2--hydroxy-5-9-dimethyl-2-allyl-6-7-benzomorphan and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol

The functions of sigma (sigma) receptors were reviewed based on electrophysiological studies. Systemic administration of sigma ligands reportedly produces a variety of effects on dopamine (DA) neurons. In the mesolimbic DA system, (+)SKF-10,047 suppressed activities of the ventral tegmental area. In the substantia nigra, DTG also suppressed these activities, while BMY-14802 increased the activity of neurons. In the cerebellum, however, activities of Purkinje cells were suppressed by locally applied DTG, with probable involvement of the catecholaminergic system. This effect on Purkinje cells may explain the action of sigma ligands on the motor system. In the hippocampus, neuronal activities were inhibited by SR31742A in vivo (CA3 region) and by (+)SKF10,047 in vitro (CA1 region). DTG at high concentration (1 mM) completely suppressed population spikes (PS) in the CA1 region of hippocampal slice preparations. In our experiments, a novel sigma ligand, OPC-24439, suppressed PS in CA1 at concentrations of 1-100 microM. However, NMDA-induced neuronal firings in CA3 in vivo were augmented by low doses of DTG in a haloperidol-sensitive manner, but high doses were ineffective. In contrast, non-NMDA responses were not affected by DTG. In addition, several sigma ligands having no effect on the NMDA response have been reported. In addition, endogenous ligands, neuropeptide Y and dehydroepiandrosterone, augmented the NMDA-induced firing. In whole-cell patch clamp recording, NMDA-induced currents were suppressed by a relatively higher concentration of DTG in a concentration-dependent manner, while non-NMDA responses were only slightly suppressed. These findings suggest that effects of sigma ligands on NMDA receptor responses are biphasic, and sigma ligands may modulate memory and learning and suppress neuronal death by anoxia. In addition, sigma ligands are also reported to suppress Ca2+ channels in hippocampal culture neurons and induce current by closing K+ channels in NCB-20 cells. Thus, sigma receptors may be involved in the modulation of a variety of neurons that relate to psychiatric function and plasticity.

Topics: Animals; Electrophysiology; Guanidines; Hippocampus; Ligands; Phenazocine; Pyrimidines; Receptors, N-Methyl-D-Aspartate; Receptors, sigma

Straub tail reaction (STR) was observed in male ddY mice after simultaneous administration with BMY 14802 (a non-specific σ receptor antagonist) and methamphetamine (METH). The intensity and duration of STR depended on the dose of BMY 14802. The tail reaction was inhibited completely by (+)-SKF 10,047 (a putative σ(1) receptor agonist) and partially by PB 28 (a putative σ(2) receptor agonist). The STR was mimicked in mice treated with BD 1047 (a putative σ(1) receptor antagonist), but not SM-21, a putative σ(2) receptor antagonist, in combination with METH. STR evoked with BD 1047 plus METH was inhibited by (+)-SKF 10,047. STR induced by BMY 14802 and METH was abolished by naloxone (a relatively non-selective opioid receptor antagonist) or U-50,488H (a selective κ-agonist), suggesting that the STR may be mediated by activation of opioid receptor system.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Animals; Antipsychotic Agents; Central Nervous System Stimulants; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Male; Methamphetamine; Mice; Mice, Inbred Strains; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Phenazocine; Pyrimidines; Receptors, Opioid, delta; Reflex; Tail; Time Factors

