Papers by Basalingappa Hungund
PloS one, 2012
While the etiology of depression is not clearly understood at the present time, this mental disor... more While the etiology of depression is not clearly understood at the present time, this mental disorder is thought be a complex and multifactorial trait with important genetic and environmental contributing factors. The role of the endocannabinoid (eCB) system in depressive behavior was examined in Wistar Kyoto (WKY) rat strain, a genetic model of depression. Our findings revealed selective abnormalities in the eCB system in the brains of WKY rats compared to Wistar (WIS) rats. Immunoblot analysis indicated significantly higher levels of fatty acid amide hydrolase (FAAH) in frontal cortex and hippocampus of WKY rats with no alteration in the level of N-arachidonyl phosphatidyl ethanolamine specific phospholipase-D (NAPE-PLD). Significantly higher levels of CB1 receptor-mediated G-protein coupling and lower levels of anandamide (AEA) were found in frontal cortex and hippocampus of WKY rats. While the levels of brain derived neurotropic factor (BDNF) were significantly lower in frontal c...
Neurochemistry international, 2006
The present study investigated the effect of ethanol (EtOH) exposure and its withdrawal on the ce... more The present study investigated the effect of ethanol (EtOH) exposure and its withdrawal on the central endocannabinoid system utilizing an EtOH vapor inhalation model, which is known to produce functional tolerance and dependence to EtOH. Swiss Webster mice (n=24) were exposed to EtOH vapors for 72h. Mice were sacrificed after 72h following EtOH exposure (n=12) and 24h after its withdrawal (n=12). Radioligand binding assays were performed to measure the density of CB(1) receptor and CB(1) receptor agonist-stimulated [(35)S]GTPgammaS binding in crude synaptic membranes isolated from the cortex, hippocampus, striatum and cerebellum. The density of CB(1) receptor was significantly decreased (31-39%) in all the brain regions when compared to the control group. The CB(1) receptor-stimulated G(i/o) protein activation was also found to be decreased (29-40%) in these brain regions of EtOH exposed mice. Recovery of the CB(1) receptor density, in addition to, the CB(1) receptor-mediated G-pro...
The Open Neuropsychopharmacology Journal, 2009
Marijuana is the most commonly abused illicit drug by pregnant women in the world. Its psychoacti... more Marijuana is the most commonly abused illicit drug by pregnant women in the world. Its psychoactive cannabinoid, 9 -tetrahydrocannabinol, crosses the placenta and accumulates in the fetus, potentially harming its development. In humans, marijuana use in early pregnancy is associated with an increased risk for miscarriage, anencephaly, as well as subtle neurodevelopmental defects in the offspring, including ADHD, psychiatric
Trends in Pharmacological Sciences, 2006
Depression is one of the most prevalent forms of neuropsychiatric disorder and is a major cause o... more Depression is one of the most prevalent forms of neuropsychiatric disorder and is a major cause of suicide worldwide. The prefrontal cortex is a crucial brain region that is thought to be involved in the regulation of mood, aggression and/or impulsivity and decision making, which are altered in suicidality. Evidence of the role of the endocannabinoid (EC) system in the neurobiology of neuropsychiatric disorders is beginning to emerge. The behavioral effects of ECs are believed to be mediated through the central cannabinoid CB 1 receptor. Alterations in the levels of ECs, and in the density and coupling efficacy of CB 1 receptors, have been reported in the prefrontal cortex of depressed and alcoholic suicide victims. These findings support our hypothesis that altered EC function contributes to the pathophysiological aspects of suicidal behavior. Here, we provide a brief overview of the role of the EC system in alcoholism, depression and suicide, and discuss possible therapeutic interventions and directions for future research.
The FASEB Journal, 2007
The endocannabinoid system is an important regulator of hepatic fibrogenesis. In this study, we d... more The endocannabinoid system is an important regulator of hepatic fibrogenesis. In this study, we determined the effects of 2-arachidonoyl glycerol (2-AG) on hepatic stellate cells (HSCs), the main fibrogenic cell type in the liver. Culture-activated HSCs were highly susceptible to 2-AG-induced cell death with >50% cell death at 10 M after 18 h of treatment.
