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Biomedical subjects

S K Kulkarni

Publications and source records attributed to S K Kulkarni.

252 records · Page 14Linked to original sources
PubMedDate not supplied

The protective effect of adenosinergic agents, Ro 5-4864 and carbamazepine against hypoxic stress-induced neurotoxicity in mice.

Mice subjected to hypoxic stress resulted in increased respiratory rate, tremor and convulsions followed by death. The latencies for convulsion and death following hypoxic stress were 33.29 +/- 1.20 and 34.36 +/- 1.16 min, respectively. In the present study effects of adenosinergic agents Ro 5-4864, a "peripheral-type" benzodiazepine receptor agonist, and carbamazepine were studied on hypoxic stress-induced neurotoxicity. Adenosinergic agents such as adenosine, 2-chloroadenosine, N6-cyclohexyladenosine and dipyridamole increased the latencies for convulsions and death due to hypoxia. Theophylline (50 mg/kg i.p.), an adenosine receptor antagonist, reversed this protective effect of adenosinergic agents. Pretreatment with Ro 5-4864 (10, 20 mg/kg i.p.) also offered theophylline (50 mg/kg, i.p.)-sensitive protection against hypoxic stress. Similarly, carbamazepine treatment (10-30 mg/kg, i.p.) significantly prolonged the latencies for convulsion and death following hypoxic stress. Prior treatment with theophylline (50 mg/kg, i.p.) reversed this protective effect of carbamazepine, indicating the possible involvement of adenosinergic mechanism in the observed protective effect of carbamazepine. These results indicate that the adenosinergic mechanism may be responsible for the observed neuroprotective effect of these agents against hypoxia.

2-Chloroadenosine↗
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Effect of venoruton on hypoxic stress-induced neurotoxicity in mice and oxygen free radical generation by human neutrophils.

Venoruton offers a protection against hypoxic stress-induced neurotoxicity (convulsions and death) in mice. It also inhibits free radical generation, since it produces a concentration-dependent (5-160 micrograms/10(6) cells/ml) decrease of chemiluminescence response from human neutrophils. The maximum inhibition was observed at 140 micrograms/10(6) cells/ml. The in vivo protective effect against hypoxic stress-induced neurotoxicity has been correlated to the inhibitory action of venoruton on oxygen free radical generation.

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Benzodiazepine inverse agonist FG-7142-induced delayed behavioral depression in mice.

Effect of acute administration of a benzodiazepine-inverse agonist, FG-7142, on forced swimming-induced depression was investigated in mice. A single injection of FG-7142 (40 mg/kg) showed a delayed increase in behavioral despair, the peak effect being observed on the 5th and 6th day of FG-7142 administration. beta-Adrenoceptor agonist isoprenaline significantly potentiated FG-7142-induced behavioral despair. FG-7142-induced depression was sensitive to reversal by chronic treatment with propranolol or desipramine. These observations suggest that the inverse agonist FG-7142 upregulates beta-adrenoceptor population leading to behavioral despair in mice.

Animals↗
PubMedDate not supplied

Involvement of postsynaptic adrenergic mechanism(s) in the ATP-contractions of the rat anococcygeus muscle and the effect of extracellular Ca2+.