The effects of sigma receptor antagonists on methamphetamine (METH)-induced stereotypy have not been examined. We examined the effects of sigma antagonists on METH-induced stereotypy in mice.. The administration of METH (10 mg/kg) to male ddY mice induced stereotyped behavior consisting of biting (90.1%), sniffing (4.2%), head bobbing (4.1%), and circling (1.7%) during an observation period of 1 h. Pretreatment of the mice with BMY 14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol; 1, 5, and 10 mg/kg), a non-specific sigma receptor antagonist, significantly increased METH-induced sniffing (19.2%, 30.5%, and 43.8% of total stereotypical behavior) but decreased biting (76.6%, 66.9%, and 49.3% of total stereotypical behavior) in a dose-dependent manner. This response was completely abolished by (+)-SKF 10,047 ([2S-(2alpha,6alpha,11R)]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol; 4 and 10 mg/kg), a putative sigma(1) receptor agonist, and partially by PB 28 (1-cyclohexyl-4-[3-(1,2,3,4-tetrahydro-5-methoxy-1-naphthalen-1-yl)-n-propyl]piperazine; 1 and 10 mg/kg), a putative sigma(2) receptor agonist. The BMY 14802 action on METH-induced stereotypy was mimicked by BD 1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine; 10 mg/kg), a putative sigma(1) receptor antagonist, but not by SM-21 ((+/-)-tropanyl 2-(4-chlorophenoxy)butanoate; 1 mg/kg), a putative sigma(2) receptor antagonist. The BD 1047 effect on METH-induced stereotypy was also abolished completely by (+)-SKF 10,047 and partially by PB 28. The overall frequency of METH-induced stereotypical behavior was unchanged with these sigma receptor ligands, despite the alteration in particular behavioral patterns. The BMY 14802 action on METH-induced stereotypy was unaffected by pretreatment with centrally acting histamine H(1) receptor antagonists (pyrilamine or ketotifen, 10 mg/kg), suggesting that these effects are independent of histamine H(1) receptor signaling systems.. In summary, modulation of central sigma(1) receptors alters the pattern of METH-induced stereotypy, producing a shift from stereotypical biting to stereotypical sniffing, without affecting the overall frequency of stereotypical behavior.

Topics: Animals; Behavior, Animal; Butyrates; Central Nervous System Stimulants; Dose-Response Relationship, Drug; Drug Interactions; Ethylenediamines; Histamine H1 Antagonists; Ketotifen; Male; Methamphetamine; Mice; Mice, Inbred Strains; Motor Activity; Naphthalenes; Phenazocine; Piperazines; Pyrilamine; Pyrimidines; Receptors, sigma; Stereotyped Behavior; Tropanes

In this study, we investigated the involvement of the interaction between sigma receptors and the nitric oxide/cyclic GMP pathway in short term memory in mice, assessed through spontaneous alternation behavior in a Y-maze. N(G)-Nitro-L-arginine methyl ester and 7-nitro indazole, both nitric oxide synthase inhibitors, impaired the spontaneous alternation behavior. These impairments were attenuated by (+) SKF 10,047 and (+) pentazocine, sigma(1) receptor agonists. Further, the sigma(1) receptor antagonist, NE-100, reversed the improvements made by sigma receptor agonists. Cyclic GMP levels and nitric oxide synthase activity in the hippocampus were reduced by treatment with N(G)-nitro-L-arginine methyl ester. The suppressive effects of N(G)-nitro-L-arginine methyl ester on the cyclic GMP levels were reversed by co-treatment with (+) SKF 10,047, but the decline in nitric oxide synthase activity was not. These results suggest that the nitric oxide/cyclic GMP pathway in the hippocampus is responsible for spontaneous alternation behavior in a Y-maze. Further, the ameliorating effects of (+) SKF 10,047 on the impairment of spontaneous alternation behavior may be mediated through activation of guanylate cyclase, but not nitric oxide synthase in the hippocampus of mice.

Topics: Analgesics, Opioid; Animals; Anti-Anxiety Agents; Antipsychotic Agents; Behavior, Animal; Brain Chemistry; Cyclic GMP; Enzyme Inhibitors; Guanidines; Indazoles; Male; Methylene Blue; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Pentazocine; Phenazocine; Pyrimidines; Receptors, sigma

A beneficial effect of sigma (sigma) agonists was previously described on several pharmacological models of learning impairments. We examined this effect in senescence-accelerated mice (SAM), which has been developed as a murine model of aging and cognitive dysfunction. SAMP8/Ta (P8, senescence-prone substrain), 10-12 months of age, showed significant impairments in mnemonic capacities, as compared to age-matched SAMR1/Ta controls (R1, senescence-resistant substrain). Tests included open-field behavior, spontaneous alternation performances in the Y-maze, step-down passive avoidance and place learning after repetitive training in a water-maze. Pretreatment with the sigma agonists JO-1784 (igmesine) or PRE-084, at 0.1-3 mg/kg, s.c., significantly improved spontaneous alternation and passive avoidance performances in P8. JO-1784 or PRE-084, at 1 mg/kg, also improved place learning in the water-maze, and retention, in term of escape latency. The implication of sigma sites was indicated by the lack of significant effect of JO-1783, the inactive enantiomer of JO-1784, and by the ability of BMY-14802 (5 mg/kg, i.p.) to antagonize the effects on passive avoidance of JO-1784 (0.5 mg/kg) or PRE-084 (1 mg/kg). Subchronic treatments with JO-1784 (0.5 mg/kg/day) or PRE-084 (1 mg/kg/day) during 10 days, allowed a significant improvement of learning during training in the water-maze, but retention was not significantly ameliorated. These results confirmed the interest of the SAM substrains as an experimental model for senile memory impairment and showed that sigma agonists could improve the quality of learning, although they seem less effective on long-term memory retrieval upon chronic administration.