Psychopharmacology, 1982
The relationship between methylphenidate (MP) oral dose and plasma concentration to social and co... more The relationship between methylphenidate (MP) oral dose and plasma concentration to social and cognitive behaviors was studied in 25 boys diagnosed as having "attention deficit disorder with hyperactivity". Children were administered successive 1-week treatment conditions under the following schedule of fixed oral doses given twice daily: placebo; 0.25 mg/kg; 0.50 mg/kg; 1.0 mg/kg; placebo. Teacher and parent ratings showed increased improvement in social behavior as a function of MP dose. No drug effects were obtained on cognitive performance. MP plasma concentrations were significantly associated with oral dose and with measures of social behavior. No relationship was found with cognitive behavior. Side effects at the largest dose were severe enough to require discontinuation of treatment for five children, but were relatively mild for the remaining children.
Neuropharmacology, 2006
Previous studies have shown that mice lacking cannabinoid (CB1) receptor gene consume markedly re... more Previous studies have shown that mice lacking cannabinoid (CB1) receptor gene consume markedly reduced levels of ethanol. Mice lacking the enzyme fatty acid amidohydrolase (FAAH) are severely impaired in their ability to degrade anandamide (AEA) and therefore represent a unique animal model in which to examine the function of AEA in vivo on ethanol-drinking behavior. In the current study, FAAH ÿ/ÿ mice were tested for ethanol, saccharin or quinine consumption and preference. Ethanol-induced hypothermia, and sleep time were used to evaluate the sensitivity to acute effects of ethanol. Ethanol intake and preference were increased only in female FAAH ÿ/ÿ mice. No significant difference in saccharin or quinine consumption or preference was observed between genotypes. Female FAAH ÿ/ÿ mice were less sensitive to the hypothermic and sedative/hypnotic effects of acute ethanol. Supersensitivity to exogenous AEA was noted in both male and female FAAH ÿ/ÿ mice. Following voluntary ethanol consumption, CB1 receptor levels and function were down-regulated in male FAAH þ/þ , FAAH ÿ/ÿ , and female FAAH þ/þ mice but not in female FAAH ÿ/ÿ mice. Our results suggest that absence of an effect in male mice indicates a sex-linked mechanism that is secondary (or modulatory) to FAAH function. Thus, the data suggest that FAAH may be indirectly related to ethanol intake and sensitivity and central endocannabinoidergic-mediated pathways may regulate ethanol consumption.
Neurochemistry International, 1994
The adaptation (tolerance) to chronic EtOH exposure was explained by the development of resistanc... more The adaptation (tolerance) to chronic EtOH exposure was explained by the development of resistance to the disordering of the membrane phospholipids (PL). This phenomenon may be associated with changes in enzymes such as phospholipase A2 (PLA2) that govern PL metabolism. The data presented here, using the mouse inhalation model, supports and confirms previously reported findings that chronic exposure to EtOH substantially increased PLA2 activity in synaptosomal preparations from rat brain. We have previously reported that pretreatment with ganglioside GM1 reduced the intoxicating effect of EtOH in mice. The present study indicates that GMI pretreatment both & vivo and in vitro reduced the EtOHinduced activation of PLA2 in synaptosomal preparations. Thus GM 1 may exert its neuroprotective effects by influencing deacylation/reacylation of membrane phospholipids.
