Inflammatory, cardio-metabolic and diabetic profiling of chronic schizophrenia.

BACKGROUND: There is a growing interest in low-grade inflammatory and metabolic alterations in patients with chronic schizophrenia (SCH). METHODS: Inflammatory (tumor-necrosis factor-α [TNF-α], interferon-γ [IFN-γ], interleukins [IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10], monocyte chemo-attractant protein-1 [MCP-1]) and growth factors (vascular endothelial growth factor [VEGF], epidermal growth factor [EGF]) were measured in blood serum samples of 105 SCH patients and 148 control subjects (CS). Simultaneously the clinical biomarkers (C-reactive protein [CRP], triglycerides [TG], low-density lipoprotein [LDL-c] and high-density lipoprotein [HDL-c] cholesterol, glycated hemoglobin [HbA1c]) were measured, and body mass index (BMI) was calculated for patients. RESULTS: Several cyto-/chemokines (IFN-γ, MCP-1, IL-2, IL-6, IL-8 and IL-10) were significantly (P<0.0000001) elevated in SCH patients compared to CS. Odds ratios, obtained from logistic regression analyses, were significantly elevated for IL-2, IL-6, IL-10, INF-γ, and decreased for TNF-α in SCH group. Among the patients, higher IL-2, IL-6, INF-γ and lower MCP-1 levels as well as male gender were together significant (P<0.000001) predictors of higher HbA1c levels, and TG/HDL-c parameter was associated with ratios of INF-γ/IL-10 (P=0.004), and INF-γ/IL-4 (P=0.049), HbA1c (P=0.005), INF-γ (P=0.009), as well as LDL-c (P=0.02) levels. CONCLUSIONS: IL-2, IL-6, IL-10 and IFN-γ were the most significant SCH-related markers among the measured cytokines in our patient group. Furthermore, significant associations between pro-/anti-inflammatory imbalance and HbA1c as well as cardio-metabolic risk marker (TG/HDL-c) were observed, indicating higher risks of diabetes and cardiovascular diseases among SCH patients.

The antidepressant action of imipramine and venlafaxine involves suppression of nitric oxide synthesis.

Depressive disorders represent a major public health problem worldwide. The limitations of current antidepressant drugs have warranted on-going research to identify pharmacological agents and strategies that offer a greater therapeutic efficacy. The NMDA/L-arginine nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) cascade is an important signaling pathway that is also implicated in the regulation of depression. In animal models detecting antidepressant activity, distinct NO synthase inhibitors display antidepressant-like action. Therefore, the aim of current study was to evaluate whether pretreatment with L-arginine (precursor of NO) could counteract antidepressant-like effects of distinct antidepressant classes in the mouse forced swimming test (FST), and whether these drugs are able to modulate the nitric oxide synthesis in the brain. We found in the FST that pretreatment with L-arginine (500 mg/kg) counteracted the antidepressant-like effect of imipramine (IMI, 15 mg/kg) and venlafaxine (VENL, 6 mg/kg), but not the effects of bupropion (BUPR, 20mg/kg) or fluoxetine (FLX, 20mg/kg). Increasing the dose of L-Arg to 1000 mg/kg attenuated the antidepressant-like effects of BUPR, but did not modify the action of FLX. L-Arginine was devoid of any locomotor effects on the animals. The effect of antidepressants on brain NO metabolism paralleled their behavioral action in case of IMI and VENL which decreased the nitrite+nitrate concentration in the brain. BUPR and FLX did not have any effect on brain nitrite+nitrate concentration. These results support the idea that some antidepressants are able to inhibit nitric oxide synthesis in the brain, an effect which could be mechanistically related to the ability of L-arginine to counteract their antidepressant-like effects.

High-performance liquid chromatography method with radiochemical detection for measurement of nitric oxide synthase, arginase, and arginine decarboxylase activities.