Clonidine, ICI-106270 (6-aryl 2,367 tetrahydro 5-H-pyrrolo(1,2-a)-imidazole derivative), B-HT-920 (6-Allyl-2-amino-5,6,7,8-tetrahydro-4H-thiozolo = [4,5-d]azepine-dihydrochloride, and guanfacine, agonists at alpha 2-adrenoceptors, produced concentration-dependent contractions of the rat anococcygeus muscle. The order of potency of these agonists in producing the response was clonidine greater than ICI-106270 greater than guanfacine greater than B-HT 920. Yohimbine (10(-6) M) competitively antagonized the contractile response due to these agents acting at alpha 2-adrenoceptors. ATP (10(-6) M-10(-4) M) also produced concentration-dependent contractions of the rat anococcygeus muscle. Prazosin (10(-8) M) an alpha 1-blocker, significantly antagonized ATP-induced contractions in a competitive manner. ATP (10(-7) M) in a concentration that had no effect on basal tension of the preparation, tends to potentiate phenylephrine responses, though not significantly. The sensitivity of the anococcygeus muscle to ATP was enhanced after 24 hr (maximum catecholamine depletion period) of reserpine (5 mg/kg, i.p.) treatment. Yohimbine (10(-6) M), a selective alpha 2-blocker, significantly antagonized ATP-induced contractions and shifted the ATP concentration-response curve towards right. The antagonism was found to be competitive. The ATP-contractions were also sensitive to inhibition by reduced calcium contents (quarter or calcium free) in the Krebs bicarbonate solution. However, it was observed that ATP was capable of producing contractions of anococcygeus muscle even in Ca-free Krebs bicarbonate solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
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Hypoxic stress-induced convulsion and death: protective effect of alpha 2-adrenoceptor and benzodiazepine receptor agonists and Ro 5-4864.

Various alpha 2-agonists such as clonidine, guanfacine, B-HT 920 and ICI 106270 were investigated for their effect in hypoxic stress in rats and mice. Pretreatment with alpha 2-adrenoceptor agonists exhibited a yohimbine sensitive antistress effect as they prolonged the latencies for convulsion and death due to hypoxia. Intracerebroventricular administration of clonidine and ICI 106270 also shared the protective effect, indicating the involvement of central alpha 2-adrenoceptors. However, their protective effect, though comparable to diazepam and CL 218872, was more pronounced. The peripheral benzodiazepine receptor agonist, Ro 5-4864, also had a marked antihypoxic stress effect.

Adrenergic alpha-Agonists↗
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Potentiation of dopamine receptor-mediated responses by B-HT 920 in mice.

The effect of B-HT 920, an alpha 2-agonist, on postsynaptic dopamine receptor-mediated stereotypic behaviour, was studied in mice. Apomorphine produced typical stereotypic responses in mice such as sniffing, rearing, biting, licking and grooming. B-HT 920, when given alone, produced mild stereotypy. Pretreatment with B-HT 920 significantly potentiated the stereotypic behaviour of apomorphine. The specific alpha 2-blockers, idazoxan and yohimbine, failed to block the potentiating effect of B-HT 920. The specific D2-receptor blockers haloperidol and molindone, completely blocked the stereotypic responses due to B-HT 920 and apomorphine. On reserpinization of animals there was a 5-fold increase in stereotypy induced by the combination of apomorphine and B-HT 920. B-HT 920 also potentiated amphetamine-induced locomotor responses in mice in a haloperidol-sensitive way. These data imply an interaction of B-HT 920 with postsynaptic dopamine receptors.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Modification by tricyclic antidepressants of cortical EEG changes induced by clonidine in conscious rats.

The effects of various tricyclic antidepressants on clonidine-induced electroencephalographic changes were investigated in rats. The EEG pattern of conscious rats was recorded by means of bipolar electrodes, implanted chronically. Clonidine (50, 150 and 300 micrograms/kg) not only synchronized cortical EEG pattern but also evoked signs of behavioural depression within 15 min of its administration. Pretreatment with imipramine, desipramine, trimipramine, amitriptyline, nortriptyline and doxepin reduced clonidine-induced EEG synchrony without showing any effects per se. Acute treatment with tricyclic antidepressants failed to modify but, chronic treatment abolished the clonidine-induced behavioural depressive signs. Chronic administration of tricyclic antidepressants (10 mg/kg/day) evoked more pronounced antagonism of the EEG effects of clonidine. Yohimbine (200 micrograms/kg) pretreatment inhibited both, clonidine-induced EEG synchrony and behavioural effects. Guanfacine as well as B-HT 920, elicited clonidine-like effects on cortical EEG pattern and behaviour. The present data suggests that antagonism of clonidine-induced EEG synchronization in conscious animals could serve as a useful test for screening of antidepressant drugs.

