Biomedical subjects

S K Kulkarni

Publications and source records attributed to S K Kulkarni.

At least 91 records · Page 5Linked to original sources

PubMed1999

Differential effects of olanzapine at dopamine D1 and D2 receptors in dopamine depleted animals.

The aim of the present study was to investigate the locomotor stimulant effects of the atypical antipsychotic agent, olanzapine, in mice depleted of their dopamine by reserpine and alpha-methyl-DL-p-tyrosine pretreatment. Olanzapine (0.5, 1 and 2 mg/kg) dose-dependently increased locomotor activity, which was completely blocked by the selective dopamine D2 receptor antagonist, pimozide (0.5 mg/kg) but not by selective dopamine D1 receptor antagonist, SCH 23390 (0.5 and 1 mg/kg). Unlike olanzapine, the selective dopamine D2 receptor antagonists such as haloperidol (0.25 and 0.5 mg/kg) and pimozide (0.5 and 1 mg/kg), the selective 5-HT2A receptor antagonist, ritanserin (0.5 and 1 mg/kg) or the antimuscarinic agent scopolamine (0.5 and 1 mg/kg) failed to produce any locomotor stimulant effect. Olanzapine (1 and 2 mg/kg) and SCH 23390 (0.5 and 1 mg/kg) blocked hyperlocomotion and stereotypy induced by the selective dopamine D1 receptor agonist, SKF 38393 (10 and 25 mg/kg). Olanzapine (1 and 2 mg/kg) blocked hyperlocomotion and stereotypy induced by B-HT 920 (1 and 2 mg/kg), a selective dopamine D2 receptor agonist, whereas it blocked the hyperlocomotion but not stereotypy induced by the non-selective dopamine receptor agonist, apomorphine (0.5 and 1 mg/kg). The higher dose (4 mg/kg) of olanzapine blocked both stereotypy and hyperlocomotion induced by apomorphine. Olanzapine, in mice depleted of their dopamine stores, exhibited properties consistent with those of a D2 partial agonist having strong D1 antagonist property. The atypical nature of its clinical effect may be explained by a dual effect, partial agonistic-like action at D2 receptors and antagonist-like activity at D1 receptors, respectively.

Adrenergic Uptake Inhibitors↗

PubMed1999

Sex and estrous cycle-dependent changes in neurosteroid and benzodiazepine effects on food consumption and plus-maze learning behaviors in rats.

Experiments were designed to investigate the influence of estrous cycle and gender of the rat on the effects of a gamma-aminobutyric acid type A (GABA(A)) receptor active neurosteroid, 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone), the benzodiazepine, triazolam, and a GABA(A) receptor antagonistic neurosteroid, delta5-androsten-3beta-ol-17-one sulfate (dehydroepiandrosterone sulfate), on food intake and elevated plus-maze learning behaviors. Allopregnanolone (0.25 mg/kg, s.c.) and triazolam (0.25 mg/kg, i.p.) produced a hyperphagic effect, while dehydroepiandrosterone sulfate (5 mg/kg, s.c.) elicited an anorectic effect. However, allopregnanolone was more potent in diestrous females, whereas triazolam exhibited significantly higher hyperphagic potency in estrus females. The extent of anorexia following dehydroepiandrosterone sulfate was alike in male and female rats. The triazolam- and allopregnanolone-induced hyperphagic effect was blocked by bicuculline (1 mg/kg, i.p.), a selective GABA(A) receptor antagonist. In contrast to triazolam, the hyperphagic effect of allopregnanolone was insensitive to flumazenil (5 mg/kg, i.p.), a benzodiazepine antagonist. Vehicle-treated diestrous rats displayed moderately higher latencies in the elevated plus-maze learning task than estrus or proestrus females. Although allopregnanolone and triazolam elicited equipotent learning deficits in plus-maze learning in male and female rats, the magnitude of impairment-induced by triazolam was significantly higher in diestrous females than proestrus females. Dehydroepiandrosterone sulfate enhanced memory performance only in male rats. Although the use of the elevated plus-maze as a learning paradigm with benzodiazepines and neurosteroids may be sensitive to changes in anxiety, the differential data suggest that neurosteroid-induced effects are at least partly specific to learning behavior. These results confirm the role of estrous cycle and sex of rats in modifying the potency of neurosteroids and benzodiazepines on food consumption and learning and memory processes.

