Rociverine citrate was evaluated for its ability to affect the motility of rat urinary bladder, in vitro and in vivo, in comparison with flavoxate hydrochloride. Rociverine counteracted both methacholine and high K⁺-induced tonic contractions of bladder strips. In anaesthetized rats, intravenous rociverine inhibited dose-dependently frequency and amplitude of the distension-induced rhythmic contractions (DIRCs) of urinary bladder and counteracted the topical high K⁺induced pressure increase in the same organ. Orally administered rociverine produced a dose-related reversal of the reserpine-induced detrusor hyperreflexia in anaesthetized rats. In each of these experimental models rociverine was more effective than flavoxate. These results point to the usefulness of rociverine in the treatment of urinary bladder motility disorders.

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The effects of putative calmodulin antagonists on the binding of [³H]-opioid ligands to rat brain membranes were examined. Chlorpromazine, trifluoperazine, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and N²-dansyl-L-arginine-4-t-butylpiperidine amide (TI 233, No. 233) inhibited the binding of [³H] [D-Ala² Met⁵]enkephalinamide ([³H]DALAMID) in a dosedependent manner, and this inhibition was not necessarily specific for Ca²⁺ The order of the inhibitory potency on the binding of [³H] DALAMID was chlorpromazine, W-7, TI 233 and trifluoperazine. From the Scatchard plots, the effects of these compounds on the binding of [³H]DALAMID were biphasic. Low concentrations of calmodulin antagonists caused a small but significant increase in the maximal binding (B_max), but upon a further increase of the concentration, a significant decrease in B_max was observable; the apparent dissociation constant for the ligandreceptor complexes increased with the increase in the concentration of calmodulin antagonists. TI 233 (1-30×10^-6 M) inhibited, somewhat in a ligand selective manner, the binding of [³H]opioid ligands that have been thought to be selective for opioid receptor types. Calmodulin antagonists caused to increase in the fluorescence anisotropy obtained from 1, 6-diphenyl -1, 3, 5-hexatriene-labeled membrane fractions from rat brains, indicating that these compounds were effective for the decrease in the membrane fluidity. The present results indicate that putative calmodulin antagonists can affect the binding of the opioid ligands to rat brain membranes, probably through a mechanism other than one involving calmodulinrelated processes.

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The relationship between the brain monoaminergic mechanism and morphine tolerance was examined in reserpinized mice. In parallel with the reduction of brain monoamine content, the analgesic effect of morphine was reduced in reserpinized animals. At the peak of the reserpine effect, 24 hr after a single dose of 2.5 mg/kg reserpine, i.p., the analgesic effect of morphine was lowered to about 45% of that in naive animals; and 5 days after reserpine treatment, it recovered to about 60% of the control activity. In these animals, the lowered effect of morphine was maintained at the same range during 6 daily repetitions, and the development of tolerance was suppressed. When daily morphine injection was started from 10 days after reserpine treatment, at the time when the brain level of monoamines was still reduced to 60 to 80% of the control, tolerance developed as rapidly as in control animals. On the other hand, daily treatment with a small dose of reserpine, 0.1 mg/kg, neither affected the brain level of norepinephrine and dopamine nor modified morphine analgesia, but completely blocked the development of tolerance. These results may suggest that suppression of the development of tolerance to morphine analgesia is not attributed to the reduction of brain norepinephrine and dopamine by reserpine. Morphine analgesia without development of tolerance in reserpinized mice may indicate the dissociation of the analgesic effect from tolerance liability.

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Calcitonin gene-related peptide (CGRP) is a novel peptide amide of 37 amino acid residues, which was first identified as the product of alternative processing of RNA transcripts of the calcitonin gene in humans and rats. Using ¹²⁵I-human CGRP (hCGRP) as the binding ligand and hCGRP or salmon calcitonin (sCT) as the specific inhibitor of binding, it was examined how the receptor-like binding sites distribute among rat tissues including the nervous system, which is already known to contain binding sites in discrete regions. Some visceral organs (liver, spleen and lung) and possibly the bone marrow of Wistar male rats (8-10 weeks old) were found to be relatively rich in these binding sites. The following parameters were calculated by Scatchard analysis of binding data for the cerebellum, spleen and liver; K_D (nM) and B_max (fmol/mg protein) were 0.61 and 408, 1.08 and 858, and 0.89 and 356, respectively. In these three tissues, both hCGRP and sCT were able to completely suppress the specific binding; the IC50s (nM) of hCGRP for the cerebellum, spleen and liver were 2.57, 2.29 and 3.02, respectively, and the IC50s (μM) of sCT 2.69, 0.41 and 1.78, respectively. The results obtained herein strongly suggest the physiological function of CGRP in these visceral organs including bone marrow.

