igmesine and 1-3-ditolylguanidine

Intracellular calcium concentration ([Ca2+]i) plays a major role in neuronal excitability, especially that triggered by the N-methyl-d-aspartate (NMDA)-sensitive glutamatergic receptor. We have previously shown that sigma1 receptor agonists potentiate NMDA receptor-mediated neuronal activity in the hippocampus and recruit Ca2+-dependent second messenger cascades (e.g., protein kinase C; PKC) in brainstem motor structures. The present study therefore assessed whether the potentiating action of sigma1 agonists on the NMDA response observed in the hippocampus involves the regulation of [Ca2+]i and PKC. For this purpose, [Ca2+]i changes after NMDA receptor activation were monitored in primary cultures of embryonic rat hippocampal pyramidal neurons using microspectrofluorometry of the Ca2+-sensitive indicator Fura-2/acetoxymethyl ester in the presence of sigma1 agonists and PKC inhibitors. We show that successive activations of the sigma1 receptor by 1-min pulses of (+)-benzomorphans or (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784) concomitantly with glutamate time dependently potentiated before inconstantly inhibiting the NMDA receptor-mediated increase of [Ca2+]i, whereas 1,3-di-o-tolyl-guanidine, a mixed sigma1/sigma2 agonist, did not significantly modify the glutamate response. Both potentiation and inhibition were prevented by the selective sigma1 antagonist N,N-dipropyl-2-[4-methoxy-3-(211phenylethoxy) phenyl]-ethylamine monohydrochloride (NE-100). Furthermore, only (+)-benzomorphans could induce [Ca2+]i influx by themselves after a brief pulse of glutamate. A pretreatment with the conventional PKC inhibitor 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo [2,3-a] pyrrolo [3,4-c] carbazole (Gö-6976) prevented the potentiating effect of (+)-benzomorphans on the glutamate response. Our results provide further support for a general mechanism for the intracellular sigma1 receptor to regulate Ca2+-dependent signal transduction and protein phosphorylation.

Topics: Animals; Anisoles; Benzomorphans; Biological Transport; Calcium; Carbazoles; Cinnamates; Cyclopropanes; Drug Interactions; Enzyme Inhibitors; Female; Glutamic Acid; Guanidines; Hippocampus; Indoles; Neurons; Propylamines; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, sigma

Extracellular single-unit recordings and iontophoresis were used to examine the effects of different selective sigma receptor ligands on dopaminergic and glutamatergic N-methyl-D-aspartate (NMDA) neurotransmissions both in origin (A10 and A9 areas) and terminal (nucleus accumbens and caudate nucleus) regions of the rat mesolimbic and nigrostriatal dopaminergic systems. The selective sigma1 receptor ligands 2-[4-(4-methoxy-benzyl)piperazin-1-yl-methyl]4-oxo[4H]-benzo-th iazolin-2-one (S-21377), systemically administered (1.2 mg/kg, i.v., cumulative dose), and 2[(4-benzyl piperazin-1-yl) mothyl] naphthalene, dichiorydrate (S-21378), iontophoretically applied, slightly increased the spontaneous firing rate and potentiated the NMDA-induced neuronal activation of dopaminergic neurons in the A9 and A10 regions. (+)N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-butyl-2-N (JO-1784), another selective sigma1 receptor ligand produced no or little effect in these areas. The systemic administration of the selective sigma2 receptor ligand 1,4-bis-spiro[isobenzofuran-1(3H), 4'-piperidin-1'yl]butane (Lu 29-252) (2 mg/kg, i.v., cumulative dose) did not modify the firing activity of A9 and A10 dopaminergic neurons, but significantly potentiated the NMDA-induced increase in firing activity of A10 dopaminergic neurons. None of the sigma receptor ligands tested had any effects on the dopamine-induced suppression of firing. In the nucleus accumbens, the systemic administration of (JO-1784), (40 microg/kg, i.v.), (+)-pentazocine (30 microg/kg, i.v.), another selective sigma1 receptor ligand, and of the non selective sigma1 receptor ligand di-tolyl-guanidine (DTG) (20 microg/i.v.) produced a significant increase of NMDA-induced neuronal activation. Microiontophoretic applications of JO-1784 also potentiated the NMDA response. They also increased significantly the suppressant effect of dopamine on NMDA and kainate-induced activations of accumbens neurons. In the caudate nucleus, (+)-pentazocine, but not JO-1784, potentiated slightly the neuronal response to NMDA. None of the sigma receptor ligands tested did modify significantly the responses of caudate and accumbens neurons to kainate. These findings suggest that at least two subtypes of sigma1 receptors may affect differentially the glutamate NMDA neurotransmission in the terminal and origin regions of the mesolimbic and nigrostriatal dopaminergic systems. These results also demonstrate the existence of a functional interac