Analysis of Variance↗

PubMed1999

Brain renin angiotensin system (RAS) in stress-induced analgesia and impaired retention.

Physiological stress is known to produce analgesia and memory disruption. Brain renin angiotensin system (RAS) has been reported to participate in stress response and plays a role in the processing of sensory information. Angiotensin receptors (AT), particularly AT1 subtypes have been reported to be distributed in brain areas that are intimately associated with stress response. The purpose of present study was to examine the modulation of AT1 receptor in the immobilization stress and angiotensin II (AngII)-induced analgesia and impaired retention, and to determine whether resultant behavioral changes involve common sensory signals. Result of present experiments showed that immobilization stress in mice and rats, and intracerebroventricular (ICV) administration of AngII (10 and 20 ng) in rats produced an increase in tail-flick latency. Similarly, post training administration of AngII or immobilization stress produced impairment of retention tested on plus-maze learning and on passive avoidance step-down task. Both these responses were sensitive to reversal by prior treatment with losartan (10 and 20 mg/kg), an AT1 AngII receptor antagonist. On the other hand, naloxone, an opiate antagonist preferentially attenuated the stress and AngII-induced analgesia and retention deficit induced by immobilization stress, but failed to reverse the AngII induced retention deficit. These results suggest immobilization stress-induced analgesia and impaired retention involves the participation of brain RAS. Further, failure of naloxone to reverse AngII-induced retention impairment shows. AngII-induced behavioral changes are under control of different sensory inputs.

Angiotensin II↗

PubMed1999

Role of centrally administered melatonin and inhibitors of COX and NOS in LPS-induced hyperthermia and adipsia.

In the present study we have examined the effect of centrally administered non-steroidal anti-inflammatory drugs (NSAIDS), nitric oxide synthase (NOS) inhibitor and melatonin on lipopolysaccharide (LPS)-induced hyperthermia and its anti-dipsogenic effect. Intracerebroventricular (i.c.v.) administration of LPS (100-200 ng/rat) induces a dose dependent elevation in body temperature and decreases water consumption in 24 h water deprived rats. Coadministration of NSAIDS (indomethacin and nimesulide: 10 nM/rat each) with LPS (100 ng) reversed, whereas NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME: 10-20 microg/rat) enhanced LPS-induced hyperthermia. In contrast L-NAME reversed the LPS-induced anti-dipsogenic effect in a dose dependent manner, whereas NSAIDS showed no change in the effect of LPS. Further, centrally administered prostaglandin E2 (PGE2, 0.5-1 microg/rat) produced hyperthermia without affecting the drinking behavior, suggesting that two independent mechanisms operate in LPS-induced hyperthermia and in the anti-dipsogenic effect. The pineal hormone melatonin is known to inhibit cellular damage caused by LPS, produced dose dependent (5-10 nM i.c.v.) inhibition of LPS-induced hyperthermia and adipsia, but failed to reverse the PGE2-induced hyperthermia, shows reversal of LPS-induced hyperthermia by melatonin is due to inhibition of prostaglandin synthesis rather than antagonism of prostaglandin action. The overall study reveals that inhibition of both NO and prostaglandin production by melatonin might be responsible for its reversal of LPS-induced hyperthermia and adipsia.

Animals↗

PubMed1999

A near-native state on the slow refolding pathway of hen lysozyme.

