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

Abstract

Though neurokinin 1 (NK 1 ) receptor antagonists are active in experimental models of depression, clinical efficacy has proven disappointing. This encourages interest in association of NK 1 receptor blockade with inhibition of serotonin (5-HT) reuptake. The selective NK 1 antagonist, GR205171, dose-dependently enhanced citalopram-induced elevations of extracellular levels of 5-HT in frontal cortex, an action expressed stereospecifically vs its less active distomer, GR226206. Further, increases in 5-HT levels in dorsal hippocampus, basolateral amygdala, nucleus accumbens, and striatum were likewise potentiated, and GR205171 similarly facilitated the influence of fluoxetine upon levels of 5-HT, as well as dopamine and noradrenaline. In parallel electrophysiological studies, the inhibitory influence of citalopram and fluoxetine upon raphe-localized serotonergic neurones was stereospecifically blunted by GR205171. Antidepressant actions of citalopram in a forced-swim test in mice were stereospecifically potentiated by GR205171, and it also enhanced attenuation by citalopram of stress-related ultrasonic vocalizations in rats. Further, GR205171 and citalopram additively abrogated the advance in circadian rhythms provoked by exposure to light in hamsters. By contrast, GR205171 stereospecifically blocked anxiogenic actions of citalopram in social interaction procedures in rats and gerbils, and stereospecifically abolished facilitation of fearinduced foot tapping by fluoxetine in gerbils. By analogy to GR205171, a further NK 1 antagonist, RP67580, enhanced the influence of citalopram upon frontocortical levels of 5-HT and potentiated its actions in the forced swim test. In conclusion, NK 1 receptor blockade differentially modulates functional actions of SSRIs: antidepressant properties are reinforced, whereas anxiogenic effects are attenuated. Combined NK 1 receptor antagonism/5-HT reuptake inhibition may offer advantages in the management of depressed and anxious states.

Genetic Deletion of Trace Amine 1 Receptors Reveals Their Role in Auto-Inhibiting the Actions of Ecstasy (MDMA)

“…Surprisingly, then, there was no phenotypic variation as regards the influence of MDMA upon 5-HT levels in dialysates of frontal cortex. Such a regional difference in the impact of MDMA on serotonergic transmission resembles observations with neurokinin1 receptor antagonists (Guiard et al, 2007;Gobert et al, 2009). …”

Imaging Drugs with and without Clinical Analgesic Efficacy

“…Suzuki et al (2003) showed an attenuation of electrophysiological responses to noxious heat in the dorsal horn neurons in NK 1 receptor-knockout mice, whereas Budai et al (2007) reported diminished activity of on-cells in rostral ventral medulla following application of an NK 1 receptor antagonist (L-733,060). The source of potentation in the supraspinal limbic circuitry observed here could arise from the coupling between antagonist action on NK 1 receptors and the 5-HT system (Gobert et al, 2009;Valentino et al, 2003). One main finding by Valentino et al was a characterization of the 5-HT-driven inhibition of neuronal activity following substance P administration: an effect suppressed by treatment with an NK 1 antagonist (Sendide).…”

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.…”

“…248 Specific examples of drug combinations include a paroxetine (SSRI) plus vestipitant (NK 1 antagonist) formulation, and fluoxetine (SSRI) plus olanzapine (atypical antipsychotic). 20,177 Network concepts of CNS function and dysfunction: the need for early intervention Mood, cognition, and other functions disrupted in depression are emergent properties of overarching cerebral circuits, rather than of individual proteins, receptors, or neurons. The brain-its organization, operation, perturbation and treatment-is best understood in terms of functional modules and networks at a hierarchy of scales: from receptors, G-proteins, and their postsynaptic partners to neuronal circuits to regions such as the frontal cortex.…”