Nitric oxide has been shown to be involved in numerous biological processes, and many studies have aimed to measure nitric oxide synthase (NOS) activity. Recently, it has been demonstrated that arginase and arginine decarboxylase (ADC), two enzymes that also employ arginine as a substrate, may regulate NOS activity. We aimed to develop a HPLC-based method to measure simultaneously the products of these three enzymes. Traditionally, the separation of amino acids and related compounds with HPLC has been carried out with precolumn derivatization and reverse phase chromatography. We describe here a simple and fast HPLC method with radiochemical detection to separate radiolabeled L-arginine, L-citrulline, L-ornithine, and agmatine. 3H-labeled L-arginine, L-citrulline, agmatine, and 14C-labeled L-citrulline were used as standards. These compounds were separated in the normal phase column (Allure Acidix 250 x 4.6 mm i.d.) under isocratic conditions in less than 20 min with good sensitivity. Using the current method, we have shown the formation of L-citrulline and L-ornithine in vitro using brain tissue homogenate of rats and that of agmatine by Escherichia coli ADC.

Combined chronic treatment with citalopram and lithium does not modify the regional neurochemistry of nitric oxide in rat brain.

A substantial number of patients do not respond sufficiently to antidepressant drugs and are therefore often co-medicated with lithium as an augmentation strategy. Also inhibitors of nitric oxide synthase (NOS) have been used as an augmentation strategy, while inhibitors of NOS exhibit antidepressant-like properties in various animal models. Therefore, we hypothesized that modulation of NOS may be involved in the long-term effects of antidepressants and lithium, and studied the influence of acute and chronic administration of citalopram, alone or in combination with lithium, on NOS activity in hippocampus, cerebellum, and frontal cortex, by determination of L-citrulline being formed. We found that administration of acute or chronic citalopram (5 mg/kg and 20 mg/kg/24h, respectively) alone or in combination with subchronic lithium (60 mmol/kg chow pellet) did not influence the activity of NOS ex vivo in all regions compared to control. In contrast, high doses of lithium caused a significant decrease in NOS activity in vitro. We conclude that basal conditions are unsuitable for the study of antidepressant effects on NOS, and that the neurochemistry of nitric oxide remains unaltered following chronic citalopram or subchronic lithium under normal physiological conditions.

Augmentation of the NO-cGMP cascade induces anxiogenic-like effect in mice.

Several studies have reported the anxiolytic-like effects of various nitric oxide synthase inhibitors in distinct animal models. However, in the context of anxiety, the possible involvement of cyclic GMP, believed to be one of the main targets of NO, remains obscure. Cyclic GMP is degraded by the specific phosphodiesterases in the brain. Therefore, we studied the effect of the selective phosphodiesterase type 5 inhibitor sildenafil in the mouse elevated plus-maze test of anxiety and in the open field test of locomotion. We found that sildenafil (0.05-10 mg/kg i.p.) alone did not affect the behavior of animals in the plus-maze or open field tests, but the anxiogenic beta-carboline DMCM given in a subconvulsive dose (2 mg/kg i.p.) decreased the time spent on open arms in the elevated plus-maze. Treatment with the NO precursor L-arginine (200 mg/kg i.p.) did not modify the behavior of animals in the plus-maze, however, when sildenafil (1 mg/kg i.p.) was administered in combination with L-arginine (200 mg/kg i.p.), both the time spent on the open arms and the percentage of open arm visits were significantly decreased. We conclude that augmentation of the NO-cGMP cascade induces anxiogenic-like effect in mice.

Cholecystokinin2 receptor-deficient mice display altered function of brain dopaminergic system.