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The effect of α-(3, 5-di-tert-butyl-4-hydroxybenzylidene)-γ-butyrolactone (KME-4), a new anti-inflammatory drug, on established adjuvant arthritis in rats was compared to that of indomethacin. When administered orally daily from days 14 to 27 starting on day 14 after the adjuvant (day 0), KME-4 (2 to 10 mg/kg) produced a dose-related reduction of the swelling of both injected and uninjected hindpaws, and it retarded body weight loss. The initiation of paw swelling after the cessation of therapy was not observed at either 5 mg/kg or 10 mg/kg of KME-4. On day 42 (15 days after discontinuation of dosing), KME-4 caused the recovery of organ weight, erythrocyte sedimentation rate (ESR) and serum albumin/globulin (A/G) ratio towards normal levels, and it also decreased radiographic bone damage scores in a dose-dependent manner. The results indicate that KME-4 produces the improvement of systemic symptoms in the established adjuvant arthritis. The results obtained with indomethacin were similiar to those with KME-4. However, the degree of the efficacy of indomethacin (2 mg/kg) was lower than that of KME-4 (10 mg/kg) as judged by the measured parameters (ESR, serum A/G ratio and bone damage).

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The affinities of typical and atypical benzodiazepines (BZs) for ³H-flunitrazepam (FLU) and ³H-Ro 5-4864, “peripheral” BZ, binding sites in the central nervous system (CNS) were compared. Each dissociation constant (K_d) value of the ³H-FLU binding sites in the cerebellum, cortex, hippocampus and spinal cord showed the similar results, although the binding maximum (B_max) for the cortex and cerebellum yielded the largest value and the smallest B_max appeared in the spinal cord. In contrast, B_max for ³H-Ro 5-4864 binding sites were about three-fold higher in the spinal cord than in the cerebellum. Among the drugs tested, brotizolam demonstrated the highest affinity for ³H-FLU binding sites in the four regions. Typical and atypical BZs did not normally show different affinities for the two BZ receptor subtypes, except for CL 218, 872 and Ro 5-4864. A series of compounds including Ro 5-4864, PK 11195, diazepam and brotizolam had high affinity for the ³H-Bo 5-4864 binding sites in the cerebellum and spinal cord. Other BZs did not show affinity for “peripheral” BZ binding sites in the CNS. In conclusion, brotizolam (or atypical BZ) had the binding affinity to both “central” and “peripheral” BZ receptors, like diazepam (a typical BZ).

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Development of tolerance to nicorandil (NCR), N-(2-hydroxyethyl) nicotinamide nitrate (ester), was compared with that to nitroglycerin (NTG) in dogs. An intra-coronary arterial (i.a.) injection of NCR (30 μg) or NTG (3 μg) produced coronary vasodilation. Development of tolerance (including cross tolerance) was determined by examining whether the coronary vasodilating effect of i.a. injection of these drugs was attenuated by a 2 hr-infusion of NCR or NTG. The effect of La. injection of NCR was not affected by either NCR infusion (10 μg/ kg/min, i.v.) or NTG infusion (1 or 3 μg/kg/min, i.v.). The effect of La. injection of NTG, however, was attenuated by the NTG infusion, while it was not affected by the NCR infusion. Additionally, the coronary vasodilating effect of NCR infusion (30 μg/kg/min, i.v.) was not attenuated by NTG infusion (3 μg/kg/min, i.v.). These results suggest that NCR does not produce tolerance, whereas NTG does, and that there is no cross-tolerance between NCR and NTG in terms of the coronary vasodilating effect.