Neurobiology of Aging, 2004
Aberrant phosphorylation of the neuronal cytoskeleton is an early pathological event in Alzheimer... more Aberrant phosphorylation of the neuronal cytoskeleton is an early pathological event in Alzheimer's disease (AD), but the underlying mechanisms are unclear. Here, we demonstrate in the brains of AD patients that neurofilament hyperphosphorylation in neocortical pyramidal neurons is accompanied by activation of both Erk1,2 and calpain. Using immunochemistry, Western blot analysis, and kinase activity measurements, we show in primary hippocampal and cerebellar granule (CG) neurons that calcium influx activates calpain and Erk1,2 and increases neurofilament phosphorylation on carboxy terminal polypeptide sites known to be modulated by Erk1,2 and to be altered in AD. Blocking Erk1,2 activity either with antisense oligonucleotides to Erk1,2 mRNA sequences or by specifically inhibiting its upstream activating kinase MEK1,2 markedly reduced neurofilament phosphorylation. Calpeptin, a cell-permeable calpain inhibitor, blocked both Erk1,2 activation and neurofilament hyperphosphorylation at concentrations that inhibit calpain-mediated cleavage of brain spectrin. By contrast, inhibiting Erk1,2 with U-0126, a specific inhibitor of Mek1,2, had no appreciable effect on ionomycin-induced calpain activation. These findings demonstrate that, under conditions of calcium injury in neurons, calpains are upstream activators of Erk1,2 signaling and are likely to mediate in part the hyperphosphorylation of neurofilaments and tau seen at early stages of AD as well as the neuron survival-related functions of the MAP kinase pathway.
![Research paper thumbnail of Upregulation of CB1 receptors and agonist-stimulated [35S]GTPγS binding in the prefrontal cortex of depressed suicide victims](https://a.academia-assets.com/images/blank-paper.jpg)
Molecular Psychiatry, 2004
Endogenous and exogenous cannabinoids (CBs) acting through the CB(1) receptors have been implicat... more Endogenous and exogenous cannabinoids (CBs) acting through the CB(1) receptors have been implicated in the regulation of several behavioral and neuroendocrine functions. Modulation of endocannabinoidergic system by ethanol in mouse brain, and the association of suicide and mood disorders with alcoholism suggest possible involvement of the cannabinoidergic system in the pathophysiology of depression and suicide. Therefore, the present study was undertaken to examine the levels of CB(1) receptors and mediated signaling in the dorsolateral prefrontal cortex (DLPFC) of subjects with major depression who had died by suicides (depressed suicides, DS). [(3)H]CP-55,940 and CB(1) receptor-stimulated [(35)S]GTPgammaS binding sites were analyzed in membranes obtained from DLPFC of DS (10) and matched normal controls (10). Upregulation (24%, P<0.0001) of CB(1) receptor density (B(max)) was observed in DS (644.6+/-48.8 fmol/mg protein) compared with matched controls (493.3+/-52.7 fmol/mg protein). However, there was no significant alteration in the affinity of receptor (DS; 1.14+/-0.08 vs control; 1.12+/-0.10 nM). Higher density of CB(1) receptors in DS (38%, P<0.001) was also demonstrated by Western blot analysis. The CB(1) receptor-stimulated [(35)S]GTPgammaS binding was significantly greater (45%, P<0.001) in the DLPFC of DS compared with matched controls. The observed upregulation of CB(1) receptors with concomitant increase in the CB(1) receptor-mediated [(35)S]GTPgammaS binding suggests a role for enhanced cannabinoidergic signaling in the prefrontal cortex of DS. The cannabinoidergic system may be a novel therapeutic target in the treatment of depression and/or suicidal behavior.
Journal of Neurochemistry, 2003
The mechanisms underlying predisposition to alcohol abuse and alcoholism are poorly understood. I... more The mechanisms underlying predisposition to alcohol abuse and alcoholism are poorly understood. In this study, we evaluated the role of cannabinoid (CB1) receptors in (i) voluntary alcohol consumption, and (ii) acute alcohol-induced dopamine (DA) release in the nucleus accumbens, using mice that lack the CB1 receptor gene (CB1 -/-). CB1 -/mice exhibited dramatically reduced voluntary alcohol consumption, and completely lacked alcohol-induced DA release in the nucleus accumbens, as compared to wild-type mice. The gender difference, with female mice consuming significantly more alcohol than wild-type male mice, was observed in wild-type mice, whereas this gender difference was nonexist-ent in CB1 mutant male and female mice. There was also a significant gender difference, with the wild-type, heterozygous, and mutant females consuming significantly more liquid and food than wild-type, heterozygous and mutant males. However, the total volume of fluid consumption and food intake did not differ between wild-type, heterozygous, and mutant mice. These results strongly suggest that the CB1 receptor system plays an important role in regulating the positive reinforcing properties of alcohol.
