Blockade of neurokinin3 receptors antagonizes drug-induced population response and depolarization block of midbrain dopamine neurons in guinea pigs

Abstract

In vivo extracellular recording techniques were used to investigate the effects of neurokinin3 (NK3) receptor blockade on the pharmacological activation of midbrain dopamine (DA) neurons in the guinea pig substantia nigra (A9) and ventral tegmental area (A10). The number of spontaneously active DA cells (population response) was largely increased in A10 and A9 by acute administration of haloperidol (1 and 0.5 mg/kg i.p., respectively) and this effect was dose-dependently prevented in both areas by the selective NK3 receptor antagonist SR142801 (0.3, 1, 3, and 1, 3, 10 mg/kg i.p., respectively). This compound, which was totally inactive by itself, also antagonized the increase of population response induced in A10 cells by the neurotensin receptor antagonist SR142948 (1 mg/kg i.p.) and in A9 cells by the NK2 receptor antagonist SR144190 (1 mg/kg i.p.). None of the effects of SR142801 were reproduced by SR142806, its (R)-enantiomer with 240-fold lower affinity for NK3 receptors. In addition, neither SR144190 (0.3 mg/kg i.p.) nor the NK1 receptor antagonist GR205171 (1 mg/kg i.p.) affected the haloperidol-induced response. The antagonistic effects of SR142801 (3 mg/kg i.p.) were also observed on the depolarization block-related decrease of A10 cell population response evoked by repeated administration (22 days) of haloperidol. Finally, SR142801 (3 mg/kg i.p.) prevented depolarization block induced in A10 cells by acute co-administration of SR142948 and haloperidol, both on population response and on single cell firing. These results on pharmacologically induced activation and depolarization block of dopamine neurons suggest that NK3 receptors play a key role in the midbrain DA function, presumably through activation by neurokinin B.

Opportunities and Challenges of Psychiatric Drug Discovery: Roles for Scientists in Academic, Industry, and Government Settings

“…Because it is difficult to 'design-in' the preferential ability of a drug to hit multiple identified molecular targets, we and others have suggested that novel chemical scaffolds and novel chemistries should be attempted to generate 'multireceptorial compounds'. In terms of the levels of preclinical validation, one of the most novel compoundsFthe NK-3 antagonist osanant, appears to have been minimally validated (Gueudet et al, 1999), despite showing efficacy in a phase IIb clinical trial . Recent phase II clinical studies demonstrating the efficacy of selective mGlu2/3 agonists for schizophrenia (Patil et al, 2007) illustrate a major example whereby preclinical models successfully predicted efficacy for compounds that act by a novel mechanism of action (Moghaddam and Adams, 1998).…”

In Vitro and In Vivo Characterization of the Non-peptide NK3 Receptor Antagonist SB-223412 (Talnetant): Potential Therapeutic Utility in the Treatment of Schizophrenia

“…Talnetant alone had no effect on basal DA efflux. This observation is consistent with previous in vivo studies, utilizing both microdialysis (Marco et al, 1998) and electrophysiology (Gueudet et al, 1999), which demonstrated that SR-142801 was without effect when administered alone. Taken together, these data suggest that there is no detectable tonic activation of NK 3 receptors on dopaminergic cell bodies in the guinea pig under these conditions.…”

“…Taken together, these data suggest that there is no detectable tonic activation of NK 3 receptors on dopaminergic cell bodies in the guinea pig under these conditions. SNpc/VTA cell firing can be increased by acute administration of haloperidol, an effect that could be attenuated with SR-142801 (Gueudet et al, 1999). We have shown that haloperidol increased extracellular DA efflux in the NAcc, presumably via blockade of the tonically active DA D 2 autoreceptor, and that pretreatment with talnetant produced a dose-related attenuation of the haloperidolinduced increase in extracellular DA.…”

“…Similarly, electrophysiological data have demonstrated that NK 3 receptor activation can augment NE (Jung et al, 1996) and DA cell firing (Nalivaiko et al, 1997) in the guinea pig brain. Furthermore, NK 3 receptor antagonists have been shown to attenuate dopaminergic cell firing in the guinea pig VTA and SN, induced by DA D 2 receptor and neurotensin receptor blockade (Gueudet et al, 1999).…”

The Orexin-1 Receptor Antagonist SB-334867 Blocks the Effects of Antipsychotics on the Activity of A9 and A10 Dopamine Neurons: Implications for Antipsychotic Therapy

“…If these hypotheses are correct, then the present results indicate that orexin-1 receptor antagonists may block the efficacy of antipsychotic drugs by blocking their action on A10 dopamine cells and block the motor side effects of antipsychotic drugs by blocking their action of A9 dopamine neurons. In this regard, the NK-3 antagonist SR142801 also was shown to block the effects of acute and chronic administration of haloperidol on A9 and A10 activity (Gueudet et al, 1999). In clinical trials, SR142801 displayed some degree of antipsychotic efficacy, albeit less than haloperidol, and caused fewer extrapyramidal symptoms than haloperidol (Meltzer et al, 2004).…”