Topics: Aging; Animals; Anti-Anxiety Agents; Antipsychotic Agents; Avoidance Learning; Cinnamates; Cyclopropanes; Learning; Maze Learning; Memory; Mice; Mice, Neurologic Mutants; Morpholines; Motor Activity; Phenazocine; Pyrimidines; Receptors, sigma

Mice exhibited a marked suppression of motility when they were replaced in the same environment in which they had previously received an electric footshock. This psychological stress-induced motor suppression, known as conditioned fear stress, was dose dependently attenuated by (+)-N-allylnormetazocine ((+)-SKF-10,047) and by dextromethorphan, putative sigma receptor agonists, but not by other sigma receptor ligands, (+)-pentazocine and 1,3-di-(2-tolyl)guanidine (DTG). Unlike (+)-SKF-10,047 and dextromethorphan, the non-competitive NMDA receptor antagonists, phencyclidine and dizocilpine, attenuated the conditioned fear stress only at high doses that induced marked hypermotility in non-stressed mice. The effects of (+)-SKF-10,047 and dextromethorphan, but not phencyclidine and dizocilpine, on the conditioned fear stress were antagonized by the sigma receptor antagonists, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2- phenylethoxy)phenyl]-ethylamine monohydrochloride) and BMY-14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine- butanol hydrochloride). Interestingly, the effects of (+)-SKF-10,047 and dextromethorphan on the stress response were enhanced by combination with phenytoin, an anticonvulsant drug, whereas those of (+)- pentazocine, DTG, phencyclidine, and dizocilpine were not. These results suggest that activation of phenytoin-regulated type sigma 1 receptors, but not of phencyclidine receptors, is involved in the ameliorating effects of (+)-SKF-10,047 and dextromethorphan on stress-induced motor suppression.

Topics: Animals; Anti-Anxiety Agents; Antipsychotic Agents; Behavior, Animal; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Male; Mice; Motor Activity; Phenazocine; Phencyclidine; Phenytoin; Pyrimidines; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Stress, Physiological

To investigate the in vivo functional interaction between phencyclidine (1-(1-phenylcyclohexyl)piperidine; PCP) binding sites and sigma receptors, we examined the effects of sigma receptor ligands on stereotyped head-weaving behavior induced by PCP, a putative PCP/sigma receptor ligand, and (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclo-hepten-5,10-imin e ((+)-MK-801; dizocilpine), a selective PCP binding site ligand, in rats. PCP (7.5 mg/kg, i.p.)-induced head-weaving behavior was inhibited by both N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine (NE-100; 0.03-1.0 mg/kg, p.o.), a selective sigma1 receptor ligand, and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperidine butanol (BMY-14802; 3 and 10 mg/kg, p.o.), a prototype sigma receptor ligand, in a dose-dependent manner, whereas NE-100 (0.1-1.0 mg/kg, p.o.) and BMY-14802 (3 and 10 mg/kg, p.o.) did not inhibit dizocilpine (0.25 mg/kg, s.c.)-induced head-weaving behavior. These results suggest that NE-100 and BMY-14802 act via sigma receptors. Dizocilpine-induced head-weaving behavior was potentiated by 1,3-di-o-tolyl-guanidine (DTG; 0.03-0.3 microg/kg, i.v.) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP; 3 and 6 mg/kg, i.p.), sigma1/sigma2 receptor ligands, as well as by (+)-N-allyl-normetazocine ((+)-SKF-10,047: 8 mg/kg, i.p.), a sigma1 receptor ligand, while DTG (0.3 microg/kg, i.v.), (+)-3-PPP (6 mg/kg, i.p.) and (+)-SKF-10,047 (8 mg/kg, i.p.) did not induce this behavior. Potentiation of dizocilpine-induced head-weaving behavior by DTG (0.3 microg/kg, i.v.), (+)-3-PPP (6 mg/kg, i.p.) and (+)-SKF-10,047 (8 mg/kg, i.p.) was completely blocked by NE-100 (0.1 mg/kg, p.o.) and BMY-14802 (10 mg/kg, p.o.). These results suggest that PCP binding sites and sigma receptors are involved in PCP-induced head weaving behavior, and that sigma1 receptors play an important role in modulation of the head-weaving behavior.