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PubMedDate not supplied

Effect of various pharmacological agonists on the rat caecum-appendix preparation: a preliminary study.

A preliminary study with various pharmacological agents revealed the presence of contractile muscarinic and H1-histamine receptors as well as inhibitory alpha- and beta-adrenoceptors and purinoceptors in rat caecum-appendix. Histamine also produced indirect actions mediated through the release of catecholamines. 5-Hydroxytryptamine produced variable response, the contractile response was mediated through 5-HT receptors and the relaxant response through the release of catecholamines.

Acetylcholine↗
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Apomorphine hypothermia: interaction with serotonergic agents.

Apomorphine (APO, 0.25 to 16 mg/kg) induced a dose dependent hypothermia in mice. Haloperidol, a dopamine antagonist, antagonized APO hypothermia due to lower doses. Clozapine and phenoxybenzamine, on the other hand, failed to modify APO hypothermia. Similarly, levopropranolol and cyproheptadine, which modify serotonergic responses, also failed to modify APO hypothermia. But fluxetine which selectively inhibits serotonin uptake, reversed APO induced hypothermia due to higher doses but not that induced by low dose of APO. The behavioral stereotypy was, however, not modified by fluoxetine pretreatment. It is concluded that APO hypothermia due to lower and higher doses are mediated by different receptors and the latter action involves the interaction of more than one type of receptor.

Animals↗
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Differential role of dopamine receptor subtypes in thermoregulation and stereotypic behavior in naive and reserpinized rats.

The present study explores the differential role of dopamine receptor subtypes and their interplay in the thermoregulation and stereotypic behavior in naive and acutely or chronically reserpinized rats. In naive rats, the D2 dopamine agonist B-HT920 (0.25-1 mg/kg) produced hypothermia, an effect sensitive to blockade by the D1/D2 antagonist haloperidol (0.5 mg/kg) and to potentiation by the D1 agonist SKF38393 (5 mg/kg). The hypothermic effect of the same doses of B-HT920 was reduced following acute reserpinization (5 mg/kg, 24 hr prior) but significantly enhanced following chronic reserpinization (1 mg/kg for 15 days), as compared with the B-HT920 effect in naive rats. Although SKF38393 (5 mg/kg) failed to elicit any significant effect on the rectal temperature, it potentiated the hypothermic effect of B-HT920 (0.25 mg/kg) in naive and acutely reserpinized rats. SKF38393 (5 mg/kg), on the contrary, produced a slight hyperthermia and failed to enhance the hypothermic effect of B-HT920 (0.25 mg/kg) following chronic reserpinization. A higher dose of SKF38393 (10 mg/kg), however, produced a significant rise in body temperature when administered alone or in combination with B-HT920 (0.25 mg/kg) in chronically reserpinized rats. Apomorphine (0.25-2 mg/kg), a mixed D1/D2 agonist, also produced a significant hypothermia in naive and acutely reserpinized rats. Following chronic reserpinization, however, apomorphine (0.25-1 mg/kg) produced a significant rise in body temperature, which was significantly enhanced upon co-administration with SKF38393 (5 mg/kg) but reversed to hypothermia when given in combination with B-HT920 (0.5 mg/kg). Similarly, B-HT920 (0.25-1 mg/kg) or apomorphine (0.25-2 mg/kg) produced a mild stereotypy in naive rats. The stereotypic effect of B-HT920 as well as of apomorphine was enhanced in parallel with the increase in the duration of reserpinization. SKF38393 (5 mg/kg) failed to elicit any significant stereotypic effect but significantly enhanced the stereotypic effect of B-HT920 (0.25 mg/kg) in naive or reserpinized rats. The above data, therefore, suggest a differential involvement of D2 and D1 receptors in temperature changes and stereotypy in naive and reserpinized rats, respectively.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMedDate not supplied

Clozapine-induced cognitive dysfunction in mice.

