Blockade of tachykinin NK1 receptors attenuates stress‐induced rise of extracellular noradrenaline and dopamine in the rat and gerbil medial prefrontal cortex

Abstract

Substance P receptor antagonists cause antidepressant- and anxiolytic-like effects in rodents that are thought to involve brain monoamines. In the present study, we examined the effects of the NK1 receptor antagonist GR-205,171 on basal and stress-induced rise of extracellular noradrenaline (NA) and dopamine (DA) in the medial prefrontal cortex (mPFC) of conscious rats and gerbils with the in vivo microdialysis technique. GR-205,171 given intraperitoneally to rats (10 and 30 mg/kg) and gerbils (0.3 and 1 mg/kg) did not affect extracellular NA in either species and increased extracellular DA in rats. Forty minutes of immobilization increased extracellular NA and DA by, respectively, 179% and 188% of baseline values in rats and 222% and 316% of baseline values in gerbils. At 10 mg/kg, GR-205,171 attenuated the stress-induced increase of extracellular NA in the rat. At 30 mg/kg, GR-205,171 suppressed the effect of stress on extracellular DA but had no effect on NA. A lower dose (1 mg/kg) attenuated the stress-induced rise of extracellular NA and DA in the mPFC of gerbils. The results show that blockade of NK1 receptors marginally increased basal extracellular DA in rats but had no effect in gerbils, whereas the stress-induced rise of extracellular NA and DA was markedly attenuated in both species. It is suggested that catecholamines may contribute to the functional effects of GR-205,171.

Perseveration by NK1R-/- (‘knockout’) mice is blunted by doses of methylphenidate that affect neither other aspects of their cognitive performance nor the behaviour of wild-type mice in the 5-Choice Continuous Performance Test

“…Alkhatib et al, 2013). Many reports indicate that a lack of functional NK1R can diminish dopaminergic transmission in the brain (Anderson et al, 1994; Brimblecombe and Cragg, 2015; Kombian et al, 2003; Loonam et al, 2003; Zocchi et al, 2003) especially during heightened arousal (Hutson et al, 2004; Renoldi and Invernizzi, 2006; Yan et al, 2011). It is possible that amelioration of this deficit by methylphenidate, which is a dopamine reuptake inhibitor, helps to prevent perseveration by these mice.…”

The Neurokinin-1 Receptor in Addictive Processes

“…Also, NK1Rs are found on the noradrenergic cell bodies of the locus coeruleus (LC) (Chen et al, 2000;Ma and Bleasdale, 2002) and influence the output of these neurons, although the direction of this influence is unclear. Most studies suggest that SP can increase LC firing and that NK1R antagonists attenuate stress-induced norepinephrine (NE) release (Guyenet and Aghajanian, 1977;Cheeseman et al, 1983;Renoldi and Invernizzi, 2006); however, there has been some suggestion that NK1R antagonists themselves can increase NE in some terminal fields (Millan et al, 2001;Maubach et al, 2002). When considering the regulation of behaviors that lie at the intersection of stress and addiction, the ability of NK1R to modulate NE transmission is especially intriguing because the NE system has been shown to mediate stress-induced reinstatement and escalated self-administration of multiple drugs of abuse (Erb et al, 2000;Shaham et al, 2000;Leri et al, 2002;Gilpin and Koob, 2010;Mantsch et al, 2010;Vranjkovic et al, 2012).…”

“…Although it is known primarily as a reward-related neurotransmitter, dopamine activity is increased during exposure to some stressors. NK1R antagonists can prevent immobilization stress-induced dopamine release in the prefrontal cortex (Hutson et al, 2004;Renoldi and Invernizzi, 2006), which is of particular interest for the NK1R's targeted role in stress-elicited drug seeking (see later discussion). The effect of the NK1R on monoamine signaling is a major mechanistic area of overlap with the functions of CRH receptors, which can influence the activity of the monoaminergic systems (Dunn et al, 2004;Valentino and Commons, 2005;Valentino et al, 2010).…”

The Periaqueductal Gray: From Longitudinal columns to defensive behaviour

“…Substance P is particularly concentrated in the amygdala and other regions that regulate affective behaviour and neurochemical responses to stress. The PAG also contains substance P-positive, medium-sized fibers with multiple varicosities (Kramer, et al, 1998, Maubach, et al, 1999, Renoldi and Invernizzi, 2006.…”