The dorsal striatum expressing adenylyl cyclase-5 controls behavioral sensitivity of the righting reflex to high-dose ethanol

Kim, Kyoung Shim; Kim, Hannah; Park, Sun-Kyu; Han, Pyung Lim

doi:10.1016/j.brainres.2012.10.016

Cited by 10 publications

(8 citation statements)

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“…A recent study showed that alcohol-induced LORR is controlled by aCaMKII-bearing neurons in the dorsal striatum (Kim et al, 2012). Here we report that the sedative properties of a high dose of alcohol were not affected by a deficit in aCaMKII autophosphorylation.…”

Section: Discussionmentioning

confidence: 46%

“…Although little is known about the role in alcohol addiction, alcohol affects CaMKII levels in the brain (Smith and Navratilova, 1999;McBride et al, 2009;Mahadev et al, 2001;Lee et al, 2011) and increases phosphorylation rate at Thr286 (Garic et al, 2011;Wang et al, 2012). Both may control alcohol effects on cellular signaling (Liu et al, 2006;Xu et al, 2008), behavior (Kim et al, 2012;Wang et al, 2012), and neurotoxicity (Garic et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

Easton

Lucchesi

Lourdusamy

et al. 2013

Neuropsychopharmacol

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The a-Ca 2 þ /calmodulin-dependent protein kinase II (aCaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of aCaMKII works as a 'molecular memory' for a transient calcium activation, thereby accelerating learning. We investigated the role of aCaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice. We found that alcohol drinking was initially diminished in aCaMKII autophosphorylation-deficient aCaMKII T286A mice, but could be established at wild-type level after repeated withdrawals. The locomotor activating effects of a low-dose alcohol (2 g/kg) were absent in aCaMKII T286A mice, whereas the sedating effects of high-dose (3.5 g/kg) were preserved after acute and subchronic administration. The in vivo microdialysis revealed that aCaMKII T286A mice showed no dopamine (DA) response in the nucleus accumbens to acute or subchronic alcohol administration, but enhanced serotonin (5-HT) responses in the prefrontal cortex. The attenuated DA response in aCaMKII T286A mice was in line with altered c-Fos activation in the ventral tegmental area after acute and subchronic alcohol administration. In order to compare findings in mice with the human condition, we tested 23 single-nucleotide polymorphisms (SNPs) in the CAMK2A gene for their association with alcohol dependence in a population of 1333 male patients with severe alcohol dependence and 939 controls. We found seven significant associations between CAMK2A SNPs and alcohol dependence, one of which in an autophosphorylation-related area of the gene. Together, our data suggest aCaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA-5-HT balance as a putative mechanism.

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Section: Discussionmentioning

confidence: 46%

Section: Introductionmentioning

confidence: 99%

αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

Easton

Lucchesi

Lourdusamy

et al. 2013

Neuropsychopharmacol

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“…Although the mechanisms of EtOH‐induced LORR are not completely understood, these results suggest that molecular events downstream of EtOH, ketamine, or pentobarbital direct action might be a site for nicotine enhancement of LORR from all 3 drugs. For example, both EtOH‐ and GABA A ‐agonist‐induced LORR were inhibited in mice lacking adenylyl cyclase type 5 (Kim et al., ). Further study of nicotine enhancement of EtOH, ketamine, and pentobarbital LORR might thus assist in identifying mechanisms of nicotine action on these sedative responses.…”

Section: Discussionmentioning

confidence: 99%

Nicotine Enhances the Hypnotic and Hypothermic Effects of Alcohol in the Mouse

Slater

Jackson

Muldoon

et al. 2016

Alcoholism Clin & Exp Res

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Background Ethanol and nicotine abuse are two leading causes of preventable mortality in the world, but little is known about the pharmacological mechanisms mediating co-abuse. Few studies have examined the interaction of the acute effects of ethanol and nicotine. Here, we examine the effects of nicotine administration on the duration of ethanol-induced loss of righting reflex (LORR) and characterize the nature of their pharmacological interactions in C57BL/6J mice. Methods We assessed the effects of ethanol and nicotine and the nature of their interaction in the LORR test using isobolographic analysis after acute injection in C57BL/6J male mice. Next, we examined the importance of receptor efficacy using nicotinic partial agonists varenicline and sazetidine. We evaluated the involvement of major nAChR subtypes using nicotinic antagonist mecamylamine and nicotinic α4 and α7 knockout mice. The selectivity of nicotine’s actions on ethanol-induced LORR was examined by testing nicotine’s effects on the hypnotic properties of ketamine and pentobarbital. We also assessed the development of tolerance after repeated nicotine exposure. Lastly, we assessed if the effects of nicotine on ethanol-induced LORR extends to hypothermia and ethanol intake in the Drinking in the Dark (DID) paradigm. Results We found that acute nicotine injection enhances ethanol’s hypnotic effects in a synergistic manner and that receptor efficacy plays an important role in this interaction. Furthermore, tolerance developed to the enhancement of ethanol’s hypnotic effects by nicotine after repeated exposure of the drug. α4* and α7 nAChRs seem to play an important role in nicotine-ethanol interaction in the LORR test. In addition, the magnitude of ethanol-induced LORR enhancement by nicotine was more pronounced in C57BL/6J than DBA/2J mice. Furthermore, acute nicotine enhanced ketamine and pentobarbital hypnotic effects in the mouse. Finally, nicotine enhanced ethanol-induced hypothermia but decreased ethanol intake in the DID test. Conclusion Our results demonstrate that nicotine synergistically enhances ethanol-induced LORR in the mouse.

