Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha(2)-adrenergic and serotonin(2C) receptors: a comparison with citalopram

Mirtazapine displayed marked affinity for cloned, human alpha(2A)-adrenergi c (AR) receptors at which it blocked noradrenaline (NA)-induced stimulation of guanosine-5'-O-(3-[S-35]thio)-triphosphate ([S-35]-GTP gamma S) binding . Similarly, mirtazapine showed high affinity for cloned, human serotonin ( 5-HT)(2C) receptors at which it abolished 5-HT-induced phosphoinositide gen eration. Alpha(2)-AR antagonist properties were revealed in vivo by blockad e of UK-14,304-induced antinociception, while antagonist actions at 5-HT2C receptors were demonstrated by blockade of Ro 60 0175-induced penile erecti ons and discriminative stimulus properties. Mirtazapine showed negligible a ffinity for 5-HT reuptake sites, in contrast to the selective 5-HT reuptake inhibitor, citalopram. In freely moving rats, in the dorsal hippocampus, f rontal cortex (FCX), nucleus accumbens and striatum, citalopram increased d ialysate levels of 5-HT, but not dopamine (DA) and NA. On the contrary, mir tazapine markedly elevated dialysate levels of NA and, in FCX, DA, whereas 5-HT was not affected. Citalopram inhibited the firing rate of serotonergic neurons in dorsal raphe nucleus, but not of dopaminergic neurons in the ve ntral tegmental area, nor adrenergic neurons in the locus coeruleus. Mirtaz apine, in contrast, enhanced the firing rate of dopaminergic and adrenergic , but not serotonergic, neurons. Following 2 weeks administration, the faci litatory influence of mirtazapine upon dialysate levels of DA and NA versus 5-HT in FCX was maintained, and the influence of citalopram upon FCX level s of 5-HT versus DA and NA was also unchanged. Moreover, citalopram still i nhibited, and mirtazapine still failed to influence, dorsal raphe serotoner gic neurons. In conclusion, in contrast to citalopram, mirtazapine reinforc es frontocortical dopaminergic and corticolimbic adrenergic, but not seroto nergic, transmission. These actions reflect antagonist properties at alpha( 2A)-AR and 5-HT2C receptors.