Agmatine in the hypothalamic paraventricular nucleus stimulates feeding in rats: involvement of neuropeptide Y.

BACKGROUND AND PURPOSE: Agmatine, a multifaceted neurotransmitter, is abundantly expressed in the hypothalamic paraventricular nucleus (PVN). Our aim was to assess (i) the effect of agmatine on feeding behaviour and (ii) its association, if any, with neuropeptide Y (NPY). EXPERIMENTAL APPROACH: Satiated rats fitted with intra-PVN cannulae were administered agmatine, alone or jointly with (i) α2-adrenoceptor agonist, clonidine, or antagonist, yohimbine; (ii) NPY, NPY Y1 receptor agonist, [Leu³¹, Pro³4]-NPY, or antagonist, BIBP3226; or (iii) yohimbine and NPY. Cumulative food intake was monitored at different post-injection time points. Furthermore, the expression of hypothalamic NPY following i.p. treatment with agmatine, alone or in combination with yohimbine (i.p.), was evaluated by immunocytochemistry. KEY RESULTS: Agmatine robustly increased feeding in a dose-dependent manner. While pretreatment with clonidine augmented, yohimbine attenuated the orexigenic response to agmatine. Similarly, NPY and [Leu³¹, Pro³4]-NPY potentiated the agmatine-induced hyperphagia, whereas BIBP3226 inhibited it. Moreover, yohimbine attenuated the synergistic orexigenic effect induced by the combination of NPY and agmatine. Agmatine increased NPY immunoreactivity in the PVN fibres and in the cells of the hypothalamic arcuate nucleus (ARC) and this effect was prevented by pretreatment with yohimbine. NPY immunoreactivity in the fibres of the ARC, dorsomedial, ventromedial and lateral nuclei of the hypothalamus was not affected by any of the above treatments. CONCLUSIONS AND IMPLICATIONS: The orexigenic effect of agmatine is coupled to increased NPY activity mediated by stimulation of α2-adrenoceptors within the PVN. This signifies the importance of agmatine or α2-adrenoceptor modulators in the development of novel therapeutic agents to treat feeding-related disorders.

Rapid and Simple RPHPLC Method for the Estimation of Metformin in Rat Plasma.

A simple reverse phase high-performance liquid chromatographic method has been developed for determining the concentration of metformin in rat plasma. The method employs C(18) column (300 mm x 2.4 mm i.d.), ammonium acetate (0.15 M) and acetonitrile (90:10; pH-5.5; 1.0 ml/min) as mobile phase and ultraviolet detection at 236 nm. Acetonitrile was used to simultaneously deproteinize rat plasma and extract metformin. The assay was linear in the concentration range of 0.33 mug-16.6 mug/ml with co-efficient of correlation 0.994. The retention time was 4.7 min. The method was found to be precise (% CV < 15%), accurate and suitable for pharmacokinetic study of orally administered metformin in rats.

Reversal of caffeine-induced anxiety by neurosteroid 3-alpha-hydroxy-5-alpha-pregnane-20-one in rats.

Caffeine has been shown to increase brain and plasma content of neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) that allosterically modulates GABA(A) receptors. The present study evaluated the role of neurosteroid 3alpha,5alpha-THP in the caffeine-induced anxiogenic-like effect using the elevated plus-maze (EPM) test in rats. Acute administration of caffeine (50 or 100mg/kg, i.p.) produced anxiogenic-like activity that was reversed by pretreatment with the neurosteroid 3alpha,5alpha-THP or progesterone, the GABA(A) agonist muscimol, or the benzodiazepine receptor agonist diazepam. On the contrary, caffeine produced higher anxiety in animals previously treated with the GABA(A) receptor antagonist, bicuculline or either of the various neurosteroid biosynthesis enzyme inhibitors viz. trilostane, finasteride or indomethacin. Furthermore, pretreatment with DHEAS, a neurosteroid that negatively modulates GABA(A) receptors also enhanced the caffeine-induced anxiety. Moreover, adrenalectomy potentiated the anxiogenic-like response of caffeine indicating the contributory role of peripheral steroidogenesis. Thus, it is speculated that neurosteroid 3alpha,5alpha-THP through positive modulation of GABA(A) receptor activity may serve as a counter-regulatory mechanism against caffeine-induced anxiety.