The refolding of four disulfide lysozyme (at pH 5.2, 20 degrees C) involves parallel pathways, which have been proposed to merge at a near-native state. This species contains stable structure in the alpha- and beta-domains but lacks a functional active site. Although previous experiments have demonstrated that the near-native state is populated on the fast refolding pathway, its relevance to slow refolding molecules could not be directly determined from previous experiments. In this paper, we describe experiments that investigate the effect of added salts on the refolding pathway of lysozyme at pH 5.2, 20 degrees C. We show, using stopped flow tryptophan fluorescence, inhibitor binding, and circular dichroism (CD), that the rate of formation of native lysozyme on the slow refolding track is significantly reduced in solutions of high ionic strength in a manner dependent on the position of the anion in the Hofmeister series. By contrast, the rate of evolution of hydrogen exchange (HX) protection monitored by electrospray ionization mass spectrometry (ESI MS) is unchanged under the refolding conditions studied. The data show, therefore, that at high ionic strengths beta-domain stabilization and native state formation on the slow refolding pathway become kinetically decoupled such that the near-native state becomes significantly populated. Thus, by changing the energy landscape with the addition of salts new insights into the relevance of intermediate states in lysozyme refolding are revealed.

Animals↗

PubMed1999

Antagonism by pimozide of olanzapine-induced hypothermia.

The atypical antipsychotic olanzapine (2.5-20 mg/kg) produced hypothermia in rats. The decrease in rectal temperature caused by olanzapine (2.5-20 mg/kg) was blocked by the selective dopamine D2 receptor antagonist pimozide (0.5 and 1 mg/kg) but not by the dopamine D1 receptor antagonist SCH 23390 (0.5 and 1 mg/kg). The dopamine D1/D2 receptor agonist apomorphine (3 mg/kg) and the selective dopamine D2 receptor agonist talipexole (0.5 mg/kg) produced hypothermia in rats. Olanzapine (10 and 20 mg/kg) significantly blocked hypothermia produced by both apomorphine and talipexole while the lower doses (2.5 and 5 mg/kg) of olanzapine failed to block it. The present results demonstrate that olanzapine behaves as a partial agonist at brain DA D2 receptor populations involved in thermoregulation in the rat.

Animals↗

PubMed1999

L-NAME, a nitric oxide synthase inhibitor, modulates cholinergic antinociception.

Systemic administration of sumatriptan and buspirone (20 mg/kg: 5-HT1A agonists) produced antinociception against acetic acid-induced writhing. The antinociceptive effect was potentiated by cholinomimetic physostigmine (0.05 mg/kg i.p.) and blocked by the muscarinic antagonist atropine (5 mg/kg i.p.). Naloxone, an opiate antagonist, failed to reverse the sumatriptan- or buspirone-induced antinociception, but pindolol (10 mg/kg), a nonselective 5-HT1A antagonist, blocked this response. Sumatriptan- or buspirone-induced antinociception was significantly potentiated by L-NAME (a nitric oxide [NO] synthase inhibitor) although L-NAME (20 mg/kg) given alone had no effect on the nociceptive threshold. Recent studies have suggested that the L-arginine/NO/cGMP pathway is involved in the modulation of pain perception. The present results suggest that NO may play a role in cholinergic antinociception-mediated 5-HT1A receptor stimulation and that NO exerts an inhibitory action on cholinergic analgesia.

Acetic Acid↗

PubMed1999

The morphine sparing effect of physostigmine.

The antinociceptive effect of morphine was studied in tail-flick- and acetic acid-induced writhing in mice. Morphine effect was dose-related (1, 2 and 5 mg/kg s.c.). Physostigmine (0.05 and 0.1 mg/kg i.p.) potentiated the antinociceptive effect of morphine, and the anticholinergic, scopolamine (1 mg/kg i.p.), reversed the potentiating effect of physostigmine, indicating the involvement of the cholinergic system in pain. Coadministration of physostigmine would increase the therapeutic index of morphine thereby sparing the dose of morphine and also possibly the side effects including the development of tolerance and addiction.

Analgesics, Opioid↗

PubMed1999

Involvement of dopamine D2 and 5-HT1A receptors in roxindole-induced antinociception.

Roxindole, a DA D2 receptor agonist (2-16 mg/kg) produced dose-dependent increase in percentage antinociception. The effect which was blocked by DA D2 antagonist (-)sulpiride (50 mg/kg) and 5-HT1A receptor antagonist (-) pindolol (5 mg/kg). Roxindole (4 and 8 mg/kg) reversed both naloxone (20 mg/kg)-induced hyperalgesia and reserpine (2 mg/kg)-induced hyperalgesia. This reversal was sensitive to blockade by both (-)sulpiride (50 mg/kg) and (-) pindolol (5 mg/kg). The present study suggests that roxindole-induced antinociception is mediated by postsynaptic DA D2 and 5-HT1A receptors.