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Gastric transmucosal potential difference (PD) is referred to an index of function and integrity of the mucosa. The features of gastric PD were studied in association with gastric acid secretion. The gastric PD was measured at the forestomach, glandular portion and pylorus in the rat in in situ preparations. Secretagogues such as bethanechol (BeCh, 50 μg/kg, .v.), tetragastrin (TG, 30 μg/kg, i.v.), and histamine (Hist, 10 mg/kg, s.c.) produced a decrease in PD at the three regions of the stomach. These PD reductions did not occur with the combined treatment with timoprazole (30 mg/kg, i.d.); a marked increase in PD was noted, especially, in the case of Hist plus timoprazole. Similarly, BeCh induced PD decrease was antagonized by atropine (30 μg/kg, i.v.) and Hist induced PD decrease was attenuated by cimetidine (10 mg/kg, i.v.), while TG induced PD decrease was not affected by either of them. Of the antisecretory drugs, only cimetidine produced an increase in basal PD, probably via a mechanism unrelated to acid secretion. These results suggest that the PD decrease by each secretagogue seen at oxyntic and non-oxyntic gland regions of the stomach primarily originates from secretory activation of the parietal cells and that its action on function unrelated to acid secretion also exerts a minor influence on gastric PD.

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In the anesthetized open-chest guinea pig, ibopamine (10-300 μg/kg, i.v.), epinine (10-100 μg/kg, i.v.) and dopamine (10-300 μg/kg, i.v.) produced dose-related increases in heart rate (prevented by 20 μg/kg pindolol, i.v.), left ventricular dP/dt max and aortic flow. Ibopamine produced pressor effects (prevented by 0.5 mg/kg phentolamine, i.v.), while dopamine produced a slight depressor effect. A biphasic response (the pressor phase followed by a depressor) was observed after epinine, although the depressor phase was not significant. Calculated total peripheral resistance (TPR) tended to be increased after ibopamine and epinine (initial phase), while it was decreased after dopamine. Pindolol potentiated the increase in TPR produced by ibopamine and epinine, while the increase in TPR was converted to the decrease after phentolamine. Decreases in TPR produced by epinine and the highest dose of dopamine were inhibited by pindolol. In the isolated guinea pig atria, ibopamine (10^-6-10^-4 M) increased the atrial rate and the developed tension in a concentration-related manner. The positive chronotropic and inotropic effects of ibopamine were of the same order as those of epinine.

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The pharmacological profile of a new histamine H₂-receptor antagonist, 2-(3-(3-(1-piperidinylmethyl)phenoxy)propylamino)-4 (3H)-quinazolinone (NO794), was studied. NO-794 was a potent and selective histamine H₂-receptor antagonist in the guinea-pig atria and gastric mucosal cells. NO-794 (1×10^-5 M) did not interact with H₁-, muscarinic and β₁-receptors. In guinea-pig atria, antagonism of NO-794 was unsurmountable. The onset of action of NO-794 was slow, and this antagonism was apparently irreversible not only on the guineapig atria but also on the gastric mucosal cells. In addition, NO-794 inhibited gastric acid secretion in pylorus ligated rats when administered intraduodenally. These results indicate that NO-794 is a powerful and unique histamine H₂-receptor antagonist and may be useful in the treatment of peptic ulcer.

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Effect of YM-12617, a selective and potent alpha₁-adrenoceptor antagonist on dose-response curves of alpha₁ -adrenoceptor agonists, norepinephrine, phenylephrine and naphazoline, was tested in isolated rabbit vascular smooth muscles such as the femoral vein, portal vein and aorta. YM-12617 shifted the dose-response curves for norepinephrine and phenylephrine to the right and also declined the maximum response in the femoral vein, where norepinephrine and phenylephrine behaved as low efficacy agonists. Similar results were obtained on the curve of naphazoline in the portal vein, where the efficacy of naphazoline was low. However, the efficacies of norepinephrine, phenylephrine and naphazoline were high in the aorta. The dose-response curves for three alpha₁-agonists were shifted by YM-12617 in a parallel manner in the aorta. The curves of norepinephrine and phenylephrine were also shifted by YM-12617 in the portal vein, where the efficacies of both the alpha₁-agonists were high. The present results suggest that the mode of antagonism between the alpha₁ -agonist and alpha₁-antagonist is dependent on the efficacy of the alpha₁-agonist which depends upon the receptordensity in the organ used.