Anxiolytic and anticonvulsive activity of Sesbania grandiflora leaves in experimental animals.

Various parts of Sesbania grandiflora have been used in the Indian system of medicine, in particular, the leaves of S. grandiflora are used in Ayurveda for the treatment of epileptic fits. In the present study we have evaluated the anticonvulsive activity of S. grandiflora leaves using a variety of animal models of convulsions. Bioassay guided separation was also carried out to identify the fraction possessing anticonvulsant activity. The benzene:ethyl acetate fraction (BE) of the acetone soluble part of a petroleum ether extract significantly delayed the onset of convulsions in pentylenetetrazol (PTZ) and strychnine (STR)- induced seizures in mice and reduced the duration of tonic hindleg extension in the maximum electroconvulsive shock (MES) induced seizures in mice. The BE contained a triterpene as a major component. In addition, the BE also inhibited electrically induced kindled seizures in mice and lithium-pilocarpine-induced status epilepticus in rats. It prolonged the duration of sleep induced by pentobarbital and antagonized the effect of D-amphetamine. Mice treated with BE preferred to remain in the open arm of the elevated plus maze indicating anxiolytic activity. The BE raised the brain contents of gamma-aminobutyric acid and serotonin. Thus the triterpene containing fraction of S. grandiflora exhibits a wide spectrum of anticonvulsant profile and anxiolytic activity.

Anticonvulsive activity of Butea monosperma flowers in laboratory animals.

The bioassay-guided fractionation of dried flowers of Butea monosperma (BM) was carried out to isolate the active principle responsible for its anticonvulsant activity. The petroleum ether extract was fractionated by column chromatography using solvents of varying polarity such as n-hexane, n-hexane:ethyl acetate, ethyl acetate, and methanol. The anticonvulsive principle of B. monosperma was found to be a triterpene (TBM) present in the n-hexane:ethyl acetate (1:1) fraction of the petroleum ether extract. TBM exhibited anticonvulsant activity against seizures induced by maximum electroshock (MES) and its PD(50) was found to be 34.2+/-18.1 mg/kg. TBM also inhibited seizures induced by pentylenetetrazol (PTZ), electrical kindling, and the combination of lithium sulfate and pilocarpine nitrate (Li-Pilo). However, TBM was not effective against seizures induced by strychnine and picrotoxin. TBM exhibited depressant effect on the central nervous system. After repeated use for 7 days, the PD(50) (MES) of TBM increased to 51.5+/-12.1 mg/kg. Similarly, after repeated use of TBM, the duration of sleep induced by pentobarbital was not reduced significantly. Further studies are required to investigate its usefulness in the treatment of epilepsy.

Behavioral action of ethanol in Porsolt's forced swim test: modulation by 3 alpha-hydroxy-5 alpha-pregnan-20-one.

Ethanol is known to increase cortical and plasma content of GABAergic neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) which is responsible for some of its behavioral and electrophysiological effects. We have previously demonstrated the antidepressant like effect of 3alpha,5alpha-THP in mice. This study investigated the role of 3alpha,5alpha-THP in acute, chronic and withdrawal effects of ethanol using mouse forced swim test (FST) paradigm. While acute systemic ethanol (2 or 2.5 g/kg) administration exhibited an antidepressant like effect, its prolonged consumption produced tolerance to this effect and its withdrawal, on the other hand, elicited enhanced behavioral despair (depression). The antidepressant like effect of ethanol was potentiated by GABA(A) receptor agonist, muscimol (0.5 mg/kg, i.p.), 3alpha,5alpha-THP (0.5, 1 or 2 microg/mouse, i.c.v.) and by neurosteroidogenic drugs viz. selective serotonin reuptake inhibitor (SSRI), fluoxetine (5 or 20 mg/kg, i.p.), agonist at mitochondrial diazepam binding inhibitor receptor, FGIN 1-27 (0.5 or 1 microg/mouse, i.c.v.), or 11beta-hydroxylase inhibitor, metyrapone (0.5 or 1 microg/mouse, i.c.v.) which are known to increase endogenous 3alpha,5alpha-THP content. Furthermore, inhibition of the endogenous neurosteroid biosynthesis by drugs like 5alpha-reductase inhibitor, finasteride (50 mg/kg, s.c.), 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane (30 mg/kg i.p.) or 3alpha-hydroxysteroid dehydrogenase inhibitor, indomethacin (5 mg/kg, i.p.) and GABA(A) receptor antagonist, bicuculline (1 mg/kg, i.p.) blocked the antidepressant like effect of ethanol. Withdrawal of ethanol from mice consuming it chronically displayed enhanced behavioral despair and elicited tolerance to antidepressant like action of acute ethanol (2.5, 3 or 3.5 g/kg). Moreover, sub-antidepressant doses (0.25 or 0.5 microg/mouse, i.c.v.) of 3alpha,5alpha-THP and fluoxetine (5 mg/kg, i.p.) but not imipramine (1 mg/kg, i.p.) reversed the depression associated with ethanol withdrawal indicating sensitization to their antidepressant action. Thus, 3alpha,5alpha-THP plays a pivotal role in the actions of ethanol and in the depression associated with ethanol withdrawal. These findings may be of potential ramification to contribute to the depression associated with alcoholism and its treatment using neurosteroids.

