Biomedical subjects

M N Subhash

Publications and source records attributed to M N Subhash.

At least 19 recordsLinked to original sources

PubMed2003

Cortical alpha-adrenoceptor downregulation by tricyclic antidepressants in the rat brain.

The aim of the present study was to examine the effect of chronic tricyclic antidepressants (TCAs) treatment on the density of alpha-adrenoceptors in the rat brain. Density of alpha1- and alpha2-adrenoceptors was measured in cortex and hippocampus of rats treated with imipramine (IMI, 5mg/kg body weight), desipramine (DMI, 10mg/kg body weight), clomipramine (CMI, 10mg/kg body weight) and amitriptyline (AMI, 10mg/kg body weight), for 40 days, using [3H]prazosin and [3H]clonidine, respectively. The density of cortical alpha1-adrenoceptors was significantly decreased with IMI (46%), DMI (21%), CMI (50%) and AMI (67%) treatment, without altering the affinity of the receptor. The density of cortical alpha2-adrenoceptors was also significantly decreased with DMI (69%), CMI (81%) and AMI (80%) treatment, without affecting the affinity for [3H]clonidine. The density of hippocampal alpha1-adrenoceptors was significantly decreased only with AMI treatment (47%), without affecting the affinity for [3H]prazosin. However, no change in hippocampal alpha2-adrenoceptor density was observed with any of these TCAs. The results suggest that chronic antidepressant (AD) treatment downregulates the cortical, but not hippocampal, alpha1- and alpha2-adrenoceptors in rat brain. The region-specific downregulation of alpha1- and alpha2-adrenoceptors density, which occur after prolonged AD treatment, may underline the therapeutic mechanism of action.

Amitriptyline↗

PubMed2002

Alterations in 5-HT(1A) receptors and adenylyl cyclase response by trazodone in regions of rat brain.

The in vivo effect of trazodone on the density of [(3)H]5-HT binding sites and 5-HT(1A) receptors and adenylyl cyclase (AC) response was studied in regions of rat brain. The chronic administration of trazodone (10 mg/Kg body wt, 40 days) resulted in a significant downregulation of [(3)H]5-HT binding sites and 5-HT(1A) receptors in cortex and hippocampus. Trazodone significantly (p < 0.0001) decreased the density of [(3)H]5-HT binding sites in cortex (42.6 +/- 3.6 fmol/mg protein, 65%) and hippocampus (12.6 +/- 1.6 fmol/mg protein, 87%) when compared to control values of 121.9 +/- 5.4 and 99.3 +/- 7.5 fmol/mg protein in these regions, respectively. Similarly there was a significant (p < 0.0001) decrease in the density of 5-HT(1A) receptors in both cortex (7.2 +/- 0.5 fmol/mg protein, 70%) and hippocampus (6.3 +/- 1.2 fmol/mg protein, 79%) when compared to control values of 24.2 +/- 2.1 and 30.6 +/- 3.7 fmol/mg protein, in these regions respectively. However, the affinity of [(3)H]5-HT to 5-HT binding sites (1.83 +/- 0.26 nM, p < 0.0001) and [(3)H]8-OH-DPAT to 5-HT(1A) receptors (0.60 +/- 0.06 nM, p < 0.05) was significantly decreased only in cortex when compared to the control K(d) values of 0.88 +/- 0.04 nM and 0.47 +/- 0.02 nM in these regions, respectively. The basal AC activity did not alter in treated rats, where as, the inhibition of forskolin-stimulated AC activity by 5-HT (10 microM) was significantly (p < 0.0001) decreased both in cortex (43%) and hippocampus (40%) when compared to control levels. In conclusion, chronic treatment with trazodone results in downregulation of 5-HT(1A) receptors in cortex and hippocampus along with concomitant increased AC response, suggesting the involvement of 5-HT(1A) receptor-mediated AC response in the mechanism of action of trazodone.

Adenylyl Cyclases↗

PubMed2002

Lamotrigine induced selective changes in 5-HT(1A) receptor mediated response in rat brain.