Journal of Molecular Neuroscience, 1999
N-acetyl-L-aspartate (NAA) is an important osmolyte in the vertebrate brain and eye, and its cycl... more N-acetyl-L-aspartate (NAA) is an important osmolyte in the vertebrate brain and eye, and its cyclical metabolism is accomplished in two separate compartments. In the brain, NAA is synthesized primarily in neurons, and after its regulated release, NAA is hydrolyzed by aspartoacylase, which is present in a glial-associated compartment. However, the precise nature of this hydrolytic compartment has remained obscure. It has been proposed that one role of aspartoacylase in the central nervous system (CNS) is as part of a molecular water pump (MWP) that uses the NAA intercompartmental cycle to remove nerve cell metabolic water against a water gradient and that oligodendrocytes comprise the second compartment in this metabolic sequence. The absence of aspartoacylase activity in Canavan disease (CD), a rare early onset genetic spongiform leukodystrophy, is associated with CNS edema, intramyelinic swelling and a progressive loss of oligdendrocytes. In order to evaluate the MWP hypothesis and its possible relationship to the etiology of CD further, both oligodendrocytes and astrocytes obtained from neonatal rat brain were grown in culture and tested for the presence of aspartoacylase activity. The results of this study show for the first time that aspartoacylase activity is expressed only in oligodendrocytes. The meaning of this observation in understanding the function of the NAA metabolic cycle is discussed.
Journal of Molecular Neuroscience, 2005
N-acetylaspartylglutamate (NAAG), a dipeptide derivative of N-acetylaspartate (NAA) and glutamate... more N-acetylaspartylglutamate (NAAG), a dipeptide derivative of N-acetylaspartate (NAA) and glutamate (Glu), is present in neurons. Upon neurostimulation, NAAG is exported to astrocytes where it activates a specific metabotropic Glu surface receptor (mGluR3), and is then hydrolyzed by an astrocyte-specific enzyme, NAAG peptidase, liberating Glu, which can then be taken up by the astrocyte. NAAG is a selective mGluR3 agonist, one of several mGluRs that, when activated, triggers Ca 2+ waves that spread to astrocytic endfeet in contact with the vascular system, where a secondary release of vasoactive agents induces a focal hyperemic response providing increased oxygen and nutrient availability to the stimulated neurons. Changes in blood oxygen levels can be assessed in vivo using a blood oxygenation level-dependent (BOLD) magnetic resonance imaging technique that reflects a paramagnetic effect of deoxyhemoglobin. In this study we used the competitive NAAG peptidase inhibitor 2-(phosphonomethyl) pentanedioic acid (2-PMPA) as a probe to interrupt the NAAG-mGluR3-Glu-astrocyte Ca 2+ activation sequence. Using this probe, we investigated the relationship between release of the endogenous neuropeptide NAAG and brain blood oxygenation levels, as measured by changes in BOLD signals. In an anesthetized mouse, using an overtly nontoxic dose of 2-PMPA of 250 mg/kg i.p., there was an initial global BOLD signal increase of about 3% above control, lasting about 4 min, followed by a decrease from control of about 4%, sustained over a 32.5-min period of the drug test procedure. Similar changes, but of reduced magnitude and duration, were observed at a dose of 167 mg/kg. The 2-PMPA-induced decreases in BOLD signals appear to indicate that blood deoxyhemoglobin is elevated when endogenous NAAG cannot be hydrolyzed, thus linking the efflux of NAAG from neurons and its hydrolysis by astrocytes to hyperemic oxygenation responses in brain.