Cataleptic effect of neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice: modulation by serotonergic agents.

The neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) induced catalepsy in mice is modified by dopaminergic, adenosinergic and GABAergic agents. In light of serotonergic agents being implicated in antipsychotic-induced catalepsy and their ability to increase brain neurosteroid content, the present study was undertaken to investigate the effect of various 5-HT agents on catalepsy induced by 3alpha,5alpha-THP in mice. Pretreatment with selective serotonin reuptake inhibitor, fluoxetine (5 mg/kg, i.p.), 5-HT releaser, fenfluramine (10 mg/kg, i.p.), 5-HT(1A) receptor agonist, 8-OH-DPAT (0.3 mg/kg, s.c.), 5-HT1B/1C receptor agonist, TFMPP (3 mg/kg, i.p.), 5-HT2A/1C receptor agonist, DOI (1.5 mg/kg, s.c.) and 5-HT3 agonist, 2-methylserotonin (5 mg/kg, i.p.) potentiated the catalepsy induced by exogenous administration of 3alpha,5alpha-THP. Furthermore, FGIN 1-27, an MDR agonist that increases endogenous content of 3alpha,5alpha-THP although per se failed to exhibit any cataleptic effect but enhanced the cataleptic response in combination with these serotonergic agents. The potentiating action of 5-HT1A, 5-HT2A/1C or 5-HT3 receptor agonist on 3alpha,5alpha-THP induced catalepsy was not blocked by prior administration of sub-effective dose (1 mg/kg, s.c.) of their respective receptor antagonists pindolol, ritanserin or ondansetron or by pretreatment with serotonergic neurotoxin 5,7-DHT (100 microg/mouse, i.c.v.). However this effect of different serotonergic agents was antagonized by the GABA(A) receptor antagonist, bicuculline (1 mg/kg, i.p.) or the 3alpha-hydroxysteroid oxidoreductase enzyme inhibitor, indomethacin (5 mg/kg, i.p.). The 5-HT agents enhance neurosteroid-induced catalepsy by increasing GABAergic tone, likely as a consequence of increased brain content of 3alpha,5alpha-THP.

Antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice forced swim test.

