The Effects of Chronic Ethanol Self-Administration on Hippocampal Serotonin Transporter Density in Monkeys

Burnett, Elizabeth J.; Davenport, April T.; Grant, Kathleen A.; Friedman, David P.

doi:10.3389/fpsyt.2012.00038

Cited by 16 publications

(14 citation statements)

References 81 publications

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“…Now these tissues and associated bioinformatics are widely available to the larger alcohol research community through the interactive MATRR website. Since its inception, the MATRR has contributed resources that have been cited in 70 peer-reviewed publications, including reports of the functional (Ariwodola et al, 2003; Budygin et al, 2003; Floyd et al, 2004; Alexander et al, 2006; Carden et al, 2006; Anderson et al, 2007; Cuzon-Carlson et al, 2012; Welsh et al, 2011), genomic (Hemby et al, 2006; Acosta et al, 2009; Burnett et al, 2012), proteomic (Freeman et al, 2006, 2010, 2011), biochemical (Ivester et al, 2003; 2007; Lebold et al, 2010) and cardiac (Cheng et al, 2010) consequences of long-term, excessive ethanol consumption. The pathophysiological effects of chronic EtOH on the hypothalamic-pituitary-adrenal axis have also been well-characterized (Morrow et al, 2006; Porcu et al, 2006a, b, 2010; Ferguson et al, 2012; Helms et al, 2012a, b, c, 2013).…”

Section: Resultsmentioning

confidence: 99%

Monkey Alcohol Tissue Research Resource: Banking Tissues for Alcohol Research

Daunais

Davenport

Helms

et al. 2014

Alcohol Clin Exp Res

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Background An estimated 18 million adults in the United States meet the clinical criteria for diagnosis of alcohol abuse or alcoholism, a disorder ranked as the third leading cause of preventable death. In addition to brain pathology, heavy alcohol consumption is co-morbid with damage to major organs including heart, lungs, liver, pancreas and kidneys. Much of what is known about risk for and consequences of heavy consumption derive from rodent or retrospective human studies. The neurobiological effects of chronic intake in rodent studies may not easily translate to humans due to key differences in brain structure and organization between species, including a lack of higher-order cognitive functions, and differences in underlying prefrontal cortical neural structures that characterize the primate brain. Further, rodents do not voluntarily consume large quantities of EtOH and they metabolize it more rapidly than primates. Methods The basis of the Monkey Alcohol Tissue Research Resource (MATRR) is that nonhuman primates (NHPs), specifically monkeys, show a range of drinking excessive amounts of alcohol (>3.0 g/kg or a 12 drink equivalent/day) over long periods of time (12–30 months) with concomitant pathological changes in endocrine, hepatic and central nervous system (CNS) processes. The patterns and range of alcohol intake that monkeys voluntarily consume parallel what is observed in humans with alcohol use disorders and the longitudinal experimental design spans stages of drinking from the ethanol-naïve state to early exposure through chronic abuse. Age- and sex-matched control animals self-administer an isocaloric solution under identical operant procedures. Results The MATRR is a unique post-mortem tissue bank that provides CNS and peripheral tissues, and associated bioinformatics from monkeys that self-administer ethanol using a standardized experimental paradigm to the broader alcohol research community. Conclusions This resource provides a translational platform from which we can better understand the disease processes associated with alcoholism.

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Section: Resultsmentioning

confidence: 99%

Monkey Alcohol Tissue Research Resource: Banking Tissues for Alcohol Research

Daunais

Davenport

Helms

et al. 2014

Alcohol Clin Exp Res

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“…For example, ETOH is known to affect 5-HTT expression (Burnett, Davenport et al 2012) and to inhibit 5-HT clearance in a 5-HTT-independent manner (Daws, Montanez et al 2006). We have previously shown that Tph2KI mice do not have significant alterations in 5-HTT expression in the brainstem, hippocampus, striatum or frontal cortex (Beaulieu, Zhang et al 2008), and thus, we do not believe that differences in 5-HTT function are responsible for any of the observed phenotypes of these animals.…”

Section: Discussionmentioning

confidence: 99%

Congenital brain serotonin deficiency leads to reduced ethanol sensitivity and increased ethanol consumption in mice