RATIONALE: Cholecystokinin (CCK) has been shown to coexist and interact with dopamine in the regulation of behaviour. Two different CCK receptors (CCK1 and CCK2) have an opposite influence on the activity of dopamine neurons. Stimulation of CCK2 receptors decreases the release of dopamine and that receptor could mediate the neuroleptic-like effect of CCK. OBJECTIVE: To investigate the activity of the dopaminergic system in pharmacological experiments on CCK2 receptor (CCK2R)-deficient mice. METHODS: We used age- and sex-matched littermates in all our experiments. To evaluate the behavioural differences, we performed the rotarod test and measured the locomotor activity of animals using computer-connected photoelectric motility boxes. Amphetamine and apomorphine, two dopaminergic drugs with different pharmacodynamic properties, were used to influence the activity of the dopaminergic system in the brain. Neurochemical differences related to the different genotype were analysed by means of high-performance liquid chromatography and radioligand binding studies. RESULTS: Motor co-ordination was significantly impaired in the rotarod test of CCK2R receptor-deficient mice. Moreover, the locomotor activity of heterozygous (+/-) and homozygous (-/-) CCK2R receptor-deficient mice was somewhat reduced. A low dose of apomorphine (0.1 mg/kg), an unselective agonist of dopamine receptors, suppressed locomotor activity significantly more in homozygous (-/-) and heterozygous (+/-) mutant mice than in their wild-type (+/+) littermates. Amphetamine (3-6 mg/kg), increasing release of dopamine from the presynaptic terminals, caused a dose-dependent motor stimulation in wild-type (+/+) mice. In heterozygous (+/-) and homozygous (-/-) mice, a lower dose of amphetamine (3 mg/kg) did not alter the locomotor activity, whereas the higher dose of (6 mg/kg) induced a significantly stronger increase in locomotor activity in homozygous (-/-) mice than in their heterozygous (+/-) and wild-type (+/+) littermates. Despite the changes in the action of apomorphine and amphetamine in homozygous (-/-) mice, we did not find any significant differences in the concentration of dopamine and their metabolites in the striatum or cortex. However, the density of dopamine D2 receptors was significantly increased in the striatum of homozygous (-/-) animals compared with wild-type (+/+) mice. CONCLUSIONS: The targeted mutation of the CCK2 receptor gene induced gene dose-dependent changes in the activity of the dopaminergic system. The sensitivity of presynaptic dopamine receptors was increased in heterozygous (+/-) and homozygous (-/-) animals, whereas the increase in sensitivity of postsynaptic dopamine receptors was apparent only in homozygous (-/-) mice.

Nitric oxide modulates lithium-induced conditioned taste aversion.

Nitric oxide (NO) has been shown to affect the behaviour in animal models of depression, anxiety and avoidance learning. Lithium has marked effect in avoidance learning, an effect that can be modulated via the 5-HT system. Experiments were carried out using the conditioned taste aversion (CTA) paradigm to investigate whether administration of NO-modifying drugs, serotonergic drugs and lithium, alone or in combination, induced or affected a CTA. The NO-precursor L-arginine (L-Arg), the non-specific inhibitor of NOS and guanylate cyclase, methylene blue (MB) and the specific NOS inhibitor 7-Nitroindazole (7-NI) all produced CTAs in a dose-dependent fashion. Furthermore, we found that L-Arg counteracted the CTAs induced by LiCl or MB but failed to modulate the CTA produced by 7-NI. The administration of the selective 5-HT1A agonist, 8-OH-DPAT, counteracted the CTAs produced by MB and 7-NI. In contrast, depletion of 5-HT by p-Chlorophenylalanine did not affect the aversions produced by MB and 7-NI, but counteracted the CTA produced by L-Arg. Our results suggest that NO plays a role in the acquisition of the CTA induced by LiCl. Furthermore, the results suggest that the 5-HT1A receptor plays an important role in the CTA induced by MB and 7-NI, thus indicating a possible interaction between the 5-HT and NO systems.

Endogenous nitric oxide decreases hippocampal levels of serotonin and dopamine in vivo.