The present study aimed to examine the antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha, 5alpha THP) using the forced swim test in mice. Intracerebroventricular (ICV, 1 or 2 microg/mouse) or intraperitoneal (IP, 0.5, 1, or 2 mg/kg) administration of 3alpha, 5alpha THP dose-dependently reduced the duration of immobility in forced swim test without accompanying changes in ambulatory or rearing behaviors in the open-field test. The antidepressant-like effect of 3alpha, 5alpha THP (1 microg/mouse, ICV) was potentiated by prior administration of the GABA(A) receptor agonist, muscimol (0. 5 mg/kg, IP) and blocked by prior administration of GABA(A) receptor antagonist, bicuculline (1 mg/kg, IP). Administration of the agonist at diazepam binding inhibitor receptors, 4'-chlorodiazepam (4'CD, 15 mg/kg, IP) or N,N-di-n-hexyl-2-(4-fluorophenyl)-indol-3-acetamide (FGIN 1-27, 1 or 2 microg/mouse, ICV), the 11beta-hydroxylase inhibitor, metyrapone (150 mg/kg, IP and 1 or 2 microg/mouse, ICV) and the selective serotonin reuptake inhibitor (SSRI), fluoxetine (20 mg/kg, IP), which are known to increase the endogenous level of neurosteroids, also reduced the duration of immobility in forced swim test. The tricyclic antidepressant, imipramine (20 mg/kg, IP), which does not increase the 3alpha, 5alpha THP in the brain, also reduced the immobility time. While the antidepressant-like effect of fluoxetine, which is known to selectively increase the brain content of 3alpha, 5alpha THP, was either blocked partially by bicuculline (1 mg/kg, IP) or potentiated by muscimol (0.5 mg/kg, IP), the antidepressant-like effect of imipramine was not modified by bicuculline. These results demonstrate the antidepressant-like effect of the neurosteroid 3alpha, 5alpha THP, and suggest further evaluation for its development as a new class of antidepressant drug.

Anticonvulsive activity of Albizzia lebbeck, Hibiscus rosa sinesis and Butea monosperma in experimental animals.

The ethanolic extracts of leaves of Albizzia lebbeck and flowers of Hibiscus rosa sinesis and the petroleum ether extract of flowers of Butea monosperma exhibited anticonvulsant activity. The bioassay guided fractionation indicated that the anticonvulsant activity lies in the methanolic fraction of chloroform soluble part of ethanolic extract of the leaves of A. lebbeck, acetone soluble part of ethanolic extract of H. rosa sinesis flowers and acetone soluble part of petroleum ether extract of B. monosperma flowers. The fractions protected animals from maximum electro shock, electrical kindling and pentylenetetrazole-induced convulsions in mice. The fractions also inhibited convulsions induced by lithium-pilocarpine and electrical kindling. However, they failed to protect animals from strychnine-induced convulsions. The fractions antagonised the behavioral effects of D-amphetamine and potentiated the pentobarbitone-induced sleep. The fractions raised brain contents of gamma-aminobutyric acid (GABA) and serotonin. These fractions were found to be anxiogenic and general depressant of central nervous system.

Serotonergic agents modulate antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice.

The present study demonstrated the antidepressant-like effect of neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha, 5alpha THP) in mouse forced swim test of depression and its modulation by different serotonergic agents. Pretreatment with the selective serotonin reuptake inhibitor, fluoxetine (5 mg/kg, i.p.), the 5-HT releaser, fenfluramine (10 mg/kg, i.p.), the 5-HT(1A) receptor agonist, 8-OH-DPAT (0.1 mg/kg, s.c.), the 5-HT(1B/1C) receptor agonist, TFMPP (4 mg/kg, s.c.) and the 5-HT(2A/1C) receptor agonist, DOI (2 mg/kg, s.c.) potentiated the antidepressant-like effect of 3alpha, 5alpha THP. At these doses the serotonergic agents per se did not modify the duration of immobility. However, fluoxetine (20 mg/kg, i.p.), fenfluramine (20 mg/kg, i.p.) or imipramine (5 or 20 mg/kg, i.p.) not only reduced immobility but also enhanced the antidepressant-like effect of 3alpha, 5alpha THP. Such a potentiating effect of the 5-HT(1A) or the 5-HT(2A/1C) receptor agonist was not antagonized by the sub-effective dose (0.1 mg/kg, s. c.) of their respective antagonists p-MPPI or ketanserin. Pretreatment with p-CPA (300x3 mg/kg, i.p.), a depleter of 5-HT neuronal store failed to block the influence of fluoxetine and fenfluramine on antidepressant-like effect of 3alpha, 5alpha THP. The accelerated effect of 3alpha, 5alpha THP in presence of serotonergic agents was antagonized by the GABA(A) receptor antagonist, bicuculline (1 mg/kg, i.p.) or the 3alpha-hydroxysteroid oxidoreductase enzyme inhibitor, indomethacin (5 mg/kg, i.p.). These findings for the first time demonstrate that serotonergic agents potentiate the antidepressant-like action of 3alpha, 5alpha THP, by enhancing the GABAergic tone as a likely consequence of increased brain content of this neurosteroid.

