Histamine H₃ receptors are autoreceptors, regulating the release of histamine. They also act as heteroreceptors, regulating the release of many other neurotransmitters (Leurs et al. 2000). By using R-α-methylhistamine (R-α-MH) to selectively activate the H₃ receptor we have attempted to characterise both pre- and postsynaptic effects at presumptive glutamatergic and GABAergic synapses.

Culture techniques and basal saline composition have been published (Verdon et al. 2000). Cortical pyramidal cells were whole cell clamped at 22-24 °C. CNQX (2 µM) and MD-APV (10 µM) were added to isolate mIPSCs. Picrotoxin (10 µM) was added to a saline designed to isolate glutamatergic currents (Thompson et al. 1992). All solutions contained 50 nM TTX. GABA (10 µM, 0.2 s pulses) was applied from a pressure pipette to evoke currents in 100 nM pyrilamine and 5 µM cimetidine (to block H1 and H2 receptors). Data, presented as means ± standard error, were analysed by (Spike 2 from CED Ltd, Prism 3 from Graphpad and University of Strathclyde software) Student’s paired t tests. P < 0.05 was considered significant.

At V_h of -70 mV, 100 nM R-α-MH significantly reduced the mean amplitude of spontaneous mIPSCs (control, 105.8 ± 13.22 pA; R-α-MH, 91.81 ± 12.89 pA; P = 0.039, n = 5), and the the time for 50 % (T₅₀) and 90 % (T₉₀) decay (T₅₀: control, 21.36 ± 1.64 ms; R-α-MH, 18.31 ± 1.58 ms; P = 0.0007; and T₉₀: control, 105.8 ± 13.22 pA; R-α-MH, 91.81 ± 12.89 pA; 0.0052, respectively, n = 5) of averaged events (typically 100-250 events). The frequency of mIPSCs was reduced significantly (control, 103.7 ± 3.02 % pretreatment bin, R-α-MH, 79.17 ± 7.81% P = 0.028, n = 6). The frequency of mEPSCs was marginally decreased by R-α-MH, but this was not consistent between cells (P = 0.066, n = 4). The peak, T₅₀ and T₉₀ of mEPSCs were not changed by R-α-MH (P = 0.613, 0.118 and 0.131, respectively, n = 4). In the presence of R-α-MH, the average size of the responses to 10 µM GABA was significantly and reversibly reduced (control, 1152.0 ± 182.8 pA; R-α-MH, 593.8 ± 93.8 pA; wash, 1078.0 ± 131.0 pA; P = 0.0012, n = 4). However, currents produced by 100 µM GABA, sufficient to evoke the maximal response, were not depressed by R-α-MH (P = 0.141, n = 4).

It is clear that the histamine H₃ receptor can modulate the release of GABA and possibly glutamate from presynaptic terminals. However, it is surprising that R-α-MH appears to have a postsynaptic interaction with the GABA_A receptor. This could be due to a postsynaptic histamine receptor, or a hitherto unsuspected direct allosteric interaction of R-α-methylhistamine with the GABA_A receptor.

Thanks to The Wellcome Trust and the College of Pharmacy Practice for equipment support. Histamine receptor ligands were kindly supplied by the James Black Foundation, King’s College London