Activation of dopaminergic and cholinergic neurotransmission by tachykinin NK3 receptor stimulation: an in vivo microdialysis approach in guinea pig

Marco, N.; Thirion, Anne-Marie; Mons, G.; Bougault, I.; Fur, G. Le; Soubrié, Philippe; Steinberg, R.

doi:10.1016/s0143-4179(98)90075-0

Cited by 104 publications

(68 citation statements)

References 29 publications

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“…Using in vivo microdialysis techniques in guinea pigs, local administration of senktide into dopaminergic cell bodies of the mesencephalic and SNpc resulted in an enhanced DA output in terminal projection regions such as mPFC, NAcc, and striatum. Again, these responses were blocked by SR-142801 confirming the NK 3 receptor-mediated dopaminergic responses (Marco et al, 1998).…”

Section: Discussionmentioning

confidence: 64%

“…Neurochemical studies have shown that NK 3 receptor activation can augment dopamine (DA) and acetylcholine (ACh) efflux in the nucleus accumbens (NAcc) and caudate putamen (Marco et al, 1998), norepinephrine (NE) efflux in the mPFC (Jung et al, 1996;Bert et al, 2002) and ACh in the hippocampus (Marco et al, 1998) of the guinea pig, and g-aminobutyric acid (GABA) in the NAcc and caudate putamen of the rat (Preston et al, 2000). 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.…”

Section: Introductionmentioning

confidence: 99%

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

Dawson

Cato

Scott

et al. 2007

Neuropsychopharmacol

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Neurokinin-3 (NK 3 ) receptors are concentrated in forebrain and basal ganglia structures within the mammalian CNS. This distribution, together with the modulatory influence of NK 3 receptors on monoaminergic neurotransmission, has led to the hypothesis that NK 3 receptor antagonists may have therapeutic efficacy in the treatment of psychiatric disorders. Here we describe the in vitro and in vivo characterization of the highly selective NK 3 receptor antagonist talnetant (SB-223412). Talnetant has high affinity for recombinant human NK 3 receptors (pK i 8.7) and demonstrates selectivity over other neurokinin receptors (pK i NK 2 ¼ 6.6 and NK 1 o4). In native tissuebinding studies, talnetant displayed high affinity for the guinea pig NK 3 receptor (pK i 8.5). Functionally, talnetant competitively antagonized neurokinin B (NKB)-induced responses at the human recombinant receptor in both calcium and phosphoinositol second messenger assay systems (pA 2 of 8.1 and 7.7, respectively). In guinea pig brain slices, talnetant antagonized NKB-induced increases in neuronal firing in the medial habenula (pK B ¼ 7.9) and senktide-induced increases in neuronal firing in the substantia nigra pars compacta (pK B ¼ 7.7) with no diminution of maximal agonist efficacy, suggesting competitive antagonism at native NK 3 receptors. Talnetant (3-30 mg/kg i.p.) significantly attenuated senktide-induced 'wet dog shake' behaviors in the guinea pig in a dose-dependent manner. Microdialysis studies demonstrated that acute administration of talnetant (30 mg/kg i.p.) produced significant increases in extracellular dopamine and norepinephrine in the medial prefrontal cortex and attenuated haloperidol-induced increases in nucleus accumbens dopamine levels in the freely moving guinea pigs. Taken together, these data demonstrate that talnetant is a selective, competitive, brain-penetrant NK 3 receptor antagonist with the ability to modulate mesolimbic and mesocortical dopaminergic neurotransmission and hence support its potential therapeutic utility in the treatment of schizophrenia.

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

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

Dawson

Cato

Scott

et al. 2007

Neuropsychopharmacol

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“…It has been suggested that the impaired performance of schizophrenics in this task is related to hippocampal deficits (Hanlon et al 2006). The stimulation of the NK 3 receptor has been demonstrated to activate cholinergic systems in the hippocampus (Marco et al 1998) and septohippocampal cholinergic neurons (Morozova et al 2008), which suggests that antagonism and/or knockout of this receptor might reduce cholinergic activity in the hippocampus. Acute cholinergic antagonism with scopolamine is well known to impair performance in the Morris water maze (Buresova et al 1986;Paylor and Rudy 1990).…”

Section: Discussionmentioning

confidence: 99%

“…It is important to note that the NK 3 receptor is also located on dopaminergic neurons in the midbrain (Lévesque et al 2007;Whitty et al 1997;Whitty et al 1995). Activation of the midbrain NK 3 receptors with the endogenous ligand neurokinin B or the highly specific agonist succinyl-[Asp6, Me-Phe8]SP(6-11) (senktide) causes increased dopamine release in the striatum and prefrontal cortex (Humpel et al 1991;Marco et al 1998;Tremblay et al 1992), as well as increased electrophysiological activity of dopaminergic neurons (Nalivaiko et al 1997;Nordquist et al, submitted;Overton et al 1992). This effect of NK 3 stimulation on the dopaminergic neurons and dopamine release implies that the NK 3 receptor may provide a means for antipsychotic action by modulating catecholamines, which would avoid the strong adverse side effects produced by D 2 receptor antagonists.…”

Section: Introductionmentioning

confidence: 99%

Cognitive performance in neurokinin 3 receptor knockout mice

et al. 2008

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Rationale The neurokinin 3 (NK 3 ) receptor is a novel target under investigation for improvement of the symptoms of schizophrenia due to its ability to modulate dopaminergic signaling. However, research on effects of NK 3 antagonism with animal models has been hindered because of species differences in the receptor between humans, rats, and mice. Objectives The aim of the present study is to further knowledge on the role of NK 3 in cognitive functioning by testing the effect of knockout of the NK 3 receptor on tests of working memory, spatial memory, and operant responding. Materials and methods NK 3 knockout mice generated on a C57Bl/6 background were tested in delayed matching to position (DMTP), spontaneous alternation, Morris water maze, and active avoidance tasks. Results NK 3 knockout mice showed better performance in the DMTP task, though not delay dependently, which points to an effect on operant performance but not on working memory. No differences were seen between the groups in spontaneous alternation, another indication that working memory is not affected in NK 3 knockouts. There was no impairment in knockout mice in Morris water maze training, and the mice also showed faster response latency in the active avoidance task during training. Conclusions Collectively, these results support a role for the NK 3 receptor in performance of operant tasks and in spatial learning but not in working memory.

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“…Neurokinins such as substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), which are synthesized and released from sensory neurons (Johnson et al, 1998;Marco et al, 1998;Otsuka and Yoshioka, 1993;Zogorodnyuc and Maggi, 1997), contribute to numerous physiological processes, including inflammatory responses (Jia and Seybold, 1996), nociception (Liu and Sandkuhler, 1997), central and peripheral cardiovascular regulation (Thompson et al, 1998), and other autonomic reflexes (Moodley et al, 1999;Serio et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Dual effects of neurokinin on calcium channel currents and signal pathways in neonatal rat nucleus tractus solitarius

Endoh

2006

Brain Research

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Activation of dopaminergic and cholinergic neurotransmission by tachykinin NK3 receptor stimulation: an in vivo microdialysis approach in guinea pig

Cited by 104 publications

References 29 publications

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

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

Cognitive performance in neurokinin 3 receptor knockout mice

Dual effects of neurokinin on calcium channel currents and signal pathways in neonatal rat nucleus tractus solitarius

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