Ethanol‐Related Behaviors in Serotonin Transporter Knockout Mice

Boyce-Rustay, Janel M.; Wiedholz, Lisa M.; Millstein, Rachel; Carroll, Jenna C.; Murphy, Dennis L.; Daws, Lynette C.; Holmes, Andrew

doi:10.1111/j.1530-0277.2006.00241.x

Cited by 75 publications

(80 citation statements)

References 57 publications

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“…Fig. S3 shows phenotypes more associated with the independent effects of the mSERT GK haplotype, and include several traits linked to alcohol sensitivity or tolerance, including mean and total ethanol consumption and ethanol-conditioned taste aversion, consistent with previous findings in SERT knockout mice (23,24). Traits influenced by interactions of Slc6a4 and Tph2 variants are provided in Table S2 (independent Tph2-associated traits are presented in Table S3).…”

Section: In Silico Identification Of Phenotypes Influenced By Slc6a4 supporting

confidence: 66%

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Carneiro¹,

Airey²,

Thompson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here, we use naturally occurring polymorphisms in recombinant inbred (RI) lines to identify multiple phenotypes associated with altered SERT function. The widely used mouse strain C57BL/ 6J, harbors a SERT haplotype defined by 2 nonsynonymous coding variants [Gly-39 and Lys-152 (GK)]. At these positions, many other mouse lines, including DBA/2J, encode, respectively, Glu-39 and Arg-152 (ER haplotype), amino acids found also in hSERT. Ex vivo synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant, a finding confirmed by in vitro heterologous expression studies. Experimental and in silico approaches using RI lines (C57BL/6J ؋ DBA/2J ‫؍‬ BXD) identify multiple anatomical, biochemical, and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are several traits associated with alcohol consumption and multiple traits associated with dopamine signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates iron-regulated DA phenotypes. Our studies provide an example of the power of coordinated in vitro, in vivo, and in silico approaches using mouse RI lines to elucidate and quantify the system-level impact of gene variation.A complex set of phylogentically conserved traits relies upon the production, secretion, and inactivation of the biogenic amine 5-HT (1). A critical and conserved mechanism to regulate 5-HT signaling involves the action of the presynaptic 5-HT transporter, SERT (2). SERTs are not only responsible for the clearance of 5-HT after release, but also recycle synaptic 5-HT to sustain adequate stores for 5-HT release (3).The recognition of the central role played by SERT in 5-HT inactivation has been reinforced by studies where mouse SERT (mSERT) has been eliminated (4), suppressed (5, 6), or enhanced (7). Although investigations with these models provide critical support for a role of SERT in presynaptic 5-HT clearance and homeostasis, inferences linking SERT to neural signaling and behavior are complicated by significant compensatory changes in other genes (8). Conversely, a lack of recognition for background genetic diversity in mouse strains likely limits the full elaboration of phenotypes associated with SERT genetic variation (9). Indeed, SERT knockout mice display different phenotypes depending on their genetic background (10).An alternative approach is the identification of traits that are sensitive to naturally occurring polymorphisms using genetic reference populations, such as BXD recombinant inbred (RI) lines (11). BXD RI lines are isogenic, homozygous mosaics of C57BL/6J and DBA/2J inbred strains, previ...

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Section: In Silico Identification Of Phenotypes Influenced By Slc6a4 supporting

confidence: 66%

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Carneiro¹,

Airey²,

Thompson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…High alcohol drinking has been associated with deficiencies in brain 5-HT levels and turnover [130]. An induced 5-HT increase, in turn, can reduce alcohol drinking [131].…”