Nitric oxide (NO) modulates the levels of various neurotransmitters in the CNS. Here we determined whether the specific nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI), the non-selective inhibitor of guanylate cyclase (GC) and NOS, methylene blue (MB), the NO-precursor L-arginine (L-Arg), and the selective soluble GC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) affect extracellular levels of serotonin (5-HT), dopamine (DA), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) in the rat ventral hippocampus by using microdialysis in freely moving animals. Local perfusion of 7-NI (1 mM) and MB (1 mM) significantly increased extracellular level of 5-HT, whereas DA was increased by 7-NI only. Systemic administration of 7-NI (50 mg kg(-1)) and MB (30 mg kg(-1)) increased the extracellular levels of 5-HT and DA. Extracellular levels of 5-HIAA was not influenced by local or systemic MB or 7-NI. In contrast, extracellular level of HVA was decreased by systemic MB and retrodialyzed MB, but was not influenced by 7-NI. Retrodialysis of L-Arg (2 mM) decreased the levels of 5-HT, DA, 5-HIAA and HVA in the hippocampus. Systemic administration of L-Arg (250 mg kg(-1)) decreased the level of 5-HT, but failed to influence DA, 5-HIAA and HVA. Local perfusion of ODQ (400 microM) did not affect 5-HT overflow in the hippocampus. We conclude that NOS inhibitors increased extracellular levels of 5-HT and DA in the rat ventral hippocampus after local or systemic administration, whereas the NO precursor L-Arg had the opposite effect. Thus, endogenous NO may exert a negative control over the levels of 5-HT and DA in the hippocampus. However, this effect is probably not mediated by cyclic GMP.

Methylene blue inhibits hippocampal nitric oxide synthase activity in vivo.

The aim of the present study was to investigate the effect of methylene blue, a guanylate cyclase inhibitor, on the hippocampal nitric oxide synthase activity in vivo. We used a microdialysis-based technique of measuring conversion of [3H]l-arginine to [3H]l-citrulline in freely moving rats. The administration of methylene blue (0.1 and 1 mM) via the microdialysis probe caused a dose-dependent decrease in [3H]l-citrulline efflux comparable with the effect of unselective NOS inhibitor NG-nitro-L-arginine (2 mM). We conclude that methylene blue inhibits brain NOS activity in vivo and thus interferes with NO-cGMP cascade in different levels.

Apomorphine-induced behavioural sensitization in rats: individual differences, role of dopamine and NMDA receptors.

Apomorphine-induced behavioural sensitization was studied in male Wistar rats. The acute administration of apomorphine (0.5 mg/kg s.c.), a dopamine agonist, did not affect the locomotor activity of rats, but it caused stereotyped behaviour characterized by repeated gnawing, licking and sniffing. A significant increase in the locomotor activity became evident after repeated treatments with apomorphine (0.5 mg/kg twice daily for 14 days). However, there were marked individual differences in the sensitization of rats to apomorphine. One third of animals did not react with increased locomotor activity even after the 2-week administration of apomorphine, whereas the other one third needed only a few injections to display increased behavioural response to apomorphine. The behavioural response of the remaining one third of rats was between weak and strong responders. Simultaneously, the stereotyped behaviour occurred earlier and its intensity tended to be lower after repeated treatment with apomorphine. Nevertheless, the established changes of stereotyped behaviour did not correlate with the increase of locomotor activity. The administration of amphetamine (2.5 mg/kg, s.c.), an indirect dopamine agonist, but not a non-competitive NMDA antagonist dizocilpine (0.25 mg/kg i.p.), tended to cause a similar response profile with apomorphine in sensitized rats. The ED50 values of the dopamine antagonists blocking apomorphine-induced increase in the locomotor activity were the following: 0.09 mg/kg for raclopride (dopamine D2 antagonist), 0.023 mg/kg for SCH 23390 (dopamine D1 antagonist), 6.42 mg/kg for clozapine (dopamine D4 antagonist). This supports the involvement of D1 and D1 receptors in the expression of apomorphine-induced behavioural sensitization. The concomitant administration of dizocilpine (0.5 mg/kg), SCH 23390 (0.05 mg/kg), raclopride (0.1 mg/kg) and clozapine (20 mg/kg) with apomorphine (0.5 mg/kg twice daily for 2 weeks) antagonized the development of behavioural sensitization to apomorphine. Accordingly, at least three different molecular targets, namely dopamine D1 and D2, and NMDA receptors, are involved in the development of apomorphine-induced behavioural sensitization.

L-Arginine abolishes the anxiolytic-like effect of diazepam in the elevated plus-maze test in rats.

