Selective blockade of neurokinin (NK)₁ receptors facilitates the activity of adrenergic pathways projecting to frontal cortex and dorsal hippocampus in rats

Abstract

The selective NK 1 receptor antagonist, GR205,171 (2.5± 40.0 mg/kg, i.p.), dose-dependently elevated dialysate levels of noradrenaline (NA), but not serotonin (5-HT), in the frontal cortex of freely moving rats. This action was exerted stereospeci®cally inasmuch as its less active isomer, GR226,206, was ineffective. In the dorsal hippocampus, GR205,171 (but not GR226,206) also signi®cantly increased dialysate levels of NA, whereas levels of 5-HT were unaffected. Further, in anaesthetized rats, GR205,171 dosedependently (1.0±4.0 mg/kg, i.v.) increased the ®ring rate of adrenergic perikarya in the locus coeruleus. In contrast, their activity was not modi®ed by GR226,206. These ®ndings indicate that selective blockade of NK 1 receptors enhances the activity of ascending adrenergic pathways in rats. Adrenergic mechanisms may, thus, be involved in the potential antidepressant and other functional properties of NK 1 receptor antagonists.

Neurokinin1 Antagonists Potentiate Antidepressant Properties of Serotonin Reuptake Inhibitors, Yet Blunt Their Anxiogenic Actions: A Neurochemical, Electrophysiological, and Behavioral Characterization

“…First, GR205171 is a highly selective antagonist of NK 1 receptors and expressed its actions across a dose range identical to that exerting other cerebral actions in rodents (Gardner et al, 1996;Millan et al, 2001b;Rupniak et al, 2001;Lejeune et al, 2002;Brocco et al, 2008). Further, its actions were stereospecific in as much as its less active isomer, GR226206, was ineffective.…”

“…The protocol used for quantification of levels of 5-HT, DA, and NA in dialysate samples was detailed elsewhere (Millan et al, 2001b). Briefly, a guide-cannula was implanted under pentobarbital anesthesia (60 mg/kg, i.p.)…”

“…Briefly, a guide-cannula was implanted under pentobarbital anesthesia (60 mg/kg, i.p.) into the FCX, nucleus accumbens, striatum, or dorsal hippocampus of rats as previously described (Millan et al, 2001b). For the BLA, coordinates were AP, 2.8; ML, ±4.9; and DV, 6.4 from dura.…”

“…In contrast to most agents, GR205171 possesses high affinity at NK 1 receptors across a broad range of species, though its affinity is higher for NK 1 receptors in gerbils and guinea pigs (which closely resemble those in humans) than rats and mice (Rupniak et al, 2000;Griffante et al, 2006;Engberg et al, 2007). GR205171 was also chosen in view of its well-characterized actions in vivo (Gardner et al, 1996;Millan et al, 2001b;Lejeune et al, 2002;Guiard et al, 2004;Chenu et al, 2006), and as clinical studies have shown that it relieves social phobia (Furmark et al, 2005;Michelgard et al, 2007). To underpin the stereospecificity of the actions of GR205171, its effects were compared to those of its less active distomer, GR226206 (op.…”

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

“…This concept is of particular interest because blockade of NK 1 receptors promotes the activity of corticolimbic adrenergic and dopaminergic pathways, complementing the effects of 5-HT reuptake inhibition. [173][174][175][176][177] Blockade of NK 1 receptors also accelerates the long-term facilitatory influence of SSRIs on serotonergic transmission, possibly by accelerating desensitization of inhibitory 5-HT 1A autoreceptors. [175][176][177] These observations suggest that dual agents may be both more effective and rapid-acting than SSRIs and, inasmuch as NK 1 antagonists enhance antidepressant actions of SSRIs yet curtail their anxiogenic effects, 3,177,178 they should be devoid of the symptoms of nervousness that patients may experience at the beginning of SSRI therapy.…”