A new anticonvulsant drug lamotrigine (LTG) has recently been reported to be effective in treating patients with bipolar affective disorder, depression and schizoaffective disorder, suggesting that it is a mood stabilizer. However, the mechanism of action underlying its efficacy in mood disorders is not understood. This study examined the in vivo effect of LTG on 5-HT(1A) receptor-mediated adenylyl cyclase (AC) response in regions of rat brain, as this pathway has been implicated in the therapeutic action of various classes of mood stabilizers. The density of 5-HT(1A) receptors was measured by radioligand binding assay using [(3)H]8-OH-DPAT (0.05-0.8nM) in frontal cortex and hippocampus of rats treated orally with LTG (5mg/kg) for 7 days. AC activity was assayed using [(3)H]ATP. The oral administration of LTG significantly decreased the density of cortical (50%, P<0.001) but not hippocampal 5-HT(1A) receptors, without significant change in the affinity of [(3)H]8-OH-DPAT to 5-HT(1A) receptor in these regions. There was no significant alteration in basal or forskolin-stimulated AC activity in either of regions. However, a significant decrease (P<0.01) in the inhibition of forskolin-stimulated AC activity by 8-OH-DPAT was observed only in cortical membranes of LTG treated rats when compared to control. These results suggest that one mode of action of LTG may be by the downregulation of cortical 5-HT(1A) receptor-mediated AC response.

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

PubMed2001

Cortical 5-HT(1A) receptor downregulation by antidepressants in rat brain.

Total 5-HT binding sites and 5-HT(1A) receptor density was measured in brain regions of rats treated with imipramine (5 mg/kg body wt), desipramine (10 mg/kg body wt) and clomipramine (10 mg/kg body wt), for 40 days, using [3H]5-HT and [3H]8-OH-DPAT, respectively. It was observed that chronic exposure to tricyclic antidepressants (TCAs) results in significant downregulation of total [3H]5-HT binding sites in cortex (42-76%) and hippocampus (35-67%). The 5-HT(1A) receptor density was, however, decreased significantly (32-60%) only in cortex with all the three drugs. Interestingly, in hippocampus imipramine treatment increased the 5-HT(1A) receptor density (14%). The affinity of [3H]8-OH-DPAT was increased only with imipramine treatment both in cortex and hippocampus. The affinity of [3H]5-HT to 5-HT binding sites in cortex was increased with imipramine treatment and decreased with desipramine and clomipramine treatment. 5-HT sensitive adenylyl cyclase (AC) activity was significantly increased in cortex with imipramine (72%) and clomipramine (17%) treatment, whereas in hippocampus only imipramine treatment significantly increased AC activity (50%). In conclusion, chronic treatment with TCAs results in downregulation of cortical 5-HT(1A) receptors along with concomitant increase in 5-HT stimulated AC activity suggesting the involvement of cortical 5-HT(1A) receptors in the mechanism of action of TCAs.

Adenylyl Cyclases↗

PubMed2001

Differential protection and recovery of 5-HT1A receptors from N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) inactivation in regions of rat brain.

The effect of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on 5-HT1A receptors was studied in Sprague Dawley rats. A single dose of EEDQ (4 mg/kg body wt., i.p.) significantly inactivated 5-HT1A receptors, as measured by [3H]8-hydroxy-2-[di-n-propylamino]-tetralin ([3H]8-OH-DPAT), in cortex (64%, p < 0.0001) and hippocampus (48%, p < 0.0001). A significant (p < 0.01) increase in the affinity of 5-HT1A receptors for radioligand was observed in both regions. A dose dependent protection of cortical 5-HT1A receptors from EEDQ inactivation with pre-treatment of different doses of 8-OH-DPAT (4-20 mg/kg) was observed, along with recovery of affinity of [3H]8-OH-DPAT for 5-HT1A receptors in both regions. Although, a dose of 4 mg/kg of 8-OH-DPAT failed to attenuate the effect of EEDQ on hippocampal 5-HT1A receptors, a significant protection of these receptors was observed with 10 and 20 mg/kg of 8-OH-DPAT. Displacement studies revealed that EEDQ has more affinity for cortical (Ki = 101.3 +/- 11.8 nM) than hippocampal (Ki = 133.5 +/- 25.8 nM) 5-HT1A receptors. A time dependent natural recovery of 5-HT1A receptors from inactivation by a single dose of EEDQ (4 mg/kg) was observed more in cortex compared to hippocampus over a period from 1 day to 14 days. The results of this study suggest that 8-OH-DPAT inhibited EEDQ inactivation of cortical and hippocampal 5-HT1A receptors in a concentration dependent manner. The synthesis and turnover of 5-HT1A receptors differ in cortex and hippocampus, as evident by earlier recovery in the cortex.

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

PubMed2000

Modulation of 5-HT1A receptor mediated response by fluoxetine in rat brain.