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The role of calcium ions in the activation of guinea pig neutrophil functions was examined by evaluating the effects of calcium antagonists. The data presented here show that calcium antagonists inhibit the activation of guinea pig neutrophil functions elicited by N-formyl-methionyl-leucyl-phenylalanine (FMLP) such as chemotaxis, superoxide anion generation and granule enzyme release in a concentration-dependent manner. The concentrations of calcium antagonists demonstrating the inhibition of neutrophil functions may be somewhat different for each function and higher than that of smooth muscle cells. Calcium ionophore A23187 (A23187) caused superoxide anion generation and granule enzyme release of the neutrophils. A23187 also potentiated the FMLP-induced superoxide anion generation and granule enzyme release of the neutrophils. On the contrary, A23187 neither elicited neutrophil chemotaxis nor affected FMLP-induced neutrophil chemotaxis. These results indicate the possibility that the inhibitory effect of calcium antagonists on the activation of neutrophil functions is probably not simply mediated by inhibition of calcium uptake but also by inhibition of a calcium-dependent intracellular target.

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We investigated which activity of myosin B (natural actomyosin), superprecipitation or ATPase, is better suited as a parameter for measuring in vitro contraction with emphasis on the response of myosin B to Sr²⁺. The Sr²⁺ concentration giving half-maximum (K_Sr²⁺) binding of Sr²⁺ to cardiac troponin was not different from that to skeletal troponin, whether the troponins were contained in the actomyosin system or in the isolated state. However, K_Sr²⁺ for the ATPase activity of cardiac myosin B is slightly smaller than that of skeletal myosin B. This difference in K_Sr²⁺ is more marked when superprecipitation was used as the indication for in vitro contraction. If the above results were compared with those of Kitazawa (1976) using glycerinated fibers of cardiac and skeletal muscle, the differences in K_Sr²⁺ between cardiac and skeletal muscle increased in the order: Sr-binding to troponin<ATPase activity<superprecipitation<contraction of glycerinated fibers. The increase in the effect of pH on Ca²⁺-related properties is also in the order: Cabinding to troponin≤ATPase activity6lang;superprecipitation<contraction of glycerinated fibers. All the results coincide with one another that the results with superprecipitation are invariably more akin to those with glycerinated fibers than to those with the ATPase activity. It is concluded that superprecipitation is a better parameter for representing in vitro contraction than ATPase activity.

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This study offers findings which should aid in the development of a convenient animal model of atherosclerosis. Inbred Fisher strain rats were fed an atherogenic diet containing 1.5% cholesterol and 0.5% cholic acid and given a single subcutaneous injection of adjuvant (Mycobacterium butyricum) into the base of the tail. The animals were maintained for 8 weeks. Rats given the atherogenic diet showed markedly increased serum cholesterol levels, and all of those given the adjuvant injection developed severe polyarthritis. Cholesterol feeding tended to delay the onset of arthritis and remarkably suppressed the inflammatory response, particularly in the early stage of development. This may have been due to the lowered lipid peroxide levels in the serum of rats fed the atherogenic diet. Adjuvant arthritis together with cholesterol feeding markedly increased the cholesterol content of the aorta, whereas either treatment alone had little effect. The amounts of the connective tissue components and minerals in the aorta were not changed by both treatments. These results show that early atherosclerosis could be produced under the conditions used and that chronic inflammation and hypercholesterolemia are principal factors in the pathogenesis.

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The effects of acute (24-, 48 or 72-hr) water deprivation on the disposition kinetics of trimethadione (TMO) and its only metabolite, dimethadione (DM0), and on the microsomal hepatic drug-oxidizing enzyme activities were investigated in male rats. The DMO/TMO ratios in the serum at 2 hr after intravenous administration of 100 mg/kg TMO were significantly decreased in 48 and 72-hr water-deprived rats, but in 24-hr water-deprived rats, the DMO/TMO ratios were not changed as compared to controls and food restrictions. In the 48 and 72-hr water-deprived rats, contents of cytochrome p-450 and activities of aminopyrine N-demethylase were significantly decreased. On the other hand, activities of aniline hydroxylase in these rats were significantly increased as compared to controls and food restrictions. These results suggest that the effects of water deprivation on drug metabolism not only depend on the time of water deprivation but also vary with the indicator substrate.

