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

Sachs, Benjamin D.; Salahi, A. Ayten; Caron, Marc G.

doi:10.1016/j.neuropharm.2013.09.010

Cited by 26 publications

(18 citation statements)

References 48 publications

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“…Post hoc analyses revealed that SDS only led to a significant reduction in social preference in Tph2KI mice, not in WT animals, and SDS-exposed Tph2KI animals exhibited lower preference ratios than any other group (P < 0.05). In contrast, 10 d of SDS induced significant social avoidance in both WT and Tph2KI animals [F (1,44) = 11.44, P = 0.0015; Fig. 1B], and no significant interactions or genotype differences were observed.…”

Section: Resultsmentioning

confidence: 99%

“…The initial pellet (from the 2,800-rpm spin) was resuspended and sonicated in protein lysis buffer (50 mM Tris·HCl, pH 7.5, 150 mM NaCl, 1% Triton X-100, 0.1% SDS, 2 mM EDTA, and protease and phosphatase inhibitors) and used as the nuclear fraction. Western blotting was performed as described previously (13,44). The protein levels of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) or actin were measured as loading controls.…”

Section: Social Avoidancementioning

confidence: 99%

See 1 more Smart Citation

Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress

Sachs¹,

Ni²,

Caron

2015

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

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106

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Brain serotonin (5-HT) deficiency and exposure to psychosocial stress have both been implicated in the etiology of depression and anxiety disorders, but whether 5-HT deficiency influences susceptibility to depression-and anxiety-like phenotypes induced by psychosocial stress has not been formally established. Most clinically effective antidepressants increase the extracellular levels of 5-HT, and thus it has been hypothesized that antidepressant responses result from the reversal of endogenous 5-HT deficiency, but this hypothesis remains highly controversial. Here we evaluated the impact of brain 5-HT deficiency on stress susceptibility and antidepressant-like responses using tryptophan hydroxylase 2 knockin (Tph2KI) mice, which display 60-80% reductions in brain 5-HT. Our results demonstrate that 5-HT deficiency leads to increased susceptibility to social defeat stress (SDS), a model of psychosocial stress, and prevents the fluoxetine (FLX)-induced reversal of SDS-induced social avoidance, suggesting that 5-HT deficiency may impair antidepressant responses. In light of recent clinical and preclinical studies highlighting the potential of inhibiting the lateral habenula (LHb) to achieve antidepressant and antidepressant-like responses, we also examined whether LHb inhibition could achieve antidepressant-like responses in FLXinsensitive Tph2KI mice subjected to SDS. Our data reveal that using designer receptors exclusively activated by designer drugs (DREADDs) to inhibit LHb activity leads to reduced SDS-induced social avoidance behavior in both WT and Tph2KI mice. This observation provides additional preclinical evidence that inhibiting the LHb might represent a promising alternative therapeutic approach under conditions in which selective 5-HT reuptake inhibitors are ineffective.serotonin | stress | antidepressants | habenula S tress is thought to play a key role in the development of neuropsychiatric disorders, but only a small percentage of individuals exposed to stress develop mental illnesses. To account for this, diathesis-stress hypotheses of neuropsychiatric disorders postulate that stress only leads to maladaptive behavior and psychiatric disease in individuals who harbor certain vulnerability factors (or diatheses) (1-3). However, the diatheses that lead to increased susceptibility to psychosocial stress remain largely unknown.Levels of brain