Analgesics↗

PubMed1999

Quinpirole, 8-OH-DPAT and ketanserin modulate catalepsy induced by high doses of atypical antipsychotics.

The effect of the selective dopamine D2 receptor agonist quinpirole, the selective 5-HT1A receptor agonist 8-OH-DPAT and the selective 5-HT2A receptor antagonist ketanserin on catalepsy induced by atypical antipsychotics clozapine, risperidone, olanzapine and sertindole at higher doses was studied in rats. Haloperidol (0.5, 1 and 2 mg/kg), clozapine (50 and 75 mg/kg) and olanzapine (15 and 30 mg/kg) produced catalepsy dose-dependently while sertindole at doses up to 40 mg/kg failed to produce catalepsy in rats. However, sertindole (15, 30 and 45 mg/kg) produced a cataleptic effect in mice in a dose-dependent manner. At a high dose (5 mg/kg), risperidone produced catalepsy in rats. Quinpirole (0.05 and 0.1 mg/kg) reversed the cataleptic effect of haloperidol (2 mg/kg), risperidone (5 mg/kg), olanzapine (30 mg/kg) and sertindole (45 mg/kg). Quinpirole (0.05 and 0.1 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15 and 0.3 mg/kg) dose-dependently reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg) without affecting the cataleptic effect of olanzapine. However, the higher dose (0.45 mg/kg) of 8-OH-DPAT reversed it significantly. 8-OH-DPAT (0.3 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15, 0.3 and 0.45 mg/kg) failed to reverse sertindole-induced catalepsy. Ketanserin (0.75 and 1.5 mg/kg) completely reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg). Ketanserin (0.75 and 1.5 mg/kg) dose-dependently reversed olanzapine (30 mg/kg) and sertindole (45 mg/kg)-induced catalepsy without any effect on clozapine (75 mg/kg)-induced catalepsy. A higher dose (3 mg/kg) of ketanserin reversed clozapine-induced catalepsy. The present study suggests that atypical antipsychotics show fewer extrapyramidal symptoms (EPS) due to greater modulation of the serotonergic system. Therefore, an antipsychotic with dopamine D2/5-HT2A antagonistic action and 5-HT1A agonistic action may prove to be superior to the existing antipsychotics.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1998

Dopamine receptor sensitive effect of dizocilpine on feeding behaviour.

The effect of intracerebroventricular administration of dizocilpine on feeding behaviour and adrenal corticrotropic hormone (ACTH)-induced anorexia in elevated plus maze was examined. Dizocilpine (10, 20 and 40 nmol/rat, i.c.v.) showed a dose-dependent increase in food intake in 16 h food deprived rats. Dopamine receptor antagonists such as SCH 23390 (0.25 and 0.5 mg/kg, i.p.), pimozide (0.5 and 1 mg/kg, i.p.) and haloperidol (0.25 and 0.5 mg/kg, i.p.) dose-dependently blocked dizocilpine (40 nmol)-induced potentiation of food intake. Brain dopamine depletion by pretreatment with reserpine (5 mg/kg, i.p.) and alpha-methyl-p-tyrosine (200 mg/kg, i.p.) decreased food intake in rats. Similarly, pretreatment with reserpine and alpha-methyl-p-tyrosine (AMPT) reversed the hyperphagic effect of dizocilpine (20 and 40 nmol). Intracerebroventricular administration of ACTH (5 microgram/rat) produced significant diminution of feeding duration and increased tasting latency and feeding latency in elevated plus maze which was reversed by dizocilpine (40 nmol). SCH 23390 (0.25 mg/kg), pimozide (0.5 mg/kg) and haloperidol (0.25 mg/kg) reversed the effect of dizocilpine on ACTH-induced behaviours in elevated plus maze. The present observations support and extend the hypothesis that endogenous excitatory aminoacids (EAAs) play a role in the control of food intake. Further, dizocilpine-induced hyperphagia and dizocilpine-induced reversal of ACTH effect on feeding behaviour in elevated plus maze involve DAergic mediation.