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Lipoic acid (Lip) was examined for its effect on the in vivo antibody response in mice. It was found that Lip significantly restored the suppressed antibody response to sheep erythrocytes (SRBC) in cyclophosphamide-injected mice when it was orally administered at 25 mg/kg twice a day for 4 consecutive days after immunization. On the other hand, Lip-administration did not affect the antibody response in normal mice immunized with SRBC. Normal or cyclophosphamide-treated mice were primed with horse erythrocytes (HRBC) and were given either saline or Lip for 3 consecutive days. HRBC-specific helper T cell activity of their spleen cells were compared by coculturing these cells with trinitrophenyl (TNP)-keyhole limpet hemocyanin-primed spleen cells in the presence of TNP-HRBC as the antigen. A significant restoration of the suppressed helper T cell activity was observed in the Lip-administered group. However, the helper T cell activity was not affected significantly by Lip-administration in normal mice. Lip could also partially restore the helper T cell activities that were suppressed by the treatment with hydrocortisone or X-ray irradiation.

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The responsiveness to three β-adrenergic agonists, isoproterenol (IPN), epinephrine (Epi) and norepinephrine (NE) in AH1 30 cells was examined compared with that in normal rat liver cells which were cultured for 24 hr after collagenase digestion. As regards to the activation of adenylate cyclase in the cell homogenates, the relative affinity of the three agonists was in order of IPN>NE>Epi in AH130 cells and IPN>Epi>NE in cultured normal liver cells. While the efficacies of the three agonists were similar in cultured liver cells, those of NE and Epi were markedly lower than that of IPN in AH130 cells and were increased to the similar level of IPN by pretreatment with phentolamine, but not with prazosin. Clonidine inhibited the activation of adenylate cyclase by IPN in AH130 cells. When cells were preincubated with islet-activating protein (IAP), the activity of adenylate cyclase n the presence or absence of agonist in both cell lines increased. In IAPtreated AH130 cells, the efficacies of NE and Epi became close to that of IPN. Adenylate cyclase in IAP-treated AH130 cells was activated by GTP in a dosedependent manner, but that in IAP-treated cultured liver cells was not. In the presence of IPN, biphasic (activatory and inhibitory) effects of GTP on the cyclase were observed, and the inhibitory phase was eliminated by the IAP-treatment in both cell lines. From these results, it is suggested that β-adrenoceptors in AH1 30 cells have similar properties to β₁ -receptors and that adenylate cyclase was restricted by inhibitory guanine nucleotide regulatory protein which closely interacts with an inhibitory receptor such as the α₂-adrenoceptor in AH1 30 cells and interacts with a stimulatory receptor such as the β₂-adrenoceptor in cultured normal rat liver cells.

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1) The contractile effects of epinephrine on the uterus and ductus deferens of the rabbit and the ductus deferens of the monkey were inhibited by the preincubation with progesterone (6.4×10^-5 M) for 1 or 3 min in Locke-Ringer solution. Epinephrine relaxed the guinea pig uterus and taenia caecum. The relaxant effects were enhanced by preincubation with progesterone. Their effects were in a dose-dependent manner. 2) There was no apparent change in the number and affinity of alpha-adrenergic receptors in the uterus of rabbits and the ductus deferens of guinea pigs during the incubation with progesterone. Progesterone has no direct effect on alpha-adrenergic receptors. 3) All smooth muscles yielded reproducible contractile reactions to Ca²⁺ when maintained in depolarizing Tyrode's solution containing K⁺ (40 mmol/I). Their concentration-response curves were inhibited by preincubation with progesterone (6.4×10^-5 M), and they were shifted to the right in a concentration-dependent manner. Established Ca²⁺induced contractions were rapidly relaxed by the addition of progesterone (6.4×10^-5 M). 4) It suggests that progesterone directly affects the plasma membrane and inhibits the voltage-dependent Ca²⁺ channel and then inhibits smooth muscle contraction.

