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Increased ethanol consumption and preference and decreased ethanol sensitivity in female FAAH knockout mice

Basavarajappa, Balapal S; Yalamanchili, Ratnakumar; Cravatt, Benjamin F; Cooper, Thomas B; Hungund, Basalingappa L
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(-/-) 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(-/-) mice. No significant difference in saccharin or quinine consumption or preference was observed between genotypes. Female FAAH(-/-) 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(-/-) mice. Following voluntary ethanol consumption, CB1 receptor levels and function were down-regulated in male FAAH(+/+), FAAH(-/-), and female FAAH(+/+) mice but not in female FAAH(-/-) 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
PMID: 16448676
ISSN: 0028-3908
CID: 137702

Role of the endocannabinoid system in the development of tolerance to alcohol

Basavarajappa, Balapal S; Hungund, Basalingappa L
The present review evaluates the evidence that the endocannabinoid system plays in the development of tolerance to alcohol. The identification of a G-protein-coupled receptor, namely, the cannabinoid receptor (CB(1) receptor), which was activated by Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive component of marijuana, led to the discovery of endogenous cannabinoid agonists. Until now, four fatty acid derivatives identified to be arachidonylethanolamide (AEA), 2-arachidonylglycerol (2-AG), 2-arachidonylglycerol ether (noladin ether) and virodhamine have been isolated from both nervous and peripheral tissues. Both AEA and 2-AG have been shown to mimic the pharmacological and behavioural effects of Delta(9)-THC. The role of the endocannabinoid system in the development of tolerance to alcohol was not known until recently. Recent studies from our laboratory have implicated for the first time a role for the endocannabinoid system in development of tolerance to alcohol. Chronic alcohol treatment has been shown to down-regulate CB(1) receptors and its signal transduction. The observed downregulation of CB(1) receptor function results from the persistent stimulation of the receptors by AEA and 2-AG, the synthesis of which has been shown to be increased by chronic alcohol treatment. The enhanced formation of endocannabinoids may subsequently influence the release of neurotransmitters. It was found that the DBA/2 mice, known to avoid alcohol intake, have significantly reduced CB(1) receptor function in the brain, consistent with other studies in which the CB(1) receptor antagonist SR 141716A has been shown to block voluntary alcohol intake in rodents. Similarly, activation of the CB(1) receptor system promoted alcohol craving, suggesting a role for the CB(1) receptor gene in excessive alcohol drinking behaviour and development of alcoholism. Ongoing investigations may lead to a better understanding of the mechanisms underlying the development of tolerance to alcohol and to develop therapeutic strategies to treat alcoholism.
PMID: 15550443
ISSN: 0735-0414
CID: 4142152

Role of endocannabinoids and cannabinoid CB1 receptors in alcohol-related behaviors

Hungund, Basalingappa L; Basavarajappa, Balapal S
This review presents the remarkable research during the past several years indicating that some of the pharmacological and behavioral effects of alcohol, including alcohol drinking and alcohol-preferring behavior, are mediated through one of the most abundant neurochemical systems in the central nervous system, the endocannabinoid signaling system. The advances, with the discovery of specific receptors and the existence of naturally occurring cannabis-like substances in the mammalian system and brain, have helped in understanding the neurobiological basis for drugs of abuse, including alcoholism. The cDNA and genomic sequences encoding G-protein-coupled cannabinoid receptors (CB1 and CB2) from several species have now been cloned. This has facilitated discoveries of endogenous ligands (endocannabinoids). To date, two fatty acid derivatives characterized to be arachidonylethanolamide and 2-arachidonylglycerol have been isolated from both nervous and peripheral tissues. Both these compounds have been shown to mimic the pharmacological and behavioral effects of Delta9-tetrahydrocannabinol, the psychoactive component of marijuana. The involvement of the endocannabinoid signaling system in tolerance development to drugs of abuse, including alcohol, were unknown until recently. Studies from our laboratory demonstrated for the first time the downregulation of CB1 receptor function and its signal transduction by chronic alcohol. The observed downregulation of CB1 receptor binding and its signal transduction results from the persistent stimulation of receptors by the endogenous CB1 receptor agonists arachidonylethanolamide and 2-arachidonylglycerol, the synthesis of which is increased by chronic alcohol treatment. The deletion of CB1 receptor has recently been shown to block voluntary alcohol intake in mice, which is consistent with our previous findings where the DBA/2 mice known to avoid alcohol intake had significantly reduced brain CB1 receptor function. These findings suggest a role for the CB1 receptor gene in excessive alcohol drinking behavior and development of alcoholism. Ongoing investigations may lead to the development of potential therapeutic agents to modulate the endocannabinoid signaling system, which will be helpful for the treatment of alcoholism.
PMID: 15542757
ISSN: 0077-8923
CID: 4142142