Section: Dopamine Activitymentioning

confidence: 99%

CaM Kinases: From Memories to Addiction

Müller

Quednow

Lourdusamy

et al. 2016

Trends in Pharmacological Sciences

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Drug addiction is a major psychiatric disorder with a neurobiological base that is still insufficiently understood. Initially, non-addicted, controlled drug consumption and drug instrumentalization are established. They comprise highly systematic behaviours acquired by learning and the establishment of drug memories. Ca 2+ /calmodulin-dependent protein kinases (CaMKs) are important Ca 2+ -sensors translating glutamatergic activation into synaptic plasticity during learning and memory formation. Here we review the role of CaMKs in the establishment of drugrelated behaviours in animal models and in humans. Converging evidence shows now that CaMKs are a crucial mechanism of how addictive drugs induce synaptic plasticity and establish various types of drug memories. Thereby, CaMKs are not only molecular relays for glutamatergic activity; they also directly control dopaminergic and serotonergic activity in the mesolimbic reward system. They can now be considered as major molecular pathways translating normal memory formation into establishment of drug memories and possibly transition to drug addiction. Keywords: Ca 2+/calmodulin-dependent protein kinase, drug dependence, addiction, psychostimulants, alcohol, opioids 3 Drug Use and AddictionDrug addiction is a major psychiatric disorder for which only limited therapies are currently available [1,2]. A striking criterion for drug abuse and addiction is that it severely threatens one's own and others well-being and health. As such, there is a persistent need to treat drug addiction effectively, and ideally reverse the behavioural repertoire of an affected individual back to normal.An important feature of drug addiction is that it develops from a behavioural repertoire, which is considered to be normal in many societies of the world: the controlled consumption and instrumentalization of psychoactive drugs [3,4].Establishing and maintaining controlled drug consumption is based on systematic learning and memory retrieval of distinct behaviours, related to drug seeking, preparation, and consumption in a specific context [5,6]. Thereby, information is encoded within different behavioural systems, which can be summarized as "drug memories" [5,[7][8][9] (Box 1). It is believed that an intensification of these memories together with a loss of impulse control (compulsivity) is responsible for the transition from controlled drug use to addiction [10][11][12]. Understanding how these drug memories are established and how they may take control over a normal behavioural repertoire should, therefore, allow to improve the prevention of addiction and to develop new and more effective treatments [13]. From Memories to Drug MemoriesIt was suggested that anatomical pathways, micro-morphological adaptations, as well as molecular mechanisms in the brain, overlap between normal learning and memory and drug memories [14][15][16]. A crucial player for memory formation in the brain is the glutamatergic system and its plasticity based on experience [17]. Addiction research considered glu...

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“…Using preference paradigms, pharmacological agents that inhibit 5-HT reuptake from the synapse reduce the voluntary consumption of ethanol solutions using the preference paradigm [142][143][144][145][146][147]. Knockout mice at the 5-HT transporter do, however, exhibit a general decrease in ethanol preference and consumption [148]. Thus, there is ample preclinical support for the notion that selective serotonin reuptake inhibitors (SSRIs) suppress ethanol consumption in animals.…”

Section: Serotonin Reuptake Inhibitorsmentioning

confidence: 99%

Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings

Johnson

2008

Biochemical Pharmacology

244

185

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The past decade has seen an expansion of research and knowledge on pharmacotherapy for the treatment of alcohol dependence. The Food and Drug Administration (FDA)-approved medications naltrexone and acamprosate have shown mixed results in clinical trials. Oral naltrexone and naltrexone depot formulations have generally demonstrated efficacy at treating alcohol dependence, but their treatment effect size is small, and more research is needed to compare the effects of different doses on drinking outcome. Acamprosate has demonstrated efficacy for treating alcohol dependence in European trials, but with a small effect size. In U.S. trials, acamprosate has not proved to be efficacious. Research continues to explore which types of alcohol-dependent individual would benefit the most from treatment with naltrexone or acamprosate. The combination of the two medications demonstrated efficacy for treating alcohol dependence in one European study but not in a multi-site U.S. study. Another FDA-approved medication, disulfiram, is an aversive agent that does not diminish craving for alcohol. Disulfiram is most effective when given to those who are highly compliant or who are receiving their medication under supervision. Of the non-approved medications, topiramate is among the most promising, with a medium effect size in clinical trials. Another promising medication, baclofen, has shown efficacy in small trials. Serotonergic agents such as selective serotonin reuptake inhibitors and the serotonin-3 receptor antagonist, ondansetron, appear to be efficacious only among certain genetic subtypes of alcoholic. As neuroscientific research progresses, other promising medications, as well as medication combinations, for treating alcohol dependence continue to be explored.

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Ethanol‐Related Behaviors in Serotonin Transporter Knockout Mice

Abstract: Data extend the finding that loss of 5-HTT gene function alters certain neural and behavioral effects of EtOH, with implications for better understanding the pathophysiology and treatment of alcoholism.

Cited by 75 publications

References 57 publications

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

CaM Kinases: From Memories to Addiction

Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings

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