Topics: Analgesics, Opioid; Animals; Caudate Nucleus; Cinnamates; Cyclopropanes; Dopamine; Electrophysiology; Excitatory Amino Acids; Glutamic Acid; Guanidines; Kainic Acid; Male; N-Methylaspartate; Neurons; Nucleus Accumbens; Pentazocine; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Dopamine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, sigma; Sigma-1 Receptor; Spiro Compounds; Substantia Nigra; Synaptic Transmission; Thiazoles; Ventral Tegmental Area

Several high affinity sigma (sigma) ligands, such as DTG, JO-1784, (+)-pentazocine, BD-737 and L-687,384, administered at low doses act as agonists by potentiating N-methyl-D-aspartate (NMDA)-induced activation of pyramidal neurons in the CA3 region of the rat dorsal hippocampus. This potentiation is dose-dependent at doses between 1 and 1000 micrograms/kg, IV but bell-shaped dose-response curves are obtained. Other sigma ligands like haloperidol, BMY-14802, (+)3-PPP and NE-100 administered at low doses act as sigma antagonists, since they do not modify the NMDA response but suppress the potentiation of the NMDA response induced by sigma agonists. Because high doses of the sigma agonists do not potentiate the NMDA response, the present experiments were undertaken to assess if, at high doses, these sigma ligands could also act as sigma antagonists and suppress the potentiation induced by low doses of sigma agonists. High doses of DTG, JO-1784, BD-737, and L-687,384, administered acutely, had an effect similar to that of low doses of haloperidol, by suppressing and preventing the potentiation induced by low doses of DTG, JO-1784, BD-737, L-687,384 and (+)-pentazocine. High doses of (+)-pentazocine suppressed the effect of a low dose of (+)-pentazocine but did not affect the potentiation induced by a low dose of the other sigma agonists. The potentiation induced by a low dose of a sigma 1 agonist was not further increased by the subsequent administration of another low dose of a sigma 1 agonist. All together, these results strongly suggest that more than two subtypes of sigma receptors exist in the CNS.

Topics: Animals; Cinnamates; Cyclohexylamines; Cyclopropanes; Dose-Response Relationship, Drug; Drug Interactions; Electrophysiology; Excitatory Amino Acid Agonists; Guanidines; Hippocampus; Ligands; Male; N-Methylaspartate; Neurons; Pentazocine; Piperidines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, sigma