Adrenocorticotropic Hormone↗

PubMed1998

5-HT2A receptor antagonists block MK-801-induced stereotypy and hyperlocomotion.

The present study was undertaken to examine the effect of 5-HT2A receptor antagonists on MK-801 (5-methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine)-induced stereotypy and hyperlocomotion. MK-801 (0.1, 0.25 and 0.5 mg/kg) dose-dependently increased stereotypy and locomotion in mice. The 5-HT2A receptor antagonists, ketanserin (2.5, 5 and 10 mg/kg) and ritanserin (0.5, 1 and 2 mg/kg), dose-dependently blocked MK-801 (0.5 mg/kg)-induced hyperlocomotion. Only the higher dose (2 mg/kg) of seganserin could block locomotor activity. Similarly, ketanserin (2.5, 5 and 10 mg/kg), ritanserin (1 and 2 mg/kg) and seganserin (0.5, 1 and 2 mg/kg) dose-dependently blocked MK-801 (0.5 mg/kg)-induced stereotypy. The results suggest the involvement of 5-HT2A receptors in MK-801-induced stereotypy and hyperlocomotion. The lack of effect on spontaneous locomotion further suggests that 5-HT2A receptor antagonists will be less prone to induce psychomotor side-effects.

Animals↗

PubMed1998

Sigma (sigma1) receptor mediated anti-depressant-like effects of neurosteroids in the Porsolt forced swim test.

This study examined the effects of neurosteroids dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS) and progesterone on the Porsolt forced swim test of depression in mice, and investigated the possible involvement of delta receptors. The immobility time in the mouse forced swimming test was significantly reduced by DHEAS (5 and 20 mg/kg, s.c.) and PS (5 mg/kg) without accompanying changes in the ambulatory or open-field activity. Pretreatment with DHEAS (10 mg/kg) or PS (10 and 20 mg/kg), however, failed to modify the immobility. The relief of behavioral despair in the immobility test by DHEAS (5 and 20 mg/kg) was dose-dependently blocked by preadministration of NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl-ethylamine monohydrochloride; 0.5 and 1 mg/kg), a putative delta1 receptor antagonist, or progesterone (10 mg/kg), a delta receptor antagonistic neurosteroid. On the other hand, PS (5 mg/kg)-induced decrease in the immobility was significantly blocked by NE-100(0.5 mg/kg), but not by progesterone (10 mg/kg). Neither NE-100 nor progesterone influenced the immobility alone. These data suggest a role for central delta receptor in the antidepressant-like effects of neurosteroids, and reinforced their potential therapeutic use in depression.

Animals↗

PubMed1998

Possible role of nitric oxide in the nootropic and antiamnesic effects of neurosteroids on aging- and dizocilpine-induced learning impairment.

The ability of the nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine methyl ester (L-NAME), to modulate the attenuating effects of neurosteroids on the aging- and NMDA receptor antagonist dizocilpine-induced learning impairment, was tested in mice using two different behavioral models of long-term memory. The performance of aged mice (16 months old) in step-down type of passive-avoidance and elevated plus-maze paradigms was significantly impaired compared to that of young mice (3 months old). Neurosteroids pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS), at 1-20 mg/kg, s.c., significantly improved the passive-avoidance and plus-maze performances in aged mice. Neurosteroids PS and DHEAS, at doses 1-20 mg/kg, s.c., significantly attenuated dizocilpine (0.1 mg/kg, i.p.)-induced amnesia, without producing any promnestic effects alone in adult mice. In both cognitive tasks, the effects exhibited by the neurosteroids tested had a bell-shaped curve. Preadministration of L-NAME (10 and 20 mg/kg, i.p.), at doses that did not disrupt cognition alone in either young or aged mice, significantly blocked the beneficial and antiamnesic effects of neurosteroids PS (5 mg/kg) and DHEAS (10 mg/kg). A selective action of L-NAME on the effects of neurosteroids was indicated, since the effects of L-NAME were completely reversed by L-arginine (300 mg/kg, i.p.), a competitive substrate for NO synthase. Neither L-NAME nor L-arginine alone affected the antinociception, locomotor activity or rota-rod performance of young or aged mice. These observations suggest that a NO-dependent mechanism may be involved in the beneficial and antiamnesic effects of neurosteroids PS and DHEAS on the aging- and dizocilpine-induced impairment of learning and memory processes.

