2-Chloro-N-[(S)-phenyl [(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide, monohydrochloride, an inhibitor of the glycine transporter type 1, increases evoked-dopamine release in the rat nucleus accumbens in vivo via an enhanced glutamatergic neurotransmission.

2-Chloro-N-S-phenyl 2S-piperidin-2-yl methyl]-3-trifluoromethyl benzamide, monohydrochloride (SSR504734) is a potent and selective inhibitor of the glycine transporter type 1, which increases central N-methyl-D aspartate glutamatergic tone. Since glutamate has been shown to play a role in the regulation of the dopaminergic system in dopamine-related disorders, such as schizophrenia, we investigated the possibility that SSR504734 may modify the basolateral amygdala-elicited stimulation of dopamine release in the nucleus accumbens via an augmentation of glutamate receptor-mediated neurotransmission. First, our data confirmed that SSR504734 is an inhibitor of GlytT1. In the nucleus accumbens of anesthetized rat, SSR504734 (10 mg/kg, i.p.) induced an increase of extracellular levels of glycine as measured by microdialysis coupled with capillary electrophoresis with laser-induced fluorescence detection. Second, the data demonstrated that SSR504734 (10 mg/kg, i.p.) enhanced the facilitatory influence of glutamatergic afferents on dopamine neurotransmission in the nucleus accumbens. Using an electrochemical technique, we measured dopamine release in the nucleus accumbens evoked by an electrical stimulation of the basolateral amygdala. SSR504734 facilitated dopamine release evoked by a 20 or a 40 Hz frequency basolateral amygdala stimulation. This facilitatory effect was dependent on glutamatergic tone, as intra-nucleus accumbens application of 6-7-dinitroquinoxaline-2,3-dione (10(-3) M) or DL-2-amino-5-phosphonopentanoic acid (10(-3) M), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl-D aspartate receptors antagonists, respectively, inhibited dopamine release evoked by basolateral amygdala stimulation. Furthermore DL-2-amino-5-phosphonopentanoic acid co-administrated with SSR504734 hampered the dopamine-evoked release facilitation. These data underline the in vivo implication of the glycine uptake mechanism in the control of subcortical glutamate/dopamine interactions.

Neuropharmacological characterization of SR 140333, a non peptide antagonist of NK1 receptors.

SR 140333 (1-[2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl) piperidin-3-yl]ethyl]-4-phenyl-1-azonia-bicyclo[2.2.2]octane , chloride), a potent non peptide ligand of the substance P (SP) NK1 receptor subtype with high affinity for NK1 receptors from both rat cortical membranes and human IM9 cells (Ki = 0.02 nM and 0.01 nM, respectively) was studied in vivo on various effects induced by NK1 agonists in rats and mice. SR 140333 given intraperitoneally (i.p.) in mice antagonized dose-dependently and in a stereoselective manner the scratching responses induced by intracerebroventricular SP and septide (ID50 = 0.73 and 0.08 mg/kg, respectively) and the turning behavior elicited by intrastriatal SP and septide (ID50 = 0.07 and 0.06 mg/kg, respectively). This compound had little effect on the scratching responses and the turning behavior elicited by [Sar9, Met(O2)11]-SP. When SR 140333 was coadministered with the peptide agonist, the compound reduced the scratching responses elicited by SP, [Sar9, Met(O2)11]-SP and septide injected intrathecally (i.t.) in mice (ID50 = 72.0, 64.3 and 52.5 ng i.t., respectively). SR 140333 antagonized the salivation induced by SP, [Sar9, Met(O2)11]-SP and septide in rats (ID50 = 0.13, 0.18 and 0.09 mg/kg i.p., respectively). SR 140333 abolished the facilitation of the tail-flick reflex induced by noxious heat in rats (total reversal at 0.06 mg/kg, i.p.). This compound was also found to inhibit the turning behavior induced by intrastriatal apomorphine in mice (ID50 = 0.1 mg/kg, i.p.). In conclusion, these results indicate that SR 140333 behaves as a potent, selective and centrally active NK1 receptor antagonist.

Facilitation of striatal acetylcholine release by dopamine D1 receptor stimulation: involvement of enhanced nitric oxide production via neurokinin-2 receptor activation.