2014

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Serotonergic dysfunction has been hypothesized to play an important role in the pathophysiology of alcoholism. However, whether congenital serotonin (5-HT) deficiency leads to increased alcohol consumption or affects ethanol-related behaviors has not been established. Here, we use a transgenic mouse line that expresses a hypofunctional variant of the 5-HT synthesis enzyme, tryptophan hydroxylase 2, to examine the impact of 5-HT deficiency on responses to alcohol. We demonstrate that these 5-HT-deficient transgenic animals (Tph2KI mice) recover their righting reflex more rapidly than wild-type controls following a high dose of ethanol and exhibit blunted locomotor retardation in response to repeated ethanol administration. In addition, compared to WT controls, 5-HT-deficient animals consume significantly more ethanol and exhibit increased preference for ethanol in two-bottle choice tests. Our data also suggest that 5-HT plays a critical role in mediating the effects of ethanol on Akt/GSK3β signaling in the nucleus accumbens. Overall, our results corroborate previous theories regarding the importance of brain 5-HT levels in mediating responsiveness to alcohol and demonstrate, for the first time, that congenital 5-HT deficiency leads to increased ethanol consumption and decreased sensitivity to the sedative-like effects of ethanol, perhaps in part through modulating Akt/GSK3β signaling.

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“…The subjects and ethanol self-administration methods used in the current study have been described in detail previously (Burnett et al, 2012). Nine individually housed adult male cynomolgus macaques ( Macaca fascicularis ) voluntarily self-administered ethanol, water and banana flavored food pellets (Research Diets Incorporated, New Brunswick, NJ) 22 hr/day for 12 months using an operant panel permanently attached to their home cage.…”

Section: Methodsmentioning

confidence: 99%

The effects of chronic ethanol self-administration on hippocampal 5-HT1A receptors in monkeys

Burnett

Grant

Davenport

et al. 2014

Drug and Alcohol Dependence

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BACKGROUND Chronic alcohol consumption reduces brain serotonin and alters the synaptic mechanisms involved in memory formation. Hippocampal 5-HT1A receptors modulate these mechanisms, but the neuroadaptive response of 5HT1A receptors to chronic alcohol self-administration is not well understood. METHODS Hippocampal tissue from monkeys that voluntarily self-administered ethanol for 12 months (n=9) and accompanying controls (n=8) were prepared for in vitro receptor autoradiography and laser capture microdissection. The 5-HT1A receptor antagonist, [3H]MPPF, and the agonist, [3H]8-OH-DPAT, were used to measure total and G-protein coupled 5-HT1A receptors respectively. The expression of the genes encoding the 5-HT1A receptor and its trafficking protein Yif1B was measured in microdissected dentate gyrus (DG) granule cells and CA1 pyramidal neurons. RESULTS An increase in G-protein coupled, but not total, receptors was observed in the posterior pyramidal cell layer of CA1 in ethanol drinkers compared to controls. Chronic ethanol self-administration was also associated with an up-regulation of total and G-protein coupled 5-HT1A receptors in the posterior DG polymorphic layer. Changes in receptor binding were not associated with concomitant changes in 5-HT1A receptor mRNA expression. Chronic ethanol self-administration was associated with a significant increase in Yif1B gene expression in posterior CA1 pyramidal neurons. CONCLUSIONS Chronic, ethanol self-administration up-regulates hippocampal 5-HT1A receptor density in a region-specific manner that does not appear to be due to alterations at the level of transcription but instead may be due to increased receptor trafficking. Further exploration of the mechanisms mediating chronic ethanol-induced 5-HT1A receptor up-regulation and how hippocampal neurotransmission is altered is warranted.

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The Effects of Chronic Ethanol Self-Administration on Hippocampal Serotonin Transporter Density in Monkeys

Cited by 16 publications

References 81 publications

Monkey Alcohol Tissue Research Resource: Banking Tissues for Alcohol Research

Monkey Alcohol Tissue Research Resource: Banking Tissues for Alcohol Research

Congenital brain serotonin deficiency leads to reduced ethanol sensitivity and increased ethanol consumption in mice

The effects of chronic ethanol self-administration on hippocampal 5-HT1A receptors in monkeys

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