Topics: Animals; Anisoles; Behavior, Animal; Binding Sites; Dizocilpine Maleate; Guanidines; Male; Phenazocine; Piperidines; Propylamines; Pyrimidines; Rats; Rats, Wistar; Receptors, Phencyclidine; Receptors, sigma

MK-801 (30-100 micrograms/kg, SC) impaired spontaneous alternation behavior of mice, a behavior related to the spatial working memory. 1,3-Di-(2-tolyl)guanidine (DTG), (+)-pentazocine and (+)-SKF 10,047 (100 micrograms/kg, SC), putative sigma agonists, administered 10 min before MK-801, partially but significantly reversed the impairment, without affecting the concomitant hyperlocomotion. The antagonizing effects by DTG were prevented by BMY-14802 (5 mg/kg, IP), a purported sigma antagonist. These findings suggest that, at low doses, sigma ligands may modulate the N-methyl-D-aspartate dependent memory processes.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Dizocilpine Maleate; Dose-Response Relationship, Drug; Guanidines; Male; Memory; Mice; Mice, Inbred Strains; Motor Activity; Pentazocine; Phenazocine; Pyrimidines; Receptors, sigma; Space Perception

Mice exhibited a marked suppression of motility (conditioned suppression) when placed in the same environment in which they had previously received an electric footshock. This stress-induced motor suppression was dose dependently attenuated by (+/-)-SKF-10,047, a sigma receptor agonist, but not by its (-)-optical isomer ((-)-SKF-10,047) and the sigma receptor ligands (+)-pentazocine and 1,3-di-(2-tolyl)guanidine. This effect of (+/-)-SKF-10,047 was antagonized by BMY-14802, a sigma receptor antagonist, and by pimozide, a dopamine receptor antagonist. When dopaminergic neurons were destroyed by pretreatment with 6-hydroxydopamine, the effect of (+/-)-SKF-10,047 on the stress response was also attenuated. Furthermore, (+/-)-SKF-10,047 dose dependently reversed the decrease in striatal dopamine turnover in the conditioned suppression group. These results suggest that stress-induced motor suppression is restored by (+/-)-SKF-10,047 acting through sigma receptors, which are closely linked to the dopaminergic neuronal system.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Anti-Anxiety Agents; Anticonvulsants; Apomorphine; Dopamine; Electroshock; Guanidines; Male; Methamphetamine; Mice; Mice, Inbred Strains; Motor Activity; Oxidopamine; Pentazocine; Phenazocine; Pimozide; Pyrimidines; Receptors, sigma; Stress, Psychological

FH-510 (5,8-dimethyl-4-(2-di-n-propylaminoethyl)carbazol) is a potent ligand for sigma ligand binding sites in rat brain membranes and has an IC50 value of 4.8 +/- 1.0 nM, which is comparable to that of haloperidol (2.2 +/- 0.2 nM). The high selectivity of FH-510 for sigma binding sites was evaluated by its lack of significant affinity for other binding sites, including those for dopamine D2 and phencyclidine. When administered to mice orally, FH-510 suppressed (+)-N-allylnormetazocine ((+)-SKF10,047)-induced stereotyped behavior with an ED25 value of 0.54 mg/kg, which is 14-fold more potent than that for (+)-alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol ((+)-BMY14802) (7.6 mg/kg). These results suggest that FH-510 may be a potent and selective sigma ligand.