Radioligand binding studies were done to investigate the effect of chronic administration of fluoxetine on 5-HT1 receptor mediated response to adenylate cyclase (AC) in rat brain. Our studies revealed a significant decrease in the densities of 5-HT1 and 5-HT1A receptor sites in cortex and hippocampus of rat brain after chronic administration of fluoxetine (10 mg/Kg body wt.). However there was no significant change in the affinity of [3H]5-HT and [3H]DPAT for 5-HT1 and 5-HT1A receptor sites, respectively. However, in striatum, along with a significant (75%) downregulation of 5-HT1 sites, the affinity of [3H]5-HT to these sites was increased, as revealed by decrease in Kd (0.50 +/- 0.08 nM). Displacement studies showed that fluoxetine has higher affinity for 5-HT1A receptors with a Ki value of 14.0 +/- 2.8 nM, than 5-HT1 sites. No significant change was observed in basal AC activity in any region after fluoxetine exposure. However, in cortex of experimental rats the 5-HT stimulated AC activity was significantly increased (16.03 +/- 0.97 pmoles/mg protein; p < 0.01), when compared to 5-HT stimulated AC activity (12.98 +/- 0.78 pmoles/mg protein) in control rats. The increase in 5-HT stimulated AC activity in cortex may be due to the significant downregulation of 5-HT1A sites in cortex after fluoxetine exposure as these sites are negatively coupled to AC. The observed significant decrease in 5-HT1 sites with concomitant increase in 5-HT stimulated AC activity, after fluoxetine treatment, suggests that fluoxetine, which has high affinity for these sites, acts by modulating the 5-HT1A receptor mediated response in brain.

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

PubMed1999

Differential effect of lithium on 5-HT1 receptor-linked system in regions of rat brain.

The effect of chronic administration (0.4% for 30 days) of lithium carbonate (Li2CO3) on 5-HT1 receptor-linked second messenger system was studied in regions of rat brain. We observed that chronic treatment of Li2CO3, significantly decreased the density of [3H]5-HT binding sites in cortex (62%), hippocampus (64%) and striatum (65%), compared to the control levels. The affinity of [3H]5-HT to 5-HT1 binding sites was significantly decreased in all the regions. A significant decrease in the density of high affinity 5-HT1A receptor sites was observed in cortex (81%) and hippocampus (42%), without change in the affinity of [3H]8-OH-DPAT for 5-HT1A sites in these regions. 5-HT-stimulated, but not basal, adenylyl cyclase activity was significantly increased in all the regions after Li treatment. The present study concludes that the increase in the 5-HT-stimulated adenylyl cyclase activity might be attributed to the functional downregulation of 5-HT1 receptors, as these are negatively coupled to adenylyl cyclase, suggesting the involvement of 5-HT1 receptor mediated response in the therapeutic efficacy of lithium.

Adenylyl Cyclases↗

PubMed1998

Effect of antidepressants on intracellular Ca++ mobilization in human frontal cortex.

BACKGROUND: It is well documented that central serotonin (5-HT)2 receptor dysfunction is involved in the biochemistry and pathophysiology of depression and might be corrected by antidepressant drug treatment. METHODS: The effect of imipramine (IMI) and fluoxetine (FLX) on 5-HT2A receptor-mediated intracellular calcium ([Ca++]i) mobilization in synaptosomes of human frontal cortex was studied. [Ca++]i was measured using Fura-2AM. RESULTS: It was observed that in response to 5-HT (10 mumol/L) there was a significant increase (254%; p < .001) in [Ca++]i compared to basal level (140.00 +/- 31.77 nmol/L/mg protein). Both IMI and FLX (10-1000 nmol/L) induce mobilization of basal [Ca++]i in a dose-dependent manner. IMI and FLX antagonize the 5-HT-stimulated [Ca++]i mobilization in a dose-dependent manner. IMI showed higher antagonizing effect at lower concentration (10 nmol/L); however, FLX showed maximum antagonizing effect at higher concentration (1000 nmol/L). CONCLUSIONS: It is observed that imipramine and fluoxetine have different effects on antagonizing the 5-HT response in frontal cortex. One mode of action of these antidepressants might be by decreasing the intracellular calcium.

Adult↗

PubMed1998

Inactivation of 5-HT1A and [3H]5-HT binding sites by N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ) in rat brain.