Aging↗

PubMed1998

The effects of neurosteroids on acquisition and retention of a modified passive-avoidance learning task in mice.

This study examined the effects of neurosteroids, pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS), on learning and memory processes in a modified passive-avoidance task in mice. The two parameters measured are number of passive-avoidance step-down descents and the active escape latency to reach shock-free zone. Each neurosteroid was administered 60 min before or immediately after the training session, or 60 min before the retention test given 24 h after acquisition. Pretraining injection of PS (0.125-10 mg/kg, s.c.) and DHEAS (0.125-10 mg/kg, s.c.) decreased the number of mistakes committed on training day but had no effect on the latency measure. Both PS (0.125-10 mg/kg, s.c.) and DHEAS (0.125-10 mg/kg, s.c.) decreased the number of mistakes and latency to reach shock-free zone, in a dose-dependent and bell-shaped manner, following pretraining and posttraining administration schedules. Neurosteroids failed to improve memory performance when administered 60 min before retention testing. Injection of PS (0.5 and 1 mg/kg) or DHEAS (1 and 5 mg/kg) before both the training and test sessions, however, also significantly facilitated memory retention. In addition, the memory-facilitating effects of PS (0.5 mg/kg, s.c.) or DHEAS (1 mg/kg) when administered posttraining are blocked by concurrent administration of haloperidol (0.25 mg/kg, i.p.), a prototype sigma receptor antagonist. These results confirm that both PS and DHEAS facilitate retention of a modified learning task when given either pretraining or posttraining, but not prior to retention test. The pretraining neurosteroid-induced memory modulation do not involve state-dependent effects. These results suggest a role for central sigma receptor in the memory-modulating effects of neurosteroids.

Animals↗

PubMed1998

Proconvulsant effects of neurosteroids pregnenolone sulfate and dehydroepiandrosterone sulfate in mice.

We have investigated the effects of chronic treatment with the neurosteroids, pregnenolone sulfate and dehydroepiandrosterone sulfate, on the potential neurotoxicity in pentylenetetrazol seizure sensitivity test in mice. Four weeks of subcutaneous treatment with pregnenolone sulfate and dehydroepiandrosterone sulfate, at a dose of 10 mg kg(-1) day(-1), significantly shifted the pentylenetetrazol dose-percent convulsions and latency curves to the left, and markedly decreased the ED50 of pentylenetetrazol for tonic convulsions, indicating the increased sensitivity of mice to seizures. Chronic neurosteroid treatment significantly decreased the body weight of the animals. However, acute treatment of neurosteroids did not modify the seizure reactivity of mice to pentylenetetrazol. Furthermore, the dehydroepiandrosterone sulfate (10 mg kg(-1), s.c.)-induced proconvulsant effect was significantly prevented by chronic pretreatment with progesterone (5 mg kg(-1), s.c.), a precursor for GABA(A) receptor active neurosteroid, allopregnanolone, and dizocilpine (0.1 mg kg(-1), i.p.), a non-competitive NMDA receptor antagonist. These results suggest that long-term administration of neurosteroids pregnenolone sulfate or dehydroepiandrosterone sulfate produces proconvulsant effects.

Animals↗

PubMed1998

Partial agonistic action of clozapine at dopamine D2 receptors in dopamine depleted animals.