The atypical antipsychotic clozapine was examined for its ability to interrupt cognitive functions in mice on passive avoidance paradigm and elevated plus maze. The posttraining intraperitoneal injection of clozapine (0.1-7.5 mg/kg) induced dysfunction in acquisition as well as retrieval, which was reversed by physostigmine (0.05 mg/kg). Clozapine showed dose-related effects on scopolamine-induced cognitive dysfunction, with higher doses having no significant effect and lower doses reversing the dysfunction. These results are explained on the basis of clozapine's effects on central cholinergic receptors.

Animals↗
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Effects of ondansetron on short-term memory retrieval in mice.

Behavioral studies have shown cognitive improvements in various animal models of learning and memory using 5-HT3 receptor antagonists. The present study investigated the cognitive role of ondansetron, a selective 5-HT3 antagonist, in naive and scopolamine-treated mice. Ondansetron attenuated the performance deficits induced by scopolamine (0.3 mg/kg) with both doses employed, although 1.0 mg/kg ondansetron was more effective in ameliorating the deficits as compared to 0.1 mg/kg. However, none of the ondansetron doses (0.01, 0.1 and 1 mg/kg) influenced the performance of naive mice in the passive avoidance step-down paradigm. These results suggest that the 5-HT receptor system, particularly the 5-HT3 receptor, may play a modulating role in learning and memory phenomena in animals.

Animals↗
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Neurosteroid coadministration prevents development of tolerance and augments recovery from benzodiazepine withdrawal anxiety and hyperactivity in mice.

Neurosteroids are potent and specific modulators of the GABAA receptors which regulate the neuronal activity through diverse neurotransmitter mechanisms. In the present study we investigated the effects of concomitant treatment with various neurosteroids on the development of tolerance and recovery from withdrawal anxiety and hyperactivity to chronic benzodiazepines. Long-term treatment of mice with full allosteric modulator (triazolam 0.25 mg/kg/day for 8 days) or selective allosteric modulator (diazepam 20 mg/kg/day for 21 days) of GABAA receptor induced tolerance to behavioral sedation on actimeter and anxiolytic effects on plus-maze, and produced a marked withdrawal anxiety and hyperactivity syndrome upon abrupt cessation of treatment, respectively. Concomitant progesterone (10 mg/kg, s.c.), a neurosteroid precursor, of 4'-chlordiazepam (0.25 mg/kg, i.p.), a mitochondrial diazepam binding inhibitor (DBI) receptor (MDR) ligand, prevented the development of tolerance and significantly augmented the recovery from withdrawal-induced anxiety and hyperlocomotion to diazepam. When administered alone for 21 days, neither progesterone nor 4'-chlordiazepam produced any per se effects on actimeter or plus-maze when tested on post-withdrawal days. Coadministration of neurosteroid allopregnanolone (AP) (0.25 and 0.5 mg/kg), or pregnenolone sulfate (PS) (2 mg/kg), but not dehydroepiandrosterone sulfate (2 mg/kg), abolished the development of tolerance and attenuated withdrawal-induced anxiety and hyperlocomotion due to triazolam, without producing any per se behavioral effects when tested at 1 and 2 days after the last injection. Coadministration of flumazenil (5 mg/kg), progesterone (10 mg/kg), 4'-chlordiazepam (0.25 mg/kg), hydrocortisone (100 mg/kg) or nifedipine (2 mg/kg) also prevented the development of tolerance and suppressed the triazolam withdrawal syndrome. However, pretreatment with PK11195 (2 mg/kg), a MDR partial antagonist, reversed the effects of 4'-chlordiazepam on triazolam tolerance and recovery from chronic triazolam. When injected simultaneously, nifedipine, a Ca2+ channel antagonist, potentiated the progesterone- and 4'-chlordiazepam-induced attenuation of triazolam tolerance and withdrawal behavior. These findings suggest that coadministration of neurosteroids allopregnanolone, pregnenolone sulfate and progesterone, and MDR ligand 4'-chlordiazepam prevents the development of tolerance to benzodiazepines and augments the recovery from chronic benzodiazepines. These results indicate that coadministration of neurosteroids may facilitate discontinuation of benzodiazepines in long-term therapy.

Animals↗