1. Long-term treatments with the sigma ligand haloperidol decrease the density of sigma receptors in mammalian CNS. We have shown that sigma ligands, such as di(2-tolyl)guanidin (DTG), potentiate dose-dependently, with bell-shaped dose-response curves, the neuronal response of pyramidal neurones to N-methyl-D-aspartate (NMDA) in the CA3 region of the rat dorsal hippocampus. sigma Ligands producing such a potentiation were denoted 'agonists'. This potentiation was suppressed by low doses of other sigma ligands denoted 'antagonists'. High doses of DTG and JO-1784 did not modify the NMDA response but acted as 'antagonists' by suppressing the potentiation induced by sigma 'agonists'. 2. Following a 21-day treatment with haloperidol as well as with high doses of DTG or JO-1784, after a 48 h washout, the acute administration of sigma 'agonists' failed to induce any potentiation of the NMDA response. Following a 21 day treatment with a low dose of DTG or JO-1784, after a 48 h washout, the neuronal response to microiontophoretic applications of NMDA was markedly increased. A 21 day treatment with low or high doses of (+)-pentazocine, after a 48 h washout, did not produce any change. 3. Following a two day treatment with a high dose of haloperidol, DTG, JO-1784 and (+)-pentazocine, after a 24 h washout, the potentiation of the NMDA response induced by the acute administration of the sigma 'agonists' was unchanged. 4. With the minipumps on board, with DTG and JO-1784, a dose-dependent enhancement of the NMDA response was seen but no effect was observed in the groups of rats treated at the same doses with haloperidol or (+)-pentazocine. 5. The present data suggest that long-term treatments with sigma 'antagonists' induce a desensitization of the th receptors, whereas long-term treatments with th 'agonists' induce a supersensitivity of the th receptors.

Topics: Animals; Cinnamates; Cyclopropanes; Guanidines; Haloperidol; Hippocampus; Male; N-Methylaspartate; Pentazocine; Rats; Rats, Sprague-Dawley; Receptors, sigma

In the CA3 region of rat dorsal hippocampus, several sigma ligands, such as 1,3-di(2-tolyl)guanidine (DTG), (+)-pentazocine and (+)-N-cyclopropylmethyl-N-methyl-1, 4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784), administered intravenously at low doses, potentiate selectively the pyramidal neuron firing activity induced by microiontophoretic applications of N-methyl-D-aspartate, without affecting those induced by quisqualate, kainate or acetylcholine. A similar potentiation of the N-methyl-D-aspartate response has also been found with microiontophoretic applications of neuropeptide Y, an effect exerted via delta receptors. The present experiments were carried out to determine the effects of these sigma ligands and of neuropeptide Y; in the CA1 and CA3 regions following unilateral destruction by a local injection of colchicine of the mossy fiber system, which is a major afference to CA3 pyramidal neurons. In the CA1 region, DTG, JO-1784 and neuropeptide Y did not potentiate the activation induced by microiontophoretic applications of N-methyl-D-aspartate. However, (+)-pentazocine potentiated the N-methyl-D-aspartate response, similarly to its effect in the CA3 region on the intact side. In the CA3 region, on the intact side, (+)-pentazocine, DTG, JO-1784 and neuropeptide Y induced a selective potentiation of N-methyl-D-aspartate-induced activation, in keeping with previous reports. On the lesioned side, the effect of (+)-pentazocine on the N-methyl-D-aspartate response was still present, but those of DTG, JO-1784 and neuropeptide Y were abolished. These results suggest that (+)-pentazocine, on the one hand, and DTG, JO-1784 and neuropeptide Y, on the other, are not acting on the same subtype of sigma receptors. Since (+)-pentazocine, JO-1784 and neuropeptide Y have been suggested to act on the sigma 1 subtype of receptors, these data suggest the existence of two subtypes of sigma 1 receptors. They also suggest that the receptors on which DTG, JO-1784 and neuropeptide Y are acting are located on the mossy fiber terminals in the CA3 region and are absent in the CA1 region.

Topics: Acetylcholine; Animals; Anticonvulsants; Cinnamates; Colchicine; Cyclopropanes; Electrophysiology; Guanidines; Hippocampus; Male; N-Methylaspartate; Nerve Fibers; Neuropeptide Y; Neurotoxins; Quisqualic Acid; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, sigma

The immobility time in the mouse forced swimming test was dose-dependently reduced by sigma 1 receptor agonists, such as 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) and (+)-pentazocine, and non-specific sigma receptor agonists, such as 1,3-di(2-tolyl)guanidine (DTG) and (+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylamin e hydrochloride (JO-1784). On the other hand, pre-treatment with N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a putative sigma 1 receptor antagonist, completely antagonized the SA4503-, (+)-pentazocine- and DTG-induced reductions in immobility time. Such phenomena indicate that sigma receptor agonists alleviate behavioral despair. In addition, these antidepressive effects involve mainly the sigma 1 receptor subtype.