Topics: Animals; Anti-Anxiety Agents; Binding, Competitive; Brain; Carbazoles; Dopamine; Haloperidol; Male; Mice; Phenazocine; Phencyclidine; Propylamines; Pyrimidines; Rats; Rats, Wistar; Receptors, sigma; Stereotyped Behavior

We examined the characteristics of the binding of radiolabeled 5,8-dimethyl-4-(2-di-n-propylaminoethyl)carbazol monohydrochloride ([3H]FH-510), a highly potent and selective sigma ligand, to guinea-pig brain membranes. [3H]FH-510 showed saturable and reversible binding to sigma binding sites. The association rate constant (k+1) and dissociation rate constant (k-1) of [3H]FH-510 were 0.023 min-1.nM-1 and 0.081 min-1, respectively. Scatchard plot analysis showed a dissociation constant (Kd) and maximal number of binding sites (Bmax) of 6.0 +/- 0.63 nM and 1763.3 +/- 177.4 fmol/mg protein (n = 7), respectively. The rank order of potency (Ki) of several structurally dissimilar sigma ligands obtained for the displacement of [3H]FH-510 binding was highly correlated with that determined for [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H](+)-3-PPP) binding. The binding of [3H]FH-510 was not influenced by histaminergic, dopaminergic, adrenergic, serotonergic or cholinergic agents at 10(-7) M. Higher [3H]FH-510 binding to brain regions was observed in the cerebellum and pons-plus-medulla. Except for the nuclear fraction, the highest level of [3H]FH-510 and [3H](+)-3-PPP binding to subcellular fractions was observed in the microsomal fraction. From these results, it is suggested that FH-510 selectively binds with high affinity to sigma binding sites in guinea-pig membranes.

Topics: Animals; Anti-Anxiety Agents; Binding Sites; Binding, Competitive; Brain; Carbazoles; Dopamine Agents; Guinea Pigs; Histamine; In Vitro Techniques; Kinetics; Male; Microsomes; Phenazocine; Piperidines; Propylamines; Pyrimidines; Radioligand Assay; Receptors, sigma; Serotonin

Pigeons were fed a fixed amount of grain-based feed and behavior was observed after administration of doses of ditolyguanidine (DTG), (+)-3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine [(+)-3-PPP], dextromethorphan, haloperidol, (+)-N-allylnormetazocine (NANM), alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol (BMY-14802) apomorphine, pentobarbital, propranolol, and MK-801. Of the drugs tested, DTG, dextromethorphan, and (+)-3-PPP each produced dose-related increases in the percentage of pigeons exhibiting an emetic response. The emetic response produced by DTG was antagonized by haloperidol and BMY-14802 but not by propranolol. These observations suggest that the emetic response in the pigeon may be mediated by sigma sites and is unlikely to be mediated by phencyclidine receptors.

Topics: Animals; Apomorphine; Columbidae; Dextromethorphan; Dizocilpine Maleate; Dopamine Agents; Guanidines; Haloperidol; Male; Pentobarbital; Phenazocine; Piperidines; Propranolol; Psychotropic Drugs; Pyrimidines; Receptors, Opioid; Receptors, sigma; Vomiting

Many PCP-like drugs interact with at least two types of binding sites in the CNS, one of which is linked to excitatory amino acid transmission and the other with an unknown function. The present experiments were designed to further clarify the mechanism of action of drugs in this class. Assessment was made of the effects of PCP, MK-801, (+)-pentazocine, (+)- and (-)-N-allyl-normetazocine (NANM), (+)-amphetamine and BMY-14802 in rats responding under a multiple timeout 600 s (TO), differential reinforcement of low rates 10 s (DRL), fixed ratio (FR) 10 schedule of reinforcement. The effects of the PCP-receptor selective drug MK-801 were compared to those of the mixed sigma/PCP drug (+)-NANM after each were combined with doses of (+)-pentazocine, PCP, BMY-14802, and (+)-amphetamine. MK-801 was also tested in combination with (+)-NANM, as was PCP with BMY-14802. When administered alone, MK-801, PCP, (+)-NANM, (+)-pentazocine, and (+)-amphetamine increased rates of responding under the DRL component of the multiple schedule. The drugs tested generally produced decreases in rates of responding under the FR component. (+)-Pentazocine and BMY-14802 did not modify the effects of (+)-NANM or of MK-801. PCP enhanced the effects of MK-801 and (+)-NANM, and (+)-amphetamine enhanced the effects of MK-801 but not of (+)-NANM. BMY-14802 attenuated the effects of PCP. Taken together, these data suggest similarities as well as some differences in the pharmacologic activities of MK-801 and (+)-NANM and PCP.