The regulation of striatal cholinergic function by dopamine D1 receptor activation was examined in vivo in urethane-anaesthetized rats with microdialysis probes. Extracellular acetylcholine levels were enhanced by activation of D1 receptors either directly by a striatal application of the D1 receptor agonist (+)-SKF-38393 (3 microM) or indirectly by the release of dopamine evoked by striatal application of neurotensin (0.1 microM) under D2 receptor blockade. SR 144190, a new potent and selective non-peptide neurokinin-2 receptor antagonist (0.03-1 mg/kg, i.p.), dose-dependently reduced the acetylcholine release induced by (+)-SKF-38393 or neurotensin. Furthermore, intrastriatal application of SR 144190 (1 nM) blocked the increase in acetylcholine release induced by the local application of (+)-SKF-38393 (3 microM), neurokinin A (1 microM) or substance P (1 microM). Finally, a role for nitric oxide in mediating the effects of D1 neurokinin-2 receptor activation on acetylcholine release is proposed since local infusion of the competitive inhibitor of nitric oxide synthase, N(G)-monomethyl-L-arginine (0.01-10 microM), blocked the increase in acetylcholine release induced by (+)-SKF-38393 (3 microM), neurotensin (0.1 microM) or neurokinin A (1 microM) without affecting the enhancing effect of the neurokinin-1 agonist septide (0.1 microM).

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.

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.

Blockade of cannabinoid receptors by SR141716 selectively increases Fos expression in rat mesocorticolimbic areas via reduced dopamine D2 function.

The present study investigated, in rats, whether blockade of cannabinoid CB1 receptors may alter Fos protein expression in a manner comparable to that observed with antipsychotic drugs. Intraperitoneal administration of the selective CB1 receptor antagonist, SR141716, dose-dependently (1.0, 3.0 and 10 mg/kg) increased Fos-like immunoreactivity in mesocorticolimbic areas (prefrontal cortex, ventrolateral septum, shell of the nucleus accumbens and dorsomedial caudate-putamen), while motor-related structures such as the core of the nucleus accumbens and the dorsolateral caudate-putamen were unaffected. In the ventrolateral septum, taken as a representative structure, the Fos-inducing effect of SR141716 (10 mg/kg) was maximal 2 h after injection and returned to near control levels by 4 h. Within the prefrontal cortex, SR141716 increased the number of Fos-positive cells predominantly in the infralimbic and prelimbic cortices, presumptive pyramidal cells being the major cell types in which Fos was induced. The D1-like receptor antagonist, SCH23390 (0.1 mg/kg), did not prevent the Fos-inducing effect of SR141716 in any brain region examined (prefrontal cortex, nucleus accumbens, ventrolateral septum and dorsomedial caudate-putamen), although SCH23390 significantly reduced Fos expression induced by cocaine (20 mg/kg) in all these regions. By contrast, the dopamine D2-like agonist, quinpirole (0.25 mg/ kg), counteracted SR141716-induced Fos-like immunoreactivity in the ventrolateral septum, the nucleus accumbens and the dorsomedial caudate-putamen, while no antagonism was observed in the prefrontal cortex. Microdialysis experiments in awake rats indicated that SR141716, at doses which increased Fos expression (3 and 10 mg/kg), did not alter dopamine release in the shell of the nucleus accumbens. Finally, SR141716 increased the levels of neurotensin-like immunoreactivity in the nucleus accumbens, but not in the caudate-putamen. Collectively, the present results show that blockade of cannabinoid receptors increases Fos- and neurotensin-like immunoreactivity with characteristics comparable to those reported for atypical neuroleptic drugs.

Effects of SR 48692, a selective non-peptide neurotensin receptor antagonist, on two dopamine-dependent behavioural responses in mice and rats.