The involvement of nitrergic mechanisms in the behavioural effects of diazepam in rats was studied in the elevated plus-maze, open-field and rotarod tests. Administration of the nitric oxide (NO) precursor L-arginine (100 mg/kg, i.p.), assumed to increase the synthesis of NO, abolished the anxiolytic-like effect of diazepam (2 mg/kg, i.p.) in the elevated plus-maze, whereas the inactive enantiomer D-arginine (100 mg/kg) did not. Neither diazepam alone nor in combination with L- or D-arginine affected the exploratory activity of animals in the open field. Pretreatment with L-arginine (100 and 200 mg/kg) did not modify the motor impairment of rats after diazepam (3 mg/kg) in the rotarod test. Diazepam (2 mg/kg i.p.) did not inhibit the cortical or hippocampal cytosolic NO synthase activity measured ex vivo by [3H]L-arginine assay. Diazepam was similarly ineffective in in vitro studies at concentrations up to 10 microM. We conclude that a suppression of NO synthase activity may be important in the anxiolytic-like effect of benzodiazepines. However, diazepam does not inhibit NO synthase directly, but may affect NO synthase activity indirectly via some unknown mechanism.

Opioid antagonist naloxone potentiates anxiogenic-like action of cholecystokinin agonists in elevated plus-maze.

This study investigated the interplay of cholecystokinin (CCK) and endogenous opioid peptides in the regulation of anxiety. The acute administration of non-selective CCK agonist caerulein (1 and 5 microg/kg) and a selective CCK(B) receptor agonist BOC-CCK-4 (1, 10 and 50 microg/kg) induced a dose-dependent anxiogenic-like action in the plus-maze model of anxiety. BOC-CCK-4 displayed a similar efficacy with caerulein, indicating that the described effect was mediated via CCK(B) receptor subtype. The opioid antagonist naloxone itself (0.5 mg/kg) did not change the exploratory activity of rats in the plus-maze. However, the combination of naloxone with the sub-effective doses of caerulein (1 microg/kg) and BOC-CCK-4 (1 microg/kg) induced a significant inhibition of exploratory behaviour in rats. Accordingly, CCK and endogenous opioid peptides have an antagonistic role in the exploratory model of anxiety in rats.

7-Nitroindazole, a nitric oxide synthase inhibitor, has anxiolytic-like properties in exploratory models of anxiety.

The action of the novel nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI) was studied in different exploratory models of anxiety. In the rat plus-maze test, 7-NI potently increased time spent on open arms and percentage of open arm visits in a dose dependent manner with the minimal effective dose of 40 mg/kg. 7-NI caused an anxiolytic-like effect in the rat social interaction test. The minimal dose increasing social interaction time was 20 mg/kg. However, the drug also produced a clear sedative effect occurring even at smaller doses (10 mg/kg) in the open field test. 7-NI also showed an anxiolytic-like profile in the mouse light-dark compartment test and in the elevated plus-maze test, but the doses required were higher (80-120 mg/kg) than in rat models. Also, the sedative effect occurred at these doses in open field. We failed to demonstrate any effect of L-arginine either in the rat elevated plus-maze test or in the open field test at doses up to 600 mg/kg IP. These results indicate that there are no major interspecies differences between rats and mice in respect of action of 7-NI. The clear anxiolytic-like action of the nitric oxide synthase inhibitor in four different models shows that nitric oxide is involved in the process of anxiety and that NOS could be a new target in developing anxiolytic drugs.

Relation of exploratory behavior of rats in elevated plus-maze to brain receptor binding properties and serum growth hormone levels.

Forty-five male Wistar rats were selected according to their behavior in the elevated plus-maze. They were separated as follows: animals with low exploratory activity ('anxious'), an 'intermediate' group and animals having high exploratory activity ('non-anxious'). Various receptor binding studies and hormonal assays were also performed in these selected rats. The affinity of 5-hydroxytryptamine 5-HT2A receptors in the frontal cortex was lower in the 'anxious' rats compared to home-cage controls and 'non-anxious' animals. Moreover, the number of cholecystokinin (CCK) receptors in the hippocampus was significantly elevated in the 'anxious' group compared to home-cage control animals. The blood levels of growth hormone (GH) were significantly lower in the 'non-anxious' rats compared to 'anxious' counterparts. In conclusion, it seems likely that the decreased exploratory activity of rats is related to the increased 5-hydroxytryptamine (5-HT) and CCK mediated neurotransmission in the brain. The different serum levels of GH in the selected rats probably reflect alterations in the activity of 5-HT and CCK.