Journal of Hepatology, 2007
04C. MOLECULAR AND CELLULAR BIOLOGY ~ C) HSCs AND FIBROSIS S133 control levels (HSC with L..obtus... more 04C. MOLECULAR AND CELLULAR BIOLOGY ~ C) HSCs AND FIBROSIS S133 control levels (HSC with L..obtusiloba alone). One XAD resolved fraction showed antifibrotic activity. t-butylhydroperoxide-induced ROS production in HSC was neutralized by the addition of non-toxic concentration of the L.obtusiloba extract. Conclusions: Aqueous extracts of L. obtusiloba exhibit direct anti-fibrotic but no toxic or apoptotic effects by inhibiting proliferation and collagen synthesis as well as ROS production of activated HSC. Our data suggest that L.obtusiloba may directly target TGF-beta induced fibrosis.
Expert Opinion on Therapeutic Targets, 2006
ABSTRACT G-protein-coupled receptor (GPCR)-mediated signalling is the most widely used signalling... more ABSTRACT G-protein-coupled receptor (GPCR)-mediated signalling is the most widely used signalling mechanism in cells, and its regulation is important for various physiological functions. The cannabinoid-1 (CB(1)) receptor, a GPCR, has been shown to play a critical role in neural circuitries mediating motivation, mood and emotional behaviours. Several recent studies have indicated that impairment of CB(1) receptor-mediated signalling may play a critical role in the pathophysiology of various neuropsychiatric disorders. In this article, the authors briefly review literature relating to the role played by the endocannabinoid system in various neuropsychiatric disorders, and the CB(1) receptor as a potential therapeutic target for the treatment of alcoholism, depression, anxiety and schizophrenia.
European Journal of Pharmacology, 2003
Ethanol increases extracellular anandamide levels in neuronal cells. However, the molecular mecha... more Ethanol increases extracellular anandamide levels in neuronal cells. However, the molecular mechanisms by which this occurs are unknown. Chronic exposure of cerebellar granule neurons to ethanol increased the levels of anandamide accumulated in the cellular medium. Anandamide uptake was saturable and was inhibited (30% at 3 min) in response to chronic exposure to ethanol. Chronic ethanol treatment did not alter the K(m), but significantly decreased V(max) of anandamide transport (33%) (P<0.0001). Fatty acid amide hydrolase activity was not affected by chronic ethanol treatment. Anandamide transport processes are independent of cannabinoid CB1 receptor, as cannabinoid CB1 receptor knockout mice exhibited time-dependent anandamide transport and cannabinoid CB1 receptor antagonists did not alter the effects of chronic ethanol on anandamide transport. Furthermore, anandamide transport was inhibited by acute ethanol in a time- and dose-dependent manner. Interestingly, acute ethanol-induced inhibition of anandamide transport was abolished in neurons exposed to chronic ethanol, suggesting that the anandamide transport processes may play a role in the development of long-term cellular tolerance to ethanol.
Drug Development Research, 1990
Hlungund, B.L., M.V. Reddy, V.A. Bharucha, and S.P. Mahadik: Monosialogangliosides (GM1 and AGF2)... more Hlungund, B.L., M.V. Reddy, V.A. Bharucha, and S.P. Mahadik: Monosialogangliosides (GM1 and AGF2) reduce acute ethanol intoxication: Sleep time, mortality, and cerebral cortical Na+, K+-ATPase. Drug Dev. Res. 19:443-451, 1989.