One major mechanism underlying the central action of neurotensin is an interaction with the function of dopamine (DA)-containing neurons. In addition, direct or indirect DA agonists have been reported to promote neurotensin release. We have found that SR 48692, a non-peptide neurotensin receptor antagonist (0.04-0.64 mg/kg orally), antagonizes (50-65%) yawning induced by apomorphine (0.07 mg/kg SC) or bromocriptine (2 mg/kg IP) in rats, and turning behaviour induced by intrastriatal injection of apomorphine (0.25 micrograms), (+) SKF 38393 (0.1 micrograms), bromocriptine (0.01 ng) or (+) amphetamine (10 micrograms) in mice. Other apomorphine-induced effects in mice and rats such as climbing, hypothermia, hypo- and hyper-locomotion, penile erections and stereotypies were not significantly modified by SR 48692. Taken together, these data suggest that neurotensin may play a permissive role in the expression of some but not all behavioural responses to DA receptor stimulation.

SR 46559A: a novel and potent muscarinic compound with no cholinergic syndrome.

The cholinergic activities of SR 46559A, 3-[N-(2 diethyl-amino-2-methylpropyl)-6-phenyl-5-propyl] pyridazinamine sesquifumarate, have been investigated in vitro and in vivo, in rodents. Using rat brain cortical membranes, SR 46559A was a competitive ligand (Ki = 112 nM) at muscarinic M1 receptors, its affinity for muscarinic M2 (cardiac) and M3 (glandular) receptors being 6-7 times lower. SR 46559A did not interact with brain nicotinic receptors and high affinity choline uptake sites nor did it inhibit brain acetylcholinesterase activity. In contrast to reference muscarinic agonists, SR 46559A (1 mM) did not inhibit the forskolin-induced activation of cAMP synthesis nor did it stimulate phosphoinositides breakdown in various brain preparations. However, this compound enhanced (+67% at 1 mM) diacylglycerol formation in rat striatal miniprisms, an effect fully reversed by atropine. As shown with reference agonists, SR 46559A inhibited (IC50 = 10 microM) the K(+)-evoked release of [3H]GABA from rat striatal slices and reduced at 0.5 and 1 microM, the population spike amplitude of the CA1 pyramidal cells induced by stimulation of the Schaffer's collateral commissural pathway in rat hippocampal slices. In mice, SR 46559A at a near lethal dose (200 mg/kg PO) did not induce the typical cholinergic syndrome nor did it modify at 30 mg/kg PO the oxotremorine-induced hypothermia. Like muscarinic agonists, SR 46559A (1 mg/kg PO) potentiated haloperidol-induced catalepsy in rats and inhibited (ED50 = 0.12 mg/kg PO) rotations induced in mice by intrastriatal injection of pirenzepine.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurochemical and behavioural effects of neurotensin vs [D-Tyr11]neurotensin on mesolimbic dopaminergic function.

Microinjection of neurotensin(1-13) or neurotensin(8-13) into the ventral tegmental area (VTA) of anaesthetized rats produced dose-dependent (1-100 pg) dopamine release in the nucleus accumbens as measured by differential pulse amperometry (DPA). Higher doses (100 pg-10 ng) of [D-Tyr11]neurotensin were required to produce an identical effect. In addition, the 3 peptides enhanced the K(+)-evoked [3H]DA release from nucleus accumbens slices. The stimulatory actions produced by 10(-8) M neurotensin(1-13) and neurotensin(8-13) were respectively of 96% and 72% while the effect of [D-Tyr11]neurotensin was only of 79% at 10(-6) M. Unilateral application of the 3 peptides in the VTA of cannulated rats produced contralateral circling. [D-Tyr11]neurotensin was effective in a dose-dependent manner, between 40 and 320 ng. Similar effects were observed with 80 ng of neurotensin(1-13) and neurotensin(8-13) in presence of the protease inhibitor thiorphan. In view of the higher potency of neurotensin(1-13) and neurotensin(8-13) versus [D-Tyr11]neurotensin to stimulate DA release both in vivo and in vitro and the higher efficacy of [D-Tyr11]neurotensin to induce circling, this study further strengthens the concept of neurotensin receptor heterogeneity.

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.

SR 57227A: a potent and selective agonist at central and peripheral 5-HT3 receptors in vitro and in vivo.