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We examined the effects of FPL-52694 and disodium cromoglycate (DSCG), mast cell stabilizers, on HCl• ethanol-induced gastric lesions in rats and investigated the factors involved in their protection. Oral (p.o.) administration of 1 ml of HCl• ethanol (60% in 150 mM HCl) induced linear hemor hagic lesions in the gastric mucosa within 1 hr. FPL-52694 (1-30 mg/kg), given both p.o. and intraperitoneally (i.p.), prevented these lesions in a dose-related manner. DSCG (3-30 mg/kg) also dose-dependently reduced the formation of these lesions when this agent was given i.p. The protective effects of these drugs on HCl•-ethanolinduced lesions were significantly attenuated by pretreatment with indomethacin (5 mg/kg, s.c.). Both gastric acid secretion and transmucosal potential difference were significantly reduced by topical application of FPL-52694 (>10 mg/kg), but were not affected by i.p. administration of FPL-52694 and DSCG. On the other hand, gastric motor activity measured as intraluminal pressure recordings was significantly inhibited for 2 hr by both FPL-52694 (p.o. and i.p.) and DSCG (i.p.), and these effects were also significantly antagonized with prior administration of indomethacin. A significant relationship was found between the effects of these two drugs on the lesion index and the motility index (r: 0.9214, P<0.01), but not other factors. These results suggest that mast cell stabilizers such as FPL-52694 and DSCG protect the gastric mucosa against HCI•ethanol through a systemic action, probably mediated with endogenous prostaglandins. Although the mechanism of cytoprotection remains unknown, this property may be related to their inhibitory effects on gastric motor activity.

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In dog mesenteric vein strips, contractions induced by histamine relative to those induced by 5 mM Ba⁺⁺ were potentiated by removal of endothelium. The induced contractions were potentiated by AA861, a lipoxygenase inhibitor, and methylene blue, a guanylate cyclase inhibitor, to an appreciably greater extent in the strips with endothelium than in those with damaged endothelium. Indomethacin did not potentiate the contraction induced by histamine. Cimetidine potentiated the contraction in control strips and those without endothelium to a similar extent whereas chlorpheniramine suppressed the contraction. Contractile responses to acetylcholine, norepinephrine, serotonin and prostaglandin (PG) F_2α were not potentiated by removal of endothelium. It may be concluded that histamine activates histaminergic receptors, possibly H₁ but not H₂, in endothelial cells and results in a release of vasodilator substance produced by lipoxygenase, which accumulates cellular cyclic GMP and relaxes mesenteric veins. The H₁ and H₂ receptors in smooth muscle cells appear to be responsible for contractions and relaxxaions, respectively. Acetylcholine, norepinephrine, serotonin and PGF_2α do not seem to release vasodilator substances from endothelium in an amount sufficient to cause significant relaxations of venous smooth muscle.

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Glycogen phosphorylase a activity in 7 rat ascites hepatoma cell lines treated with adrenergic agents, phenylephrine, epinephrine and isoproterenol, was investigated as compared with that in freshly isolated rat hepatocytes. Basal phosphorylase activities in hepatoma cells except AH7974 cells were lower than that in hepatocytes. Phosphorylase in hepatoma cells was not activated by any of the agents, while the enzyme activity in hepatocytes was clearly increased in a doseand time-dependent manner. Phosphorylase in hepatocytes was sensitive to glucagon, but it was found to be insensitive to glucagon in all hepatoma cells. The present results suggest that rat ascites hepatoma cells may escape the glycogenolytic regulation by catecholamines and glucagon.

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Pretreatment of cerebral synaptic membranes with arachidonic acid (10 nM—1 μM) at 37°C for 40 min caused a significant increase in [³H]clonidine binding but pretreatment at 4°C did not. Scatchard analysis showed that 100 nM arachidonic acid pretreatment resulted in a significant elevation of the B_max value of the low affinity site. PGD₂, PGE₂ and PGF_2α (10-100 μM) pretreatment also enhanced binding. These polyunsaturated fatty acids could be involved in regulation of the α₂-adrenoceptor binding in rat cerebral cortical membranes.

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Interactions of beta-adrenergic partial agonists with the beta-adrenoceptor were studied in isolated guinea-pig taenia caecum. The competitive inhibition curve for specific binding of a high concentration (50 nM) of [³H]-befunolol by befunolol showed a biphasic shape, although the curve for specific binding of a low concentration (1 nM) was monophasic. All the competitive inhibition curves for specific binding of [³3H]-befunolol (1 nM and 50 nM) by isoprenaline and propranolol showed monophasic shapes. These results suggest that befunolol may be able to discriminate two different binding sites of the betaadrenoceptor: the high affinity site and the low affinity site.

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Effects of subchronic administration of haloperidol on the circling behavior induced by dopamine agonists were examined in rats treated with colchicine. Methamphetamine and apomorphine produced contralateral or ipsilateral rotation in colchicine-treated rats, and these circling behaviors were significantly increased by subchronic treatment with haloperidol. These results suggest that development of supersensitivity following colchicine and subchronic haloperidol may occur through different mechanisms.

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