Inactivation of 5-HT1A and [3H]5-HT binding sites by N-Ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ) was studied in regions of rat brain. After exposure to EEDQ (4 mg/kg body wt.) for 7 days, it is observed that the density of 5-HT1 receptor sites was decreased by nearly 20% in both cortex and hippocampus. The decrease, however, in 5-HT1A sites was more significant (70%) in both the regions. The affinity of [3H]5-HT to 5-HT1 sites was decreased significantly in both cortex and hippocampus after exposure to EEDQ, without affecting the Kd of 5-HT1A sites. Displacement studies suggested that EEDQ has high affinity to 5-HT1 sites with a Ki of 42.9+/-2.4 nM. After exposure neither basal nor 5-HT stimulated adenylyl cyclase activity was changed in cortex. The results of this study suggest that EEDQ decreases the density of 5-HT1 and 5-HT1A receptor sites but does not cause functional downregulation of these sites in rat brain.

Adenylyl Cyclases↗

PubMed1997

Gender but not stimulus parameters influence prolactin response to electroconvulsive therapy.

The post-ictal prolactin (PRL) response represents one of the most consistent findings of electroconvulsive therapy (ECT), but correlates variably with the gender of the patient, ECT stimulus waveform, dose and electrode placement. Forty patients with endogenous depression (29 drug-naive) received either high-energy (240 mC) or low-energy (60 mC) bilateral brief-pulse ECT once or three times a week. The PRL and growth hormone (GH) levels were estimated using double antibody radioimmunoassay. The average post-ECT PRL levels differed significantly from the pre-ECT levels, with a seven- to nine-fold increase in PRL at each week of treatment. No such difference was observed in the GH levels. All patients showed an increase in PRL levels, whereas 42% failed to show an increase in GH levels. The delta PRL response (difference between post-ECT and pre-ECT serum hormone levels) was not significantly different between the drug-naive and medicated patients nor between the high-energy and low-energy groups at first ECT. Similarly, no difference was observed between the once-weekly and thrice-weekly groups at the third week of ECT. At each week of treatment, the delta PRL was significantly higher in females than in males, unlike the GH response. Electroencephalographic (EEG) seizure duration did not correlate with either delta PRL or delta GH at first ECT and third week ECT. Apart from gender, none of the variables, such as age, baseline severity of illness, presence of psychotic symptoms, drug-naive status, stimulus dose, seizure duration, seizure strength, pattern and symmetry, frequency of ECT and degree of improvement predicted the delta PRL response. Neither stimulus energy nor frequency of ECT had a significant effect on PRL response. Gender differences in PRL response to ECT merit further investigations.

Adult↗

PubMed1997

Imipramine-induced changes in 5-HT2 receptor sites and inositoltrisphosphate levels in rat brain.

The effect of chronic administration of Imipramine on [3H]Spiperone binding to 5-HT2 sites and inositoltrisphosphate (IP3) levels in rat cerebral cortex was studied. Our data shows that treatment with imipramine (5 mg/kg body weight, intraperitoneally) for 30 days significantly down regulates 5-HT2 receptors sites (262 +/- 29 fmol/mg protein) in cerebral cortex (38%), compared to control rats (425 +/- 60 fmol/mg protein., P < 0.001). However there was no significant change in the affinity of [3H]-Spiperone binding (kd) to 5-HT2 sites in cerebral cortex after exposure to imipramine (Kd = 0.84 +/- 0.11 nM). It is also observed that imipramine treatment significantly reduces 5-HT stimulated [3H]IP3 formation in cerebral cortex (6,411 +/- 708 dpm/mg protein), compared to the saline treated rats (12,238 +/- 1,544 dpm/mg protein; P < 0.001), with concomitant decrease in Pdtlns-4-5-P2. This study suggests that the therapeutic action of imipramine in brain might be by reducing hypersensitivity of 5-HT2 receptors by down regulation, which leads to reduced levels of inositolphospholipids. This inturn reduces the levels of IP3. In conclusion, imipramine acts at presynaptic site by blocking the reuptake of serotonin and at post synaptic site it downregulates 5-HT2 sites with decreased IP3 levels after chronic exposure.

Animals↗

PubMed1996

Increased acetylcholinesterase activity in selected regions of rat brain after chronic (-)-deprenyl administration.