GABAergic involvement in motor effects of an adenosine A(2A) receptor agonist in mice.

Adenosine A(2A) agonists are known to induce catalepsy and inhibit dopamine mediated motor hyperactivity. An antagonistic interaction between adenosine A(2A) and dopamine D(2) receptors is known to regulate GABA-mediated neurotransmission in striatopallidal neurons. Stimulation of adenosine A(2A) and dopamine D(2) receptors has been shown to increase and inhibit GABA release respectively in pallidal GABAergic neurons. However, the role of GABAergic neurotransmission in the motor effects of adenosine A(2A) receptors is not yet known. Therefore in the present study the effect of GABAergic agents on adenosine A(2A) receptor agonist (NECA- or CGS 21680) induced catalepsy and inhibition of amphetamine elicited motor hyperactivity was examined. Pretreatment with GABA, the GABA(A) agonist muscimol or the GABA(B) agonist baclofen potentiated whereas the GABA(A) antagonist bicuculline attenuated NECA- or CGS 21680-induced catalepsy. However, the GABA(B) antagonists phaclophen and delta-aminovaleric acid had no effect. Administration of NECA or CGS 21680 not only reduced spontaneous locomotor activity but also antagonized amphetamine elicited motor hyperactivity. These effects of NECA and CGS 21680 were potentiated by GABA or muscimol and antagonized by bicuculline. These findings provide behavioral evidence for the role of GABA in the motor effects of adenosine A(2A) receptor agonists. Activation of adenosine A(2A) receptors increases GABA release which could reduce dopaminergic tone and induce catalepsy or inhibit amphetamine mediated motor hyperactivity.

Anticonvulsant and behavioral actions of triterpene isolated from Rubia cordifolia Linn.

Effect of a triterpene isolated from the acetone soluble part of petroleum ether extract of R. cordifolia was studied on convulsions induced by maximum electro shock (MES), electrical kindling and various chemoconvulsants in rats and mice. The effect of triterpene was also investigated on behavior and gamma-aminobutyric acid (GABA) and serotonin (5-HT) content in mouse brain. Triterpene inhibited seizures induced by MES, electrical kindling, pentylenetetrazol (PTZ), and lithium-pilocarpine. However, seizures induced by strychnine were not inhibited. Triterpene reduced locomotion as well as rearing. Pentobarbitone induced sleep was potentiated and amphetamine induced stereotypy was inhibited. The triterpene was found to possess anxiogenic activity. Brain GABA and 5-HT contents were raised by the compound. The study suggests that the triterpene isolated from R. cordifolia bear a potential for further study.

Adenosinergic modulation of 3alpha-hydroxy-5alpha-pregnan-20-one induced catalepsy in mice.

RATIONALE: Neurosteroid 3alpha, 5alpha THP, a positive allosteric modulator of the GABA(A) receptor Cl- ionophore complex, induces catalepsy-like dopamine antagonists, adenosine agonists or GABA agonists. Adenosine and dopamine receptors are co-localized on GABAergic neurons in the striatum and regulate GABA-mediated neurotransmission. Moreover, the antagonistic interactions between specific subtypes of adenosine and dopamine receptors are involved in motor depressant or motor stimulant effects of adenosine receptor agonists or antagonists, respectively. Such interaction may modulate neurosteroid-induced catalepsy. OBJECTIVE: This study examined the modulation of 3alpha, 5alpha THP-induced catalepsy by adenosinergic agents. METHODS: Catalepsy induced by 3alpha, 5alpha THP (2-8 microg, ICV) was assessed by bar test periodically up to 3 h in mice. Adenosine A1, A2A or A3 receptor agonists or antagonists were given IP or ICV prior to 3alpha, 5alpha THP. Some animals received IP dopamine D2 receptor agonist or antagonist 30 min prior to above combination treatment. RESULTS: Adenosine A1, A2A, and A3 receptor agonists potentiated, whereas adenosine A2A receptor antagonists, but not A1 antagonists, reversed 3alpha, 5alpha THP-induced catalepsy. These effects of adenosine agonists and antagonists were abolished by prior administration of bromocriptine, the dopamine D2 receptor agonist and spiperone, the dopamine D2 receptor antagonist, respectively. CONCLUSIONS: These findings suggest specific adenosine-dopamine receptor interaction in the striatum to modulate 3alpha, 5alpha THP-induced catalepsy.

The neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one induces catalepsy in mice.

Intracerebroventricular injection of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alphaTHP) induced catalepsy in mice, within less than 10 min of its administration, which lasted for more than 3 h. This catalepsy was reversed by i.p. administration of picrotoxin, bicuculline, bromocriptine and levodopa-plus-carbidopa combination. A low i.p. dose of 3alpha,5alphaTHP (1.5 mg/kg) did not induce catalepsy. However, significant catalepsy was noted when 3alpha,5alphaTHP (1.5 mg/kg) was administered by the i.p. route in the mice pretreated with subcataleptic doses of haloperidol, muscimol or aminooxyacetic acid. The results, for the first time, demonstrate the cataleptogenic potential of 3alpha,5alphaTHP and suggest that neurosteroids may affect central dopaminergic transmission through their direct action on GABA(A) receptors.

Effect of serotonergic agents on adenosine A2 receptor mediated catalepsy in mice.

The effect of serotonergic agents was studied on the adenosine A2 receptor agonist NECA-induced catalepsy in mice. The 5-HT releaser fenfluramine, the 5-HT1A agonist 8-OH-DPAT, the 5-HT(2A/1C) receptor agonist DOI and the 5-HT(2A/1C) receptor antagonists ketanserin and mianserin reversed NECA-induced catalepsy. p-MPPI and ketanserin reversed the anticataleptic actions of 8-OH-DPAT and DOI, respectively. Further, the 5-HT reuptake inhibitor fluoxetine, the 5-HT(1B/1C) receptor agonist TFMPP, the 5-HT synthesis inhibitor p-CPA, the selective 5-HT1A receptor antagonist p-MPPI, the 5-HT(1A/1B) receptor antagonist pindolol and the 5-HT3 receptor antagonist LY 278, 584 had no effect on NECA-induced catalepsy. The anticataleptic action of fenfluramine was not affected by pretreatment with p-CPA. In p-CPA treated rats, ketanserin did not affect the anticataleptic effect of fenfluramine, whereas p-MPPI partially reversed this effect. It is concluded that modulation of serotonergic neurotransmission at 5-HT1A and 5-HT(2A/1C) receptors affects the cataleptic action of experimental antipsychotic agents with adenosine A2 receptor agonistic activity.

Central administration of FMRFamide produces antipsychotic-like effects in rodents.

Neuropeptide FMRFamide (Phe-Met-Arg-Phe-NH2) was evaluated in animal models of psychosis. FMRFamide (0.5-100 micrograms, i.c.v.) produced blockade of conditioned avoidance response in rats and antagonized apomorphine-induced climbing behaviour in mice. Similarly, FMRFamide at lower doses (0.1-10 micrograms, i.c.v.) inhibited 5-hydroxy-L-tryptophan (5-HTP)-induced head twitches in rats. These effects of the peptide were similar to haloperidol (1 mg/kg, i.p.). However, unlike haloperidol, FMRFamide per se did not induce any catalepsy in rats at the doses employed in the above paradigms. These results indicate antipsychotic-like activity for the neuropeptide FMRFamide with possible involvement of the dopaminergic/5-HT2 systems.

Neurobehavioral effects of low level fenvalerate exposure in mice.

Effect of oral administration of fenvalerate, a pyrethroid insecticide was studied in different behavioral paradigms in mice. Fenvalerate at 15, 30 and 45 mg/kg dose increased start latency, decreased ambulation and rearing in open-field, increased immobility in tail-suspension test and attenuated haloperidol-induced catalepsy in a dose-dependent manner. The time-course of data shows that these effects of fenvalerate may sustain up to several hours of its oral administration. The study indicates that pyrethroids can cause adverse behavioral effects even after a very low-level exposure. Although, it is difficult to extrapolate these findings directly to behavioral changes in man, they indicate that subtle behavioral dysfunction also occur in humans at exposures which do not cause acute toxicity.