In the present experiments, the locomotor and stereotypic stimulant effects of the atypical antipsychotic agent, clozapine were studied in mice depleted of their brain dopamine by reserpine and alpha-methyl-p-tyrosine pretreatment. Clozapine at a dose of 1 mg/kg produced slight stimulation of locomotor activity, but failed to produce any stereotypy. However, clozapine at 0.5 or 2 mg/kg failed to show increase in locomotor activity or stereotypy. Clozapine potentiated the locomotor activity and stereotypy induced by selective dopamine D1 receptor agonist, SKF 38393 but blocked locomotor activity and stereotypy induced by dopamine D2 agonist, B-HT 920 (1 mg/kg) and stereotypy induced by higher dose of B-HT 920 (2 mg/kg). The synergistic action of clozapine and SKF 38393 was partially blocked by the dopamine D1 selective antagonist SCH 23390 and the dopamine D2 selective antagonist, sulpiride, respectively. Clozapine potentiated the stereotypy induced by apomorphine (0.5 and 1 mg/kg) but did not affect locomotor stimulating activity of apomorphine. These behavioral effects of clozapine suggested that it has partial agonistic action at dopamine D2 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1998

The role of GABA-A and mitochondrial diazepam-binding inhibitor receptors on the effects of neurosteroids on food intake in mice.

The present studies were undertaken to investigate the neuroactive steroidal modulation of feeding behavior and possible involvement of gamma-aminobutyric acid type-A (GABA-A) and mitochondrial diazepam binding inhibitor (DBI) receptors (MDR) in food-deprived male mice. Allopregnanolone (0.5-2 mg/kg), a neurosteroid, progesterone (1-10 mg/kg), a neurosteroid precursor, and 4'-chlordiazepam (0.25-1 mg/kg), a specific high affinity MDR agonist, produced a dose-dependent hyperphagic effects. In contrast, neurosteroids pregnenolone sulfate (PS) (1-10 mg/kg) and dehydroepiandrosterone sulfate (DHEAS) (1-10 mg/kg) produced a hypophagic effect, in a dose-dependent manner. The allopregnanolone-, progesterone- and 4'-chlordiazepam-induced hyperphagic effect was blocked by picrotoxin (1 mg/kg), a GABA-A chloride channel antagonist, but not by flumazenil (2 mg/kg), a benzodiazepine (BZD) antagonist. The 4'-chlordiazepam-induced hyperphagic effect was prevented by pretreatment with PK11195 (2 mg/kg), a selective partial MDR antagonist. The hypophagic effect of DHEAS (10 mg/kg) was reversed by dizocilpine (10 microg/kg), an NMDA receptor antagonist, but resistant to muscimol (0.1 mg/kg), a selective GABA-A receptor agonist. In contrast, the PS (10 mg/kg)-induced hypophagic response was resistant to dizocilpine, but sensitive to muscimol (0.1 mg/kg). Both the sulfated neurosteroids PS and DHEAS also reversed the hyperphagic effect of allopregnanolone. In addition, the BZD agonist triazolam (0.05-0.25 mg/kg) also produced a flumazenil- and picrotoxin-sensitive hyperphagic effects, thereby suggesting the changes in feeding behavior by neurosteroids represent GABA-A receptor mediated hyperphagic action. Although the possible antistress or anxiolytic actions of neurosteroids may confound the hyperphagia, behavioral effects observed were specific to food because the mice were adopted to the test environment and diet, and of a possible variation between various neurosteroids in the extent to which antistress or anxiolytic effect produced at hyperphagic doses. The hyperphagic effects of progesterone and 4'-chlordiazepam resembled that of neurosteroid allopregnanolone. Therefore, the effect of progesterone may be imputed to its metabolism to allopregnanolone, while the 4'-chlordiazepam-induced hyperphagic response is related to its MDR-stimulated neurosteroidogenesis and subsequent modulation of GABA-A receptors. The hypophagic response following DHEAS may, at least partly, involve an NMDA receptor mechanism. However, PS-induced hypophagia may be mediated by GABA-A or other receptor systems. These data suggest a pivotal role for GABA-A and mitochondrial DBI receptors in the hyperphagic effects of neurosteroids and reinforces a role for endogenous neurosteroids in regulating feeding behavior. Future studies may lead to the development of neurosteroid-based anorectic/hyperphagic agents for therapeutic use.

Animals↗