(-)-Deprenyl, 0.05, 1.0, 2.0, and 10.0 mg/kg body weight, was administered intraperitonially to Wistar rats for 30 days. The activity of acetylcholinesterase, and monoamine oxidase A and B were assayed in different brain regions. After the experimental period acetyl cholinesterase activity was found to be significantly increased in frontal cortex [P < 0.001] and hippocampus [P < 0.001] but not in striatum and brainstem at 0.1, 1.0, and 2.0 mg/kg dose, the maximum increase being at 0.1 mg/kg dose. Monoamine oxidase B activity was inhibited by more than 90% at 1.0, 2.0, and 10.0 mg/kg dose while 0.05 and 0.1 dose inhibited only about 55% and 70% respectively. Monoamine oxidase A activity was inhibited to more than 70% at 1.0 mg dose and to more than 90% at 2.0 and 10.0 mg/kg dose. At 0.05 and 0.1 mg/kg dose monoamine oxidase A activity was not significantly altered.

Acetylcholinesterase↗

PubMed1995

Effect of chronic administration of phenytoin on regional monoamine levels in rat brain.

Phenytoin (DPH) is a widely used anticonvulsant drug but a conclusive mode of action is not yet clear. This study was undertaken to assess the effects of chronic administration of DPH on monoamine levels. DPH (50 mg/kg body weight) was administered to adult male Wistar rats by intraperitoneal injections for 45 days and the regional brain levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were assayed using high performance liquid chromatographic (HPLC) method. The experimental rats revealed no behavioral deficits of any kind nor body and brain weight deficits were observed. Increased NE levels were observed after DPH administration in motor cortex (P < 0.05), striatum-accumbens (P < 0.01) and hippocampus (P < 0.01), whereas, NE level was decreased in brain stem (P < 0.05). DA levels were increased in striatum-accumbens (P < 0.05), hypothalamus (P < 0.001) and cerebellum (P < 0.001) but decreased in brainstem (P < 0.01). In DPH treated rats, 5-HT levels were increased in motor cortex (P < 0.001) but decreased in cerebellum (P < 0.001) when compared to control group of rats. The present study suggest that chronic administration of DPH induces alterations in monoamine levels in specific brain regions. DPH seems to mediate its anticonvulsant action by selectively altering the monoamine levels in different brain regions.

Animals↗

PubMed1995

The effect of chronic chlorpromazine administration on monoamine levels in various regions of rat brain.

The neuroleptic drug, chlorpromazine (CPZ) has been shown to exert its antipsychotic effect by blocking post synaptic dopamine receptors. However, its effect on steady state levels of monoamines is still in discrepancy. In the present study, CPZ (4 mg/kg body weight) was administered intraperitoneally to adult Wistar rats chronically for 75 days and the levels of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) were assayed in various brain regions by high performance liquid chromatography (HPLC). After the experimental period body and brain weights were not statistically different from controls. NE and 5-HT levels were increased only in hippocampus by 15% (p < 0.01) and 16% (p < 0.01) respectively. DA levels were consistently increased in cortex by 39% (p < 0.001), striatum-accumbens by 18% (p < 0.01), hippocampus by 27% (p < 0.01), hypothalamus by 34% (p < 0.001), cerebellum by 36% (p < 0.001) and brainstem by 40% (p < 0.001) in CPZ treated rats compared to controls. The results suggest that chronic CPZ administration increases DA levels in almost all regions of brain and reflect the ability of CPZ to preferentially interfere with synaptic transmission mediated by DA in brain. It also suggests that this increase in DA might be responsible for certain side effects seen in patients after chronic CPZ treatment.

Animals↗

PubMed1994

Early onset Parkinson's disease: are juvenile- and young-onset different?

It is controversial if early onset Parkinson's disease (EOPD) (onset at < 41 years of age) is Parkinson's disease (PD) occurring at a younger age or a different disease. This controversy is due to some clinical and pathological differences between EOPD and PD. Within EOPD, there appear to be two groups namely: young onset Parkinson's disease (YOPD), with onset between 21 and 40 years, and juvenile parkinsonism (JP), with onset at < 20 years. The two major clinical differences between these groups are a higher familial occurrence of PD and dystonia in JP. In this study, we determine if the two groups have the classical features of PD, namely rest tremors, rigidity, bradykinesia, and postural instability, and have a meaningful response to levodopa. Furthermore, we compare their other clinical features, autonomic and cognitive functions, and levels of CSF monoamine metabolites to determine differences between these groups. We observe that all YOPD (100%) and JP (85%) patients had rest tremors. Most of these patients also had a meaningful response to levodopa (YOPD: 72%; JP: 100%). The prevalence of family history of PD was similar, whereas dystonia was more frequent in JP (43%) compared to YOPD (9%). Autonomic symptoms were twice as common in JP (42%) compared to YOPD (17%). However, bedside autonomic functions were abnormal in similar proportions and, like in PD, suggest involvement of parasympathetic nervous system. Cognitive dysfunction does occur but with no difference in severity between the two groups. The difference in number of patients between YOPD and JP groups makes statistical comparison of the occurrence of clinical features like dystonia and autonomic dysfunction difficult.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1994

Alterations in monoamine levels in discrete regions of rat brain after chronic administration of carbamazepine.