Topics: Animals; Anisoles; Cinnamates; Cyclopropanes; Guanidines; Male; Mice; Mice, Inbred Strains; Motor Activity; Pentazocine; Piperazines; Propylamines; Receptors, sigma; Stress, Physiological

1. The in vivo effects of the high affinity sigma ligands 1,3-di(2-tolyl)guanidine (DTG), (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1- ethyl-but-3-en-1-ylamine hydrochloride (JO-1784), (+)-pentazocine and haloperidol, as well as of those of neuropeptide Y (NPY), on N-methyl-D-aspartate (NMDA)- and quisqualate (Quis)-induced neuronal activations of CA3 pyramidal neurones were assessed, using extracellular unitary recording, in control rats and in rats pretreated with a local injection of pertussis toxin (PTX), to evaluate the possible involvement of Gi/o proteins in mediating the potentiation of the neuronal response to NMDA by the activation of sigma receptors in the dorsal hippocampus. 2. Microiontophoretic applications as well as intravenous injections of (+)-pentazocine potentiated selectively the NMDA response in control rats as well as in PTX-pretreated animals. In contrast, the PTX pretreatment abolished the potentiation of the NMDA response by DTG, JO-1784 and NPY. Moreover, microiontophoretic applications of DTG induced a reduction of NMDA-induced neuronal activation. Neither in control nor in PTX-treated rats, did the sigma ligands and NPY have any effect on Quis-induced neuronal response. 3. In PTX-treated rats, the potentiation of the NMDA response induced by (+)-pentazocine was suppressed by haloperidol, whereas the reduction of the NMDA response by DTG was not affected by haloperidol. 4. This study provides the first in vivo functional evidence that sigma ligands and NPY modulate the NMDA response by acting on distinct receptors, differentiated by their PTX sensitivity.

Topics: Animals; Anticonvulsants; Cinnamates; Cyclopropanes; Drug Synergism; GTP-Binding Proteins; Guanidines; Haloperidol; Hippocampus; Ligands; Male; N-Methylaspartate; Neurons; Neuropeptide Y; Pentazocine; Pertussis Toxin; Pyramidal Cells; Quisqualic Acid; Rats; Rats, Sprague-Dawley; Receptors, sigma; Virulence Factors, Bordetella

The ulceroprotective effects of JO 1784 [(+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-yl amine, hydrochloride], a new specific and highly selective sigma ligand, were examined in rats.. Different models of gastric ulcers (4-hour restraint stress, aspirin, ethanol, and taurocholate) and cysteamine-induced duodenal ulcers were used. The gastric acid secretion (4-hour Shay rat preparation) and the duodenal bicarbonate secretion were also studied.. JO 1784 elicited a potent protection against duodenal ulcers but had a weaker protective effect on any of the gastric ulceration models tested. It displayed no gastric antisecretory activity but induced a dose-dependent stimulation of duodenal bicarbonate secretion. Haloperidol, hexamethonium, tetrodotoxin, bivagotomy (but not atropine), and the intravenous but not intracerebroventricular administration of devazepide, a cholecystokinin A antagonist, inhibited the stimulatory effect of JO 1784.. These results show that JO 1784, a selective sigma ligand, is a potent protector of the duodenal mucosa. This activity may be related to its stimulating effect on bicarbonate secretion, which is driven through a complex nervous mechanism involving muscarinic synapses, vagal afferent fibers, and peripheral cholecystokinin receptors. This drug might open a new specific way in the treatment of duodenal ulcers.

