by an IPSC depression of −18.8% ± 1.6% (n = 6). This CCK-induced IPSC depression was blocked by pretreatment with proglumide (100 μM; −3.7% ± 6.9%; n = 4) and by LY225910 (100 nM), a selective CCK_B receptor antagonist (4.4% ± 2.6%; n = 4). It was not blocked by SCH23390 (10 μM; −23.5% ± 1.3%; P < 0.05; n = 7) or sulpiride (10 μM; −21.8% ± 5.1%; P < 0.05; n = 4), dopamine receptor antagonists. By contrast, it was blocked by CGP55845 (1 μM; −0.4% ± 3.4%; n = 5) a potent GABA_B receptor antagonist, and by forskolin (50 μM; 9.9% ± 5.2%; n = 4), an adenylyl cyclase activator, and H-89 (1 μM; 6.9% ± 3.9%; n = 4), a protein kinase A (PKA) inhibitor. These results indicate that CCK acts on CCK_B receptors to increase extracellular levels of GABA, which then acts on GABA_B receptors to decrease IPSC amplitude.