Carbamazepine (25 mg/kg body weight) was administered intraperitoneally to adult male Wistar rats for 45 days and norepinephrine (NE), dopamine (DA) and serotonin (5-HT) levels were simultaneously assayed in discrete brain regions by high performance liquid chromatographic (HPLC) method. Experimental rats displayed no behavioral abnormalities. Body and brain weights were not significantly different from control group of rats. After exposure it was observed that norepinephrine levels were elevated in motor cortex (P < 0.01) and cerebellum (P < 0.05), while dopamine levels were decreased in these two regions (P < 0.001, P < 0.05). However, dopamine levels were increased in hippocampus (P < 0.01). Serotonin levels were significantly decreased in motor cortex (P < 0.001) and hypothalamus (P < 0.001) but increased in striatum-accumbens (P < 0.001) and brainstem (P < 0.001). These results suggest that carbamazepine may mediate its anticonvulsant effect by differential alterations of monoamine levels in discrete brain regions particularly in motor cortex and cerebellum.

Animals↗

PubMed1994

Disulfiram lowers Ca2+, Mg(2+)-ATPase activity of rat brain synaptosomes.

The chronic administration of disulfiram (DS) to rats resulted in significant decrease of synaptosomal Ca2+, Mg(2+)-ATPase activity. In vitro studies indicated that DS (ID50 = 20 microM) produced a dose-dependent inhibition of Ca2+, Mg(2+)-ATPase. However, diethyldithio-carbamate, a metabolite of DS, failed to modify Ca2+, Mg(2+)-ATPase activity, implying that the decrease in ATPase activity in DS administered rats was due to the effect of parent compound. The DS-mediated inhibition (48%) of ATPase activity was comparable with a similar degree of inhibition (49%) achieved by treating the synaptosomal membranes with N-ethylmaleimide (ID50 = 20 microM) in vitro. Furthermore, the inhibition by DS was neither altered by washing the membranes with EGTA nor reversed by treatment with sulfhydryl reagents such as GSH or dithiothreitol. About 74% and 68% decrease of synaptosomal Ca2+, Mg(2+)-ATPase specific activity was observed when treated with DS (30 microM) and EGTA (100 microM) respectively. The remaining 25-30% of total activity is suggested to be of Mg(2+)-dependent ATPase activity. This indicates that both these drugs may act on a common target, calmodulin component that represents 70-75% of total Ca2+, Mg(2+)-ATPase activity. Therefore, DS-mediated modulation of synaptosomal Ca2+, Mg(2+)-ATPase activity could affect its function of maintaining intracellular Ca2+ concentration. This could contribute to the deleterious effects on CNS.

Animals↗

PubMed1994

Sodium valproate induced alterations in monoamine levels in different regions of the rat brain.

Sodium valproate is a well established anticonvulsant drug but its exact mode of action is not yet clear. With a view to find out whether the mechanism of action of sodium valproate is mediated by alteration in monoamine levels, apart from GABA, in brain, sodium valproate (200 mg/kg body wt) was administered i.p. to male adult Wistar rats for 45 days. The levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were assayed in different brain regions using high performance liquid chromatographic (HPLC) method. It was noted that at the end of the experimental period there was no change in body or brain weight nor were there any neurological deficits as a result of sodium valproate administration. However, after administration of sodium valproate there was a significant increase in norepinephrine levels in hippocampus (P < 0.01) and brainstem (P < 0.01) while a significant decrease was noted in hypothalamus (P < 0.001). Dopamine levels were significantly increased in motor cortex (P < 0.01), hippocampus (P < 0.01) and hypothalamus (P < 0.001). Serotonin levels were significantly increased in striatum-accumbens and brain stem (P < 0.001). However a marginal increase was also observed in motor cortex and hippocampus. 5-HT levels were significantly decreased in hypothalamus (P < 0.001) and cerebellum (P < 0.01). The present findings suggest the possibility that the anticonvulsant effect of sodium valproate could be due to alterations in monoamine levels apart from its action on GABA, which would indicate also the efficacy of this drug in different types of seizures.

Animals↗