Drug Development Research, 1991
Hungund, B.L., V.S. Gokhale, T.B. Cooper, and S.P. Mahadik: Prenatal ganglioside GM1 treatment pr... more Hungund, B.L., V.S. Gokhale, T.B. Cooper, and S.P. Mahadik: Prenatal ganglioside GM1 treatment protects ethanol-induced sleep time in rats exposed to ethanol in utero during gestation days 7 and 8. Drug Dev. Res. 24:261-267, 1991. Pregnant rats were treated with ethanol intragastrically (5.8 g/kg in two divided doses) spaced 4 hr apart on gestation days (GD) 7 and 8. Ganglioside GM1 was injected (10 mg/kg, IM) 24 hr and 1 hr prior to ethanol on GD7 and 1 hr prior on GD8. The controls received saline only. Maternal blood alcohol reached peak levels of 4.3 rng/ml within 2 hr in both groups. There were no significant differences between the groups gain body weight, gestation time, or the litter size. There were also no significant differences in birth weight and the brain weight of the pups. At the age of 45 days, equal number of male offspring from each group were tested for hypnotic effect (sleep time) of ethanol challenge dose (3.5 g/kg). Animals that received ethanol alone in utero had a shorter sleep time compared to no ethanol controls (81 r 19 and 130 -C 28 min respectively, R . 0 1 ) . Ganglioside GM1 treated animals had sleep time similar to that of controls (131 ? 21 min). There were no significant differences in wakeup blood alcohol between the groups. These results indicate that pretreatment with GMI ganglioside of maternal rats antagonized decrease in sleep time in offspring induced by prenatal ethanol exposure.
Brain Research, 1998
The effects of chronic ethanol (EtOH) consumption on the central nervous system may be related in... more The effects of chronic ethanol (EtOH) consumption on the central nervous system may be related in part to its action on biological membranes by altering various receptor functions. In the current study, we examined the effects of chronic EtOH (4 day inhalation) on cannabinoid receptors (CB1) labeled with [3H]CP55,940 in synaptic plasma membranes (SPM) isolated from mouse brain. Our results indicate the presence of a high level of CB1 receptors in controls (Bmax=12.0+/-0.3 pmol mg-1 protein) which decreased significantly (-58%) in SPM from mouse brain chronically exposed to EtOH. This effect occurs without any changes in the receptor affinity (Kd=2. 3+/-0.3 nM for control and 2.9+/-0.3 nM for EtOH group, P>0.05). Dissociation kinetic results showed a dissociation rate constant (K-1) of 0.09+/-0.01 min-1 for control and this dissociation rate constant decreased significantly in the chronic EtOH treated mice brain (0.05+/-0.01 min-1, P<0.05). The competition studies with anandamide resulted in a substantial decrease in [3H]CP55,940 binding in both the control and EtOH group, with a decrease (P<0.05) in the Ki values in the SPM of chronic EtOH exposed mice. Hill transformation analysis showed an nH close to one in control (0. 92+/-0.01). This did not change significantly after chronic EtOH (0. 95+/-0.01) administration, which indicates the existence of a single class of receptor for [3H]CP55,940 binding in SPM from control and EtOH treated mice. The observed down-regulation of CB1 receptors by chronic EtOH may indicate the involvement of cannabinoid receptors in EtOH tolerance and dependence.
Birth Defects Research Part B: Developmental and Reproductive Toxicology, 2008
Marijuana is the most commonly abused illicit drug by pregnant women. Its major psychoactive cons... more Marijuana is the most commonly abused illicit drug by pregnant women. Its major psychoactive constituent, Delta(9)-THC (Delta(9)-tetrahydrocannabinol), crosses the placenta and accumulates in the foetus, potentially harming its development. In humans, marijuana use in early pregnancy is associated with miscarriage, a fetal alcohol-like syndrome, as well as learning disabilities, memory impairment, and ADHD in the offspring. Classical studies in the 1970 s have reached disparate conclusions as to the teratogenic effects of cannabinoids in animal models. Further, there is very little known about the immediate effects of Delta(9)-THC on early embryogenesis. We have used the chick embryo as a model in order to characterize the effects of a water-soluble Delta(9)-THC analogue, O-2545, on early development. Embryos were exposed to the drug (0.035 to 0.35 mg/ml) at gastrulation and assessed for morphological defects at stages equivalent to 9-14 somites. We report that O-2545 impairs the formation of brain, heart, somite, and spinal cord primordia. Shorter incubation times following exposure to the drug show that O-2545 interferes with the initial steps of head process and neural plate formation. Our results indicate that the administration of the cannabinoid O-2545 during early embryogenesis results in embryotoxic effects and serves to illuminate the risks of marijuana exposure during the second week of pregnancy, a time point at which most women are unaware of their pregnancies.
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Papers by Basalingappa Hungund