Calpain mediates calcium-induced activation of the erk1,2 MAPK pathway and cytoskeletal phosphorylation in neurons: relevance to Alzheimer's disease

Veeranna; Kaji T; Boland B; Odrljin T; Mohan P; Basavarajappa BS; Peterhoff C; Cataldo A; Rudnicki A; Amin N; Li BS; Pant HC; Hungund BL; Arancio O; Nixon RA
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
PMCID:1618589
PMID: 15331404
ISSN: 0002-9440
CID: 46128

Calpain mediates calcium-induced activation of the ERK 1,2 MAPK pathway and cytoskeletal phosphorylation in neurons: Relevance to Alzheimer's disease [Meeting Abstract]

Veeranna; Kaji, T; Boland, B; Odrljin, T; Mohan, P; Basavarajappa, BS; Peterhoff, C; Cataldo, AM; Rudnicki, A; Li, BS; Pant, HC; Hungund, BL; Arancio, O; Nixon, RA
ISI:000223058700583
ISSN: 0197-4580
CID: 47723

Upregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS binding in the prefrontal cortex of depressed suicide victims

Hungund, B L; Vinod, K Y; Kassir, S A; Basavarajappa, B S; Yalamanchili, R; Cooper, T B; Mann, J J; Arango, V
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
PMID: 14966476
ISSN: 1359-4184
CID: 137550

Chronic ethanol inhibits the anandamide transport and increases extracellular anandamide levels in cerebellar granule neurons

Basavarajappa, Balapal S; Saito, Mariko; Cooper, Thomas B; Hungund, Basalingappa L
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
PMID: 12679143
ISSN: 0014-2999
CID: 58086

Nitrate and fluoride levels in ground waters of Davanagere Taluka in Karnataka

Manjappa, S; Basavarajappa, B E; Desai, G P; Hotanahalli, S S; Aravinda, H B
The quality of ground water supplies in Davanagere Taluk, situated in central part of Karnataka has been investigated with respect to pH, dissolved solids, chlorides, nitrates and fluorides. The levels of pH, dissolved solids and chlorides were found within the safe limits as prescribed by BIS, for more than 95% of the samples. Out of the 61 different borewell samples analysed, selected from different areas of Davanagere taluk, 26% of the samples are found to contain fluorides less than 0.50 PPM (lower safe limit prescribed by BIS) and 11.5% of the samples are found to contain more than 1.5 PPM of fluorides (higher safe limit prescribed by BIS). Further, it was also found during study that, 16.00% of the borewell samples analyzed, were found to contain more than 100.00 PPM of nitrates (measured as NO3 mg/L, safe limit prescribed by BIS). The values of fluorides and nitrates observed in different samples were in the range of 0.19 - 2.06 PPM and 0.08 - 308 PPM, respectively.
PMID: 15270349
ISSN: 0367-827x
CID: 4142132

Cannabinoid CB1 receptor knockout mice exhibit markedly reduced voluntary alcohol consumption and lack alcohol-induced dopamine release in the nucleus accumbens

Hungund, Basalingappa L; Szakall, Istvan; Adam, Agota; Basavarajappa, Balapal S; Vadasz, Csaba
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 nonexistent 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
PMID: 12562514
ISSN: 0022-3042
CID: 94003

Ethanol, endocannabinoids, and the cannabinoidergic signaling system

Hungund, Basalingappa L; Basavarajappa, Balapal S; Vadasz, Csaba; Kunos, George; Rodriguez de Fonseca, Fernando; Colombo, Giancarlo; Serra, Salvatore; Parsons, Loren; Koob, George F
This article represents the proceedings of a symposium at the 2001 annual meeting of the Research Society on Alcoholism in Montreal, Canada. The chairpersons were Appa Hungund and George Koob. The presentations were (1) Role of endocannabinoids in ethanol tolerance, by Appa Hungund; (2) Modulation of cannabinoid receptor and its signal transduction in chronic alcoholism, by B. S. Basavarajappa; (3) Endocannabinoid involvement in the control of appetitive behavior, by George Kunos; (4) Regulation of voluntary ethanol intake by cannabinoid receptor agonists and antagonists in alcohol-preferring sP rats, by Giancarlo Colombo; (5) Role of endogenous cannabinoid system in alcoholism, by Fernado Rodriguez de Fonseca; and (6) Endocannabinoids and dopamine interactions in vivo, by Loren Parsons and George Koob
PMID: 11981134
ISSN: 0145-6008
CID: 32464