Topics: Animals; Bicarbonates; Cinnamates; Cyclopropanes; Cysteamine; Duodenal Ulcer; Duodenum; Gastric Acid; Guanidines; Male; Rats; Rats, Sprague-Dawley; Receptors, sigma; Stomach Ulcer

The effects of putative sigma ligands and two neuropeptides on intestinal ion transport were evaluated in isolated sheets of whole mouse jejunum mounted in Ussing flux chambers. Serosal administration of neuropeptide Y (NPY), peptide YY (PYY), (+)-N-cyclopropylmethyl-N-methyl-1,4- diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride (JO 1784), di(ortho-tolyl)guanidine (DTG) and (+)- or (-)-N-allyl-normetazocine (NANM) produced concentration-related decreases in short-circuit current (Isc) without changes in tissue conductance. Although NPY and PYY were active in nanomolar concentrations, JO 1784, DTG and (+)- and (-)-NANM were active in micromolar concentrations; the rank order of potency in inhibiting Isc was PYY > NPY >> JO 1784 = (-)-N- cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride > DTG > (+)-NANM = (-)-NANM. Serosal application of tetrodotoxin effectively blocked the decrease in Isc associated with all of the ligands tested. The activity of the serosally applied ligands was blocked by prior application of chlorisondamine, a ganglionic blocker. The effects of JO 1784 and NPY were evaluated using antagonists of several receptor types. Although application of serosal haloperidol had no effect alone up to concentrations of 1 microM, this compound produced a rightward displacement in both the NPY and JO 1784 concentration-effect curves. In contrast, sulpiride, SCH-23390, naloxone, yohimbine and prazosin failed to antagonize the effects of NPY or JO 1784.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cinnamates; Cyclopropanes; Guanidines; In Vitro Techniques; Ion Transport; Jejunum; Male; Mice; Mice, Inbred ICR; Neuropeptide Y; Peptide YY; Peptides; Phenazocine; Receptors, sigma

Acute and repeated administration of antipsychotic drugs produce distinctive profiles of electrophysiological effects on the population activity of midbrain dopaminergic (DA) neurons which correlate with their clinical effects. Sigma receptors have been hypothesized to be involved in psychosis and in the efficacy of antipsychotic drugs, but little is known about the effects of repeated treatment with sigma ligands on the activity of midbrain DA neuronal populations. In the present study, the cells-per-track cell-sampling method was used to evaluate the effects of 3 sigma ligands on the numbers of spontaneously active A9 and A10 DA neurons in chloral hydrate-anesthetized rats. One-hour pretreatment with either (+)-pentazocine (10 mg/kg, i.p.), DTG (2 mg/kg, i.p.), or JO 1784 (1 or 10 mg/kg, s.c.) did not alter the number of spontaneously active DA neurons encountered per electrode track. Repeated treatment (21 daily injections) with (+)-pentazocine (1 or 10 mg/kg) or DTG (0.2 or 2 mg/kg) increased the number of A10 DA cells per track; JO 1784 (10 mg/kg but not 1 mg/kg) moderately decreased the number of active A9 DA cells and increased the firing rate of A10 DA neurons. The effect of JO 1784 on A9 DA neurons was not due to depolarization inactivation. The effects of all 3 sigma ligands differ from those of antipsychotic drugs, all of which inactivate A10 DA neurons after repeated treatment. Clinical studies are necessary to determine if selective sigma ligands will provide a novel alternative to DA antagonists in the treatment of psychosis.

