Control by tachykinin NK(2) receptors of CRF(1) receptor-mediated activation of hippocampal acetylcholine release in the rat and guinea-pig.

In vivo microdialysis was employed to explore the effects of different selective non-peptides NK(1),NK(2) and NK(3) receptor antagonists on the corticotropin releasing factor (CRF)-induced release of acetylcholine (ACh) in the hippocampus of rats and guinea-pigs. In both species, the intracerebroventricular (i.c.v.) administration of CRF produced a time- and dose-dependent increase in hippocampal ACh release that was totally suppressed by an intraperitoneally (i.p.) pretreatment with the selective non-peptide CRF(1) receptor antagonist antalarmin (30 mg/kg). Pretreatment with the selective NK(2) receptor antagonist SR48968 (1mg/kg, i.p.) significantly reduced the increase of ACh induced by CRF. In contrast, its low-affinity enantiomer SR48965 (1mg/kg, i.p.) or the NK(1) receptor antagonist, GR205171 (1mg/kg, i.p.) did not exert any antagonist effect. Moreover, administration of the selective NK(3) receptor antagonist SR142801 (1mg/kg, i.p.) did not significantly reduce the CRF-induced hippocampal ACh release in guinea-pigs (the only species studied). The selective activity of SR48968 versus GR205171 or SR142801 indicates that NK(2) receptors play a major role in the control of CRF-induced hippocampal ACh release. Moreover, in freely moving rats, two sessions of stroking of the neck and back of the rat for 30 min, at 90 min intervals, known to be a stressful stimulus, produced a marked and reproducible increase in hippocampal ACh release. This effect was prevented by the administration of the two selective non-peptide CRF1 and NK(2) receptor antagonists antalarmin (30 mg/kg, i.p.) and SR48968 (1mg/kg, i.p.), respectively. This suggests that stress-induced activation of the hippocampal ACh system may be under the control of both endogenously released CRF and NKA, and opens the possibility of the existence of a functional interplay between the pathways containing these peptides as we observed in our experiments on anaesthetized animals.

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

The regulation of dopaminergic and cholinergic function by neurokinin-3 (NK3) receptor activation was examined in vivo in urethane-anaesthetized guinea pigs with microdialysis probes. The local application of the NK3 tachykinin receptor agonist senktide in the region of dopamine cell bodies (pars compacta of the substantia nigra and ventral tegmental area) and in the area of cholinergic cell bodies (septal area) markedly enhanced the extracellular dopamine (DA) and acetylcholine (ACh) concentration throughout their respective target areas, i.e. striatum, nucleus accumbens, prefrontal cortex for dopaminergic systems and hippocampus for cholinergic neurons. The enhancing effect of senktide on neurotransmitter release was dose dependently blocked by the selective non-peptide NK3 receptor antagonist SR142801 (0.1-1 mg/kg, i.p.), whereas its inactive S-enantiomer SR142806 (0.3-1 mg/kg, i.p.) did not exert any antagonistic activity on the effect of intranigral or intraseptal application of senktide. These results demonstrate that NK3 receptors can modulate the activity of central DA and ACh systems.

Electrophysiological, behavioural and biochemical evidence for activation of brain noradrenergic systems following neurokinin NK3 receptor stimulation.

The objective of the present in vitro and in vivo experiments was to examine the involvement of neurokinin NK3 receptors in the regulation of the noradrenergic function in gerbils and guinea-pigs. Application of senktide, a peptide NK3 receptor agonist, on guinea-pig locus coeruleus slices increased the firing rate of presumed noradrenergic neurons (EC50 = 26 nM) in a concentration-dependent manner. Given i.c.v., senktide (0.5-2 micrograms) and (MePhe7)neurokinin B (1-10 micrograms), another NK3 receptor agonist, reduced exploratory behaviour in gerbils in a dose-dependent manner (2 micrograms of senktide producing a 50% reduction of locomotor activity and rearing). In vivo microdialysis experiments in urethane-anaesthetized guinea-pigs showed that senktide (2-8 micrograms i.c.v.) induced a dose-dependent increase in norepinephrine release in the medial prefrontal cortex. The electrophysiological, behavioural and biochemical changes elicited by senktide were concentration- or dose-dependently reduce by SR 142801, the selective non-peptide NK3 receptor antagonist. In the locus coeruleus slice preparation, complete antagonism of senktide (30 nM) was observed with 50 nM of SR 142801, while injected i.p. (0.1-1 mg/kg) it abolished the senktide-induced norepinephrine release in guinea-pigs. In gerbils, SR 142801 (1-10 mg/kg i.p.) reversed the reduction of exploratory behaviour induced by senktide (1 microgram). By contrast, the 100-fold less active enantiomer, SR 142806, did not exert any antagonism in these models. Finally, the reduction of exploratory behaviour in gerbils was found to be reversed by prazosin (0.25-2.56 micrograms/kg i.p.) and to some extent by clonidine, drugs known to depress noradrenergic function. All these experiments strongly support the hypothesis that brain noradrenergic neurons can be activated by stimulation of neurokinin NK3 receptors.

SR 48692-sensitive neurotensin receptors modulate acetylcholine release in the rat striatum.

The effects of stimulation and blockade of neurotensin receptors on striatal acetylcholine release were examined in anaesthetized rats using microdialysis. Local perfusion with neurotensin (100 nM) did not influence the release of acetylcholine. Application of neurotensin (100 nM) 30 min after haloperidol (125 micrograms/kg, i.p.) increased acetylcholine levels to 188% compared to 120% when haloperidol was administered alone. SR 48692 (3-100 micrograms/kg, i.p.) dose-dependently reduced the stimulatory effect of neurotensin in the presence of haloperidol. Comparable antagonism was observed with SR 48527, a chemically-related compound with high affinity for neurotensin receptors, but not with SR 49711, its low-affinity antipode. These results indicate that high affinity neurotensin receptors regulate acetylcholine release, when D2-dopaminergic inhibitory input is suppressed.

SR 48692, a non-peptide neurotensin receptor antagonist differentially affects neurotensin-induced behaviour and changes in dopaminergic transmission.

Unilateral microinjection of neurotensin in the ventral tegmental area of the rat (2.5 micrograms/0.5 microliter) produced behavioural excitation illustrated by contralateral circling. Given orally, SR 48692, a selective and potent non-peptide neurotensin receptor antagonist, significantly reduced these rotations with a triphasic dose-effect relationship. Inhibition occurred at 0.12 mg/kg; further increases in dose up to 2.5 mg/kg produced no significant antagonism, then at doses > or = 5 mg/kg, a second phase of antagonism was observed. Bilateral injection of neurotensin (0.5 microgram each side) into the nucleus accumbens antagonized the increase in locomotor activity following intraperitoneal injection of amphetamine. Given orally, SR 48692 reduced dose-dependently (0.1-1 mg/kg) these intra-accumbens neurotensin effects. Using high pressure liquid chromatography with electrochemical detection, we showed that microgram amounts of neurotensin injected into the ventral tegmental area increased dihydroxyphenylacetate/dopamine ratios in the nucleus accumbens. Using in vivo voltammetry techniques, we found that the injection of nanogram and picogram amounts of neurotensin in the ventral tegmental area stimulated dopamine efflux in the nucleus accumbens. None of these biochemical changes were affected by SR 48692 (0.1-10 mg/kg). These results indicate complex interactions between neurotensin and the mesolimbic dopamine system. More particularly, the differential ability of SR 48692 to affect neurotensin-evoked behavioural versus biochemical changes supports the concept of neurotensin receptor heterogeneity.