Topics: Animals; Conditioning, Operant; Dextroamphetamine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Pentazocine; Phenazocine; Phencyclidine; Psychotropic Drugs; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, sigma; Reinforcement Schedule

In the longitudinal muscle-myenteric plexus preparation (LMMP) of the guinea-pig ileum, the non-opioid sigma receptors agonists, 1,3-di-ortho-tolylguanidine (DTG) and (+)N-allyl-N-normetazocine [(+)SKF 10,047], had opposite effects on nerve-mediated cholinergic contractions caused by electrical field stimulation. DTG (0.1-10 microM) inhibited and (+)SKF 10,047 (0.1-10 microM) markedly enhanced these contractile responses. Both effects were evaluated in the presence (0.5 or 1 microM) of the putative antagonists at central sigma sites: haloperidol, rimcazole, BMY 14802 and dextromethorphan. Haloperidol and dextromethorphan were ineffective. Rimcazole antagonized the effect of both DTG and (+)SKF 10.047. BMY 14802 antagonized the (+)SKF 10.047-mediated excitatory response only. These results suggest that two sigma receptor subtypes are present in enteric cholinergic motor neurons innervating the longitudinal coat. Rimcazole and BMY 14802 may provide useful tools for the characterization of peripheral non-opioid sigma receptors.

Topics: Animals; Anti-Anxiety Agents; Antipsychotic Agents; Carbazoles; Dextromethorphan; Electric Stimulation; Guanidines; Guinea Pigs; Haloperidol; In Vitro Techniques; Male; Motor Neurons; Myenteric Plexus; Parasympathetic Nervous System; Phenazocine; Pyrimidines; Receptors, Opioid; Receptors, sigma

Evidence for a drug-induced activation of central sigma systems is presented. The model is the locomotor activation initiated by a subcutaneous (SC) challenge of 1.6 mg/kg of (+)-butaclamol, (+)-BUT, given 30 min before 10 mg/kg SC of (-)-N-allylnormetazocine, (-)-NAN, in Sprague-Dawley male rats which have been pretreated with four daily injections of 10 mg/kg SC of (-)-NAN. The locomotor activation is characterized by an initial 20 min period of retropulsion and sideways-circling followed by 90 to 100 min of forward locomotion. The locomotor syndrome is antagonized by 10 mg/kg of (+/-)-BMY 14802, 20 mg/kg of rimcazole, and 0.2 mg/kg of haloperidol, but not by 0.04 mg/kg of R(+)SCH23390, 100 mg/kg of S(-)sulpiride, 10 mg/kg of naltrexone, or 2.5 mg/kg of MR2266. The data suggest that the manifestation of the (+)-BUT/(-)-NAN-induced syndrome depends upon intact transmission at central sigma sites.

Topics: Animals; Benzazepines; Benzomorphans; Butaclamol; Carbazoles; Dopamine Antagonists; Haloperidol; Kinetics; Male; Models, Biological; Motor Activity; Naltrexone; Narcotic Antagonists; Phenazocine; Pyrimidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Sulpiride

The putative sigma receptor antagonists, haloperidol, HR 375, BMY 14802 and BW 234U potently inhibited both [3H]d-N-allylnormetazocine binding to sigma receptors in brain homogenates and [3H]haloperidol binding to sigma receptors in spleen homogenates. An excellent correlation of inhibitory potencies in the two assay systems was obtained. The results support the view that [3H]d-N-allylnormetazocine and [3H]haloperidol both label the same receptor populations, and suggest that sigma antagonists may be useful in elucidating physiological role(s) of sigma receptors in the nervous and immune systems.

Topics: Animals; Antipsychotic Agents; Brain Chemistry; Carbazoles; Guinea Pigs; Haloperidol; In Vitro Techniques; Isoquinolines; Male; Phenazocine; Piperazines; Pyrimidines; Receptors, Opioid; Receptors, sigma; Spleen; Tritium