Topics: Animals; Cinnamates; Cyclopropanes; Dopamine; Guanidines; Ligands; Male; Mesencephalon; Neurons; Pentazocine; Rats; Rats, Sprague-Dawley; Receptors, sigma; Time Factors

The effects of the high affinity sigma (sigma) ligands 1,3-di(2-tolyl)guanidine (DTG), (+)N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1- ethyl-but-3-en-1-yl-amine hydrochloride (JO-1784), (+)3-[3-hydroxyphenyl]-N-(1-propyl)piperidine hydrochloride [(+)3-PPP] and haloperidol were studied on N-methyl-D-aspartate (NMDA)-evoked release of [3H]noradrenaline (NA) from preloaded hippocampal slices made from Sprague-Dawley rats. The [3H]NA release was evoked once by a 4 min exposure to NMDA, 40 min after the beginning of superfusion with a Mg+(+)-free Krebs' solution. In the absence of any drug, NMDA evoked a concentration-dependent [3H]NA release. Mg++ and EGTA abolished the [3H]NA release induced by NMDA. JO-1784 and (+)3-PPP potentiated in a concentration-dependent manner NMDA-induced [3H]NA release, without affecting the basal outflow. DTG concentration-dependently inhibited the overflow of [3H]NA evoked by NMDA, without affecting the basal efflux. Haloperidol, which did not modify NMDA-evoked [3H]NA release by itself, completely prevented the effects of JO-1784, (+)3-PPP and DTG. In contrast, spiperone, also a potent dopamine receptor antagonist but with low affinity for sigma binding sites, failed to prevent the potentiation of NMDA-evoked release of [3H]NA by JO-1784 and (+)3-PPP. The possible involvement of Gi/o proteins in the modulation by sigma ligands of NMDA-evoked [3H]NA release in the rat hippocampus was also investigated. To this end, Gi/o proteins were inactivated with pertussis toxin (PTX), injected locally 3 to 11 days prior to the experiment or with in vitro preincubation with N-ethylmaleimide (NEM) for 30 min prior the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Calcium; Cinnamates; Cyclopropanes; Dose-Response Relationship, Drug; Ethylmaleimide; GTP-Binding Proteins; Guanidines; Haloperidol; Hippocampus; In Vitro Techniques; Magnesium; Male; N-Methylaspartate; Norepinephrine; Pertussis Toxin; Piperidines; Rats; Rats, Inbred Strains; Spiperone; Tritium; Virulence Factors, Bordetella

In an in vivo electrophysiological paradigm, we have shown in the companion paper that neuropeptide Y (NPY) potentiates N-methyl-D-aspartate (NMDA)-induced neuronal activation via a non-Y1, non-Y2, non-Y3 receptor subtype, in the rat CA3 dorsal hippocampus. Because sigma ligands have also been shown to potentiate NMDA-induced activation and because NPY and peptide YY have been reported to have high affinity for sigma binding sites, the present study was carried out to assess the possibility that the modulation of the NMDA response by NPY might be mediated by a sigma receptor. In the same electrophysiological paradigm, low doses of haloperidol and alpha-(4-fluorophenyl)-4-(5-fluoro-2- pyrimidinyl)-1-piperazine butanol, two antagonists of sigma receptors, reversed the potentiation of the NMDA response induced by NPY, [Leu31, Pro34]NPY or NPY13-36 and blocked the suppressant effect of desamido-NPY on the NMDA response. In contrast, spiperone, which has low affinity for sigma sites, was ineffective in suppressing NPY, as well as desamido-NPY-induced modulation of the NMDA response. In our model, peptide YY, which acts as a NPY antagonist by suppressing the potentiation of the NMDA response induced by NPY, also antagonized the potentiation of the NMDA response induced by the administration of low doses of di(2-tolyl)guanidine and (+)N-cyclopropyl-methyl-N-,methyl-1,4- diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride, two high-affinity sigma agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cinnamates; Cyclopropanes; Drug Synergism; Guanidines; Haloperidol; Hippocampus; Male; N-Methylaspartate; Neuropeptide Y; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Receptors, sigma; Spiperone