SR 57227A (4-amino-(6-chloro-2-pyridyl)-1 piperidine hydrochloride) is a novel compound with high affinity and selectivity for the 5-HT3 receptor. The compound had affinities (IC50) varying between 2.8 and 250 nM for 5-HT3 receptor binding sites in rat cortical membranes and on whole NG 108-15 cells or their membranes in vitro, assayed under various conditions with [3H]S-zacopride or [3H]granisetron as radioligand. Like reference 5-HT3 receptor agonists, SR 57227A stimulated the uptake of [14C]guanidinium into NG 108-15 cells in the presence of substance P (EC50 = 208 +/- 16 nM) and contracted the isolated guinea-pig ileum (EC50 = 11.2 +/- 1.1 microM), effects that were antagonised by the 5-HT3 receptor antagonist tropisetron. The agonist effect of SR 57227A was also observed in vivo, as the compound elicited the Bezold-Jarisch reflex in anesthetised rats (ED50 = 8.3 micrograms/kg i.v.), an effect that was blocked by tropisetron and R,S-zacopride, but not by methysergide. When injected unilaterally into the mouse striatum, SR 57227A, like 2-methyl-5-HT, elicited contralateral turning behaviour which was antagonised by ondansetron. Furthermore, microiontophoretic application of SR 57227A markedly inhibited the firing rate of rat cortical neurones, an effect antagonised by tropisetron. Finally, in contrast to reference 5-HT3 agonists, SR 57227A bound to 5-HT3 receptors on mouse cortical membranes after systemic administration (ED50 = 0.39 mg/kg i.p. and 0.85 mg/kg p.o.). These results suggest that SR 57227A is a potent agonist at peripheral and central 5-HT3 receptors, both in vitro and in vivo. In view of the dearth of 5-HT3 receptor agonists which are capable of crossing the blood-brain barrier, SR 57227A may be useful in the characterisation of the neuropharmacological effects produced by the stimulation of these receptors.

Evidence for a tachykinin/cholinergic mediation of D1 agonist-induced turning in mice.

The turning behavior induced by the intrastriatal injection of the D1 agonist (+)SKF 38393 was blocked by the two selective nonpeptide tachykinin NK1 (SR 140333) (ID50 = 0.09 mg/kg ip) and NK2 (SR 48968) (ID50 = 1.4 mg/kg ip) receptor antagonists and by atropine (ID50 = 2.6 mg/kg ip). In addition, the turning induced by the intrastriatal injection of NK1 (septide) and NK2 ([Nle10]NKA(4-10)) receptor agonists were antagonized by atropine (ID50s = 1.1 mg/kg ip and 0.78 mg/kg ip, respectively). This behavioral study shows that tachykinin receptor activation is an essential component of DA-D1/Ach interaction in the mouse striatum and confirms the previously suggested functional importance of NK2 receptors in the central nervous system.

Blockade of neurotensin receptors by the antagonist SR 48692 partially prevents retrograde axonal transport of neurotensin in rat nigrostriatal system.

The effect of SR 48692, a potent and selective non-peptide antagonist of the neurotensin receptor, was investigated on the retrograde axonal transport of neurotensin in the rat nigrostriatal dopamine pathway. When rats were injected in the striatum with (3-[125I]iodotyrosyl3)neurotensin, a substantial accumulation of radioactivity appeared in the ipsilateral substantia nigra 1.5 h after injection, and highest levels (336 +/- 23 dpm/mg of protein) were observed 2.5-3.5 h after the injection. The phenomenon required a pretreatment of the animals with thiorphan (30 micrograms) an inhibitor of endopeptidase. The amount of radioactivity accumulated (3.5 h) was found to be reduced (25%) by local (100 nM) or peripheral administration of SR 48692 (5, 10, 20 mg/kg, i.p.; 25%, 40%, 40%, respectively). Our results indicate that blockade of neurotensin receptors by a selective non-peptide receptor antagonist affects the retrograde axonal transport of the tridecapeptide, and further suggest the notion that this process involves neurotensin receptors.

Intrastriatal injection of cannabinoid receptor agonists induced turning behavior in mice.