Nitric oxide mediates caerulein-induced suppression of locomotor activity.

Caerulein, a non-selective agonist of cholecystokinin (CCK) receptors, is shown to suppress locomotor activity in rodents via stimulation of CCK(A) receptors. In the present study we examined the possible involvement of nitric oxide (NO) in caerulein-induced hypolocomotion in rats. Caerulein (10 microg/kg) markedly decreased the horizontal and vertical components of locomotor activity in rats measured in dark motility boxes. Pretreatment with a nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), at 5 mg/kg i.p., abolished the inhibiting action of caerulein on the horizontal activity, but did not affect the reduced frequency of rearing. The other doses of L-NAME (1, 10 and 20 mg/kg) were ineffective against caerulein. As L-NAME at this dose range does not stimulate locomotor activity, it is likely that NO is involved in the motor suppressant effect of systemically administered caerulein.

Inhibition of nitric oxide synthase causes anxiolytic-like behaviour in an elevated plus-maze.

The action of inhibition of nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester (L-NAME) (1-20 mg kg-1) on the exploratory behaviour of rats in the elevated plus-maze was studied. L-NAME induced an anxiolytic-like effect in the plus-maze test, showing a reverse U-shape action behaviour, with a maximal effect at 10 mg kg-1. This effect was not related to a non-specific increase in motor activity, since in the open field test L-NAME did not affect locomotor activity of rats. Pretreatment of rats with L-NAME (1-10 mg kg-1) also tended to attenuate the anti-exploratory action of CCK agonist caerulein (5 micrograms kg-1), but this action was not significant. In conclusion, it appears that NO may be involved in the process that can lead to anxiety in the rat.

Role of N-methyl-D-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats.

We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine agonist (0.5 mg/kg s.c. twice daily, 10 days), in rats. The first signs of defensive aggressiveness appeared on the third day of apomorphine treatment and were generally seen on the 7th day. Aggressiveness induced by a challenge dose of apomorphine (0.5 mg/kg s.c.) on the 11th day was antagonized by haloperidol (0.05 and 0.1 mg/kg i.p.) and clozapine (10 mg/kg i.p.). An antagonist of N-methyl-D-aspartate (NMDA)-gated channels, dizocilpine (MK-801), also blocked the aggressive behaviour at 0.25 and 0.5 mg/kg i.p. but caused ataxia. When dizocilpine (0.25 mg/kg i.p.) and apomorphine were coadministered for 10 days, aggressive behaviour did not develop. At 0.025 mg/kg i.p., dizocilpine even accelerated the appearance of apomorphine-induced aggressive behaviour, which manifested on the 3rd day in all rats. In a separate study, a 7-day treatment with dizocilpine (0.25-1 mg/kg i.p.) of rats, sensitized by a prior 10-day apomorphine treatment, did not reverse the established aggressive behaviour. The coadministration of apomorphine and cholecystokinin (CCK) -A or -B antagonists, devazepide or L-365,260 (0.01-2.5 mg/kg i.p.) respectively, neither affected development of apomorphine-induced aggressive behaviour nor intensity of aggressiveness in the sensitized rats. In binding studies neither density nor affinity of striatal dopamine D2 receptors was changed by acute or chronic apomorphine treatment. The number of [3H]pCCK-8 binding sites in the frontal cortex increased already after a single injection of apomorphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Further studies on the role of cholecystokinin-A and B receptors in secretion of anterior pituitary hormones in male rats.