JO 1784 ((+)-N-Cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylami ne, hydrochloride), has been recently described as a selective ligand for the sigma receptor with an IC50 of 39 +/- 8 nM28. In the present study the effects of JO 1784 on experimental induced amnesia were investigated using one trial passive avoidance task in rats. Amnesia was produced by injecting scopolamine (1 mg/kg i.p.) 30 min before the second session (T2) on day 2 of the passive avoidance task. The anti-amnesic effect of JO 1784 was compared with other typical and atypical psychotropic drugs which interact at the sigma and or the phencyclidine site. JO 1784 was studied at 5 doses; 0.0625, 0.25, 1.0, 4.0 and 16.0 mg/kg i.p. ((+)-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine ((+)-3-PPP). Rimcazole, (+)-N-allylnormetazocine ((+)-NANM), 1,3-di(2-tolyl) guanidine (DTG) were studied at 4 doses; 0.25, 1.0, 4.0 and 8.0 mg/kg i.p. All drugs were administered 60 min before the test (T2) on day 2 i.e. 30 min before scopolamine. Piracetam (1000 mg/kg p.o.) administered in the same test conditions was used as a reference compound in each experiment. Of the drugs investigated JO 1784 (0.25, 1.0, 4.0 and 16.0 mg/kg i.p.), (+)-3-PPP (0.25, 1.0 and 4.0 mg/kg i.p.), DTG (1.0, 4.0 and 8.0 mg/kg) and piracetam significantly reversed scopolamine induced amnesia on day 3 (T3). At the lower dose, JO 1784 (0.0625 mg/kg) failed to reverse the amnesic effects of scopolamine on day 3. These results suggest that JO 1784 the selective sigma ligand, may be beneficial in amnesic status.

Topics: Amnesia; Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Carbazoles; Cinnamates; Cyclopropanes; Dopamine Agents; Dose-Response Relationship, Drug; Guanidines; Ligands; Male; Phenazocine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Scopolamine

The influence of central vs. peripheral administration of sigma ligands (dl- and l-N-allylnormetazocine, 1-3-di-o-tolylguanidine, (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene and phencyclidine on colonic motility was investigated in fasted and fed dogs equipped with strain-guage transducers implanted on proximal and transverse colon. When injected intravenously at a dose of 0.25 mg/kg just before feeding, dl- or d-N-allylnormetazocine, 1-3-di-o-tolylguanidine, and (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene (but not phencyclidine) enhanced the colonic motor response to a meal by increasing the 0-4-hour motility indexes from 64.1%-159.3% in both the proximal and transverse colon but had no effect on colonic motility in fasted animals or animals injected intracerebroventricularly. The motor-stimulatory effects of d-N-allylnormetazocine (1 mg/kg), 1-3-di-o-tolylguanidine (0.25 mg/kg), and (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene (1 mg/kg) were abolished after previous treatment with haloperidol (0.5 mg/kg, intravenous) but not after sulpiride (0.1 mg/kg) or (+) R-(+)-8-chloro-2,3,4,5-tetrahydro-3- methyl-5-phenyl-1-H-3-benzozepine-OH. Prazosin (0.1 mg/kg, intravenous) and 1-methyl-3-(2-indolyl)amino-5-phenyl-3H-1,4-benzodiazepin-2-one (0.01 mg/kg) also suppressed the enhancement of the colonic motor response to eating induced by d-N-allylnormetazocine, 1-3-di-o-tolylguanidine, and (+)cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene whereas naltrexone did not affect their effects. It is concluded that d-N-allylnormetazocine, 1-3-di-o-tolylguanidine, and (+)cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene stimulate the postprandial colonic motility in dogs by acting selectively on sigma receptors located peripherally and probably by affecting the release of cholecystokinin octapeptide through a central adrenergic mechanism.

Topics: Animals; Cinnamates; Colon; Cyclopropanes; Dogs; Drug Antagonism; Eating; Gastrointestinal Motility; Guanidines; Injections, Intravenous; Injections, Intraventricular; Phenazocine; Phencyclidine; Receptors, Opioid; Receptors, sigma; Stereoisomerism