Adenosine A2 receptors modulate haloperidol-induced catalepsy in rats.

The effect of adenosine A1 and A2 receptor agonists and antagonists was investigated on haloperidol-induced catalepsy in rats. Pretreatment (i.p.) with the non-selective adenosine receptor antagonist, theophylline, or the selective adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), significantly reversed haloperidol-induced catalepsy, whereas the selective adenosine A1 receptor antagonists, 8-phenyltheophylline and 8-cyclopentyl-1,3-dipropylxanthine produced no effect. Similar administration of the adenosine A2 receptor agonists, 5'-(N-cyclopropyl)-carboxamidoadenosine and 5'-N-ethylcarboxamidoadenosine (NECA), and the mixed agonists with predominantly A1 site of action, N6-(2-phenylisopropyl) adenosine or 2-chloroadenosine, potentiated haloperidol-induced catalepsy. Higher doses of the adenosine agonists produced catalepsy when given alone. However, N6-cyclopentyladenosine, a highly selective adenosine A1 receptor agonist, was ineffective in these respects. The per se cataleptic effect of adenosine agonists was blocked by DMPX and the centrally acting anticholinergic agent, scopolamine. Scopolamine also attenuated the potentiation of haloperidol-induced catalepsy by adenosine agonists. Further, i.c.v. administration of NECA and DMPX produced a similar effect as that produced after their systemic administration. These findings demonstrate the differential influence of adenosine A1 and A2 receptors on haloperidol-induced catalepsy and support the hypothesis that the functional interaction between adenosine and dopamine mechanisms might occur through adenosine A2 receptors at the level of cholinergic neurons. The results suggest that adenosine A2, but not A1, receptor antagonists may be of potential use in the treatment of Parkinson's disease.

Haloperidol-induced catalepsy: a model for screening antidepressants effective in treatment of depression with Parkinson's disease.

Incidence of severe depression is very common in Parkinson's disease (PD). Use of antidepressants in such cases is known to improve or worsen the existing PD. However, prediction of the effect of antidepressant on symptoms of PD is limited due to lack of suitable animal model. The present study examines the possibility of using haloperidol-induced catalepsy model in rats for this purpose. Antidepressants showed distinct effect on haloperidol-induced catalepsy, although most of them reduced forced-swimming induced immobility. In general, antidepressants with greater noradrenergic reuptake inhibition (desipramine, imipramine, amitriptyline, nortriptyline, protriptyline and maprotiline) reduced, whereas those with serotonergic reuptake inhibition (fluoxetine and clomipramine) increased haloperidol-induced catalepsy. Mianserin, an atypical antidepressant, and alprazolam, a benzodiazepine receptor analogue had no effect on haloperidol-induced catalepsy. The results suggest that haloperidol-induced catalepsy model in rats needs to be incorporated in the screening procedure when evaluating the utility of antidepressant drugs for the treatment of depression associated with PD.

Baclofen-induced catatonia: modification by serotonergic agents.

Baclofen, a GABAB receptor agonist can induce catatonia in rats. This catatonia may serve as a tool for the study of GABAB receptor function. Reciprocal interactions between serotonin (5-HT) and GABAB receptors in the CNS are known to occur. In the present study we examined the effect of various agents that influence serotonergic neurotransmission on baclofen-induced catatonia in rats. The catatonia was rated by means of a scoring method, according to the severity of motor symptoms produced by baclofen (10-15 mg/kg, i.p.). All serotonergic drugs were injected intraperitoneally 30 min prior to baclofen, except the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA), which was injected 72 and 48 hr prior to baclofen. The 5-HT releaser fenfluramine (10 mg/kg) and the uptake inhibitor fluoxetine (10 mg/kg) reversed, whereas the 5-HT1A agonist buspirone (3 mg/kg) potentiated baclofen-induced catatonia. The 5-HT synthesis inhibitor PCPA (150 x 2 mg/kg), the non-specific 5-HT antagonist cyproheptadine (5 mg/kg), the 5-HT1A/1B antagonist pindolol (3 mg/kg) and the 5-HT2 antagonist sulpiride (20 mg/kg) enhanced baclofen-induced catatonia. It is concluded that the manipulations of central serotonergic mechanisms modulate baclofen-induced catatonia.