We compared the effects of unselective cholecystokinin (CCK) agonists (caerulein and CCK-8s) and a CCKB agonist CCK-4 on the secretion of thyrotropin (TSH), growth hormone (GH) and prolactin (PRL) in male rats. The subcutaneous (s.c.) administration of caerulein and CCK-8s suppressed dose-dependently TSH and GH levels. In contrast, when given into the 3rd brain ventricle (i.c.v.) caerulein dose-dependently elevated the GH levels. Next the importance of the afferent vagal nerves was studied in the action of caerulein and CCK-4. Subdiaphragmatic vagotomy itself decreased cold-stimulated TSH levels but abolished the suppressing effect of intraperitoneal (i.p.), and apparently also that of the i.c.v. caerulein. GH and PRL levels were altered neither by vagotomy nor caerulein. CCK-4 did not affect hormone levels. Atropine and butylscopolamine (i.p.) themselves did not alter TSH, PRL or GH secretion in intact rats. Neither did they reverse the effect of caerulein on TSH. In conclusion, CCKA receptors dominate in TSH and CCKB receptors in GH regulation. CCKA receptors in the gastrointestinal tract, related to the nervus vagus are mediating the inhibitory effect of caerulein upon TSH secretion but inhibition of GH secretion does not depend on the nervus vagus. CCKB receptors in the brain stem or near the 3rd brain ventricle are responsible for stimulation of GH secretion.

Pharmacological comparison of antipsychotic drugs and sigma-antagonists in rodents.

We compared antipsychotic drugs (haloperidol, chlorpromazine and clozapine) and sigma antagonists (remoxipride, cinuperone, alpha-(4-fluorophenyl)-4-(-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY 14802) and rimcazole) in the radio-ligand binding and behavioural experiments in rodents. A good correlation was established between the affinity of compounds at dopamine2-receptors in the striatum and their ability to block apomorphine-, amphetamine- and quipazine-induced behavioural effects in rodents. By contrast, no correlation was found between the behavioural effects of these drugs and their affinity at dopamine1-5-HT2- and sigma receptors. The rank order of potency among the studied antipsychotic drugs in the behavioural tests and at dopamine2-receptors was following: haloperidol >> chlorpromazine > or = clozapine. The effectiveness of chlorpromazine and clozapine was nearly similar against apomorphine-induced aggressiveness and yawning, whereas at 5-HT2-receptors clozapine was more active than chlorpromazine. The weak activity of sigma antagonists at dopamine2 receptors could be a possible reason why these compounds were less effective in the behavioural studies compared to antipsychotic drugs. However, the antagonism of remoxipride against apomorphine-induced stereotypy and aggressiveness is not related to its activity at sigma receptors, because the other sigma antagonists did not block these effects of apomorphine. It is probable that remoxipride exerts its action through blocking of dopamine2 receptors. In conclusion, the present study revealed only weak activity of sigma antagonists in the behavioural models widely used to study the antipsychotic drugs. Therefore, the antipsychotic activity of sigma antagonists is doubtful.

Subdiaphragmatic vagotomy does not prevent the anti-exploratory effect of caerulein in the elevated plus-maze.

We compared the action of subdiaphragmatic vagotomy upon the anti-exploratory and motor depressant effects of caerulein, an agonist of cholecystokinin (CCK) receptors, in male rats. Vagotomized rats entered more frequently into the open arms of elevated plus-maze compared to intact control rats. Caerulein (1 microgram/kg subcutaneously (s.c.)) significantly suppressed the exploratory behaviour in vagotomized rats but not in intact and sham-operated rats. In contrast, subdiaphragmatic vagotomy did not change the locomotor activity of rats in open field compared to intact and sham-operated animals. At a higher dose (10 micrograms/kg s.c.), the caerulein pretreatment markedly decreased the number of line crossings, rearings and head-dippings of intact animals in open field. In sham-operated rats caerulein also suppressed the locomotor activity, whereas in vagotomized rats it only tended to reduce the frequency of rearings. Consequently, the present study revealed the different action of vagotomy upon the motor depressant and anti-exploratory effects of caerulein. These results support the view that CCKA receptors in the gastrointestinal tract are mediating the motor depressant, whereas CCKB receptors in the brainstem are involved into the mediation of anti-exploratory effect of caerulein.