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“…Adenylyl cyclase type 5 (AC5) is preferentially expressed in the dorsal striatum and nucleus accumbens along with broad expression, to a lesser extent, in the other brain regions including the prefrontal cortex [ 23 , 24 ]. Owing to its essential function as an effector for multiple receptors and as a regulator for cAMP-signaling signaling cascades in various brain regions, AC5 KO mice are resistant to the haloperidol actions [ 23 ], morphine actions [ 25 ], ethanol effects [ 26 , 27 ], and L-DOPA-induced dyskinesia [ 28 ], and show reduced anxiety [ 29 ] and reduced pain responses [ 30 ], but they are highly sensitive to stress [ 31 ]. Thus, AC5 is a key component in the striatum and prefrontal cortex, and so functions as a gate-keeper in various cognitive and emotional behaviors.…”

Section: Introductionmentioning

confidence: 99%

Adenylyl cyclase-5 in the dorsal striatum function as a molecular switch for the generation of behavioral preferences for cue-directed food choices

Kim

et al. 2014

Mol Brain

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BackgroundBehavioral choices in habits and innate behaviors occur automatically in the absence of conscious selection. These behaviors are not easily modified by learning. Similar types of behaviors also occur in various mental illnesses including drug addiction, obsessive-compulsive disorder, schizophrenia, and autism. However, underlying mechanisms are not clearly understood. In the present study, we investigated the molecular mechanisms regulating unconditioned preferred behaviors in food-choices.ResultsMice lacking adenylyl cyclase-5 (AC5 KO mice), which is preferentially expressed in the dorsal striatum, consumed food pellets nearly one after another in cages. AC5 KO mice showed aversive behaviors to bitter tasting quinine, but they compulsively chose quinine-containing AC5 KO-pellets over fresh pellets. The unusual food-choice behaviors in AC5 KO mice were due to the gain of behavioral preferences for food pellets containing an olfactory cue, which wild-type mice normally ignored. Such food-choice behaviors in AC5 KO mice disappeared when whiskers were trimmed. Conversely, whisker trimming in wildtype mice induced behavioral preferences for AC5 KO food pellets, indicating that preferred food-choices were not learned through prior experience. Both AC5 KO mice and wildtype mice with trimmed whiskers had increased glutamatergic input from the barrel cortex into the dorsal striatum, resulting in an increase in the mGluR1-dependent signaling cascade. The siRNA-mediated inhibition of mGluR1 in the dorsal striatum in AC5 KO mice and wildtype mice with trimmed whiskers abolished preferred choices for AC5 KO food pellets, whereas siRNA-mediated inhibition of mGluR3 glutamate receptors in the dorsal striatum in wildtype mice induced behavioral preferences for AC5 KO food pellets, thus mimicking AC5 KO phenotypes.ConclusionsOur results show that the gain and loss of behavioral preferences for a specific cue-directed option were regulated by specific cellular factors in the dorsal striatum, such that the preferred food choices were switched on when either the mGluR3-AC5 pathway was inactive or the mGluR1 pathway was active, whereas the preferred food-choices were switched off when mGluR1 or its downstream pathway was suppressed. These results identify the AC5 and mGluR system in the dorsal striatum as molecular on/off switches to direct decisions on behavioral preferences for cue-oriented options.

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The dorsal striatum expressing adenylyl cyclase-5 controls behavioral sensitivity of the righting reflex to high-dose ethanol

Cited by 10 publications

References 50 publications

αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

Nicotine Enhances the Hypnotic and Hypothermic Effects of Alcohol in the Mouse

Adenylyl cyclase-5 in the dorsal striatum function as a molecular switch for the generation of behavioral preferences for cue-directed food choices

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