When injected unilaterally into the mouse striatum, cannabinoid agonists such as Win 55212-2 (1-100 ng/mouse), CP 55940 (0.1-50 ng/mouse), and anandamide (0.5-50 ng/mouse), the putative endogenous ligand of CB1 receptor, dose-dependently induced turning behavior. SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H- pyrazole-3-carboxamide hydrochloride], the selective antagonist of CB1 receptor, antagonized the three cannabinoid receptor agonists-induced turning with similar ED50s (0.13-0.15 mg/kg, IP). Spiroperidol (a D2 receptor blocker), (+)-SCH 23390 (a D1 receptor blocker), or prior 6-OHDA lesions of the striatum blocked Win 55212-2- and CP 55940-induced turning, thus suggesting the involvement of DA transmission in cannabinoid-induced turning. Taken together, these findings reinforce the notion of a cannabinoid receptor-mediated control of nigrostriatal function.

Pharmacological evaluation of minaprine dihydrochloride, a new psychotropic drug.

Minaprine (3-[2-morpholino-ethlamino]-4-methyl-6-phenyl-pyridazine dihydrochloride; 30038CM; trade name in France: Cantor) is a new psychotropic drug. The therapeutic profile of minaprine differs from that of other known psychotropic agents; in man the drug antagonizes the "inhibitory syndrome" characterized by decreased spontaneous activity, reduction in basic drives, slowed thoughts, feelings of tiredness and social withdrawal. Preliminary clinical trials have indicated that minaprine may also be effective in certain depressive states. This finding prompted us to study the effects of minaprine in animal models for depression. Like most antidepressants minaprine antagonizes behavioral despair, but the effect exhibits a slow onset and maximal activity is reached 24 h after administration. Minaprine also antagonizes reserpine-induced ptosis, this effect has a rapid onset, and is long-lasting. In contrast, minaprine poorly antagonizes reserpine-induced hypothermia. Unlike most antidepressants minaprine does not potentiate yohimbine-induced lethality. Minaprine potently antagonizes prochlorperazine-induced catalepsy in rats and potentiates amphetamine-induced stereotyped behavior, suggesting that the drug may enhance dopaminergic transmission. Finally, minaprine does not antagonize either oxotremorine-induced tremors or physiostigmine-induced lethality. Taken together the results of the present study indicate that minaprine is active on certain, but not all, animal models for depression and suggest the drug may have a potential clinical utility in the treatment of human depressions.

Expression and presence of septal neurokinin-2 receptors controlling hippocampal acetylcholine release during sensory stimulation in rat.

We examined the expression and presence of NK2 receptors in the septal area of rat brain, and investigated their functional role in the regulation of the septohippocampal cholinergic system. Using reverse transcription-polymerase chain reaction (RT-PCR) analysis, we showed the presence of NK2 receptor mRNA expression in the septal area, and detected septal NK2 binding sites by using a fluorescent-tagged neurokinin A (NKA) derivative. In vivo microdialysis was employed to explore the functional role of NK2 receptors in the release of hippocampal acetylcholine evoked by tactile stimulation in freely moving rats. Two sessions of stroking of the neck and back of the rat for 30 min, at 90 min intervals, produced a marked and reproducible increase in hippocampal acetylcholine release. This effect was dose-dependently prevented by intraperitoneal administration of the two selective non-peptide tachykinin NK2 receptor antagonists SR144190 (0.03-0.3 mg/kg, i.p.) and SR48968 (0.3 and 1 mg/kg, i.p.), but not by the inactive enantiomer of SR48968 (SR48965, 1 mg/kg) nor by the two non-peptide NK1 receptor antagonists SR140333 (3 mg/kg, i.p.) and GR205171 (1 mg/kg, i.p.). Furthermore, the intraseptal application of SR144190 (10(-8) M) reduced the sensory response. Finally, intraseptal perfusion of neurokinin A (0.01-10 microM) in anaesthetized rats produced a concentration-dependent increase in hippocampal acetylcholine release. The response to neurokinin A (0.1 microM) was prevented by SR144190 (0.03-0.3 mg/kg, i.p.) and SR48968 (0.3-1 mg/kg, i.p.). In conclusion, this study provides direct evidence for the role of endogenous NKA/substance P, through the activation of NK2 receptors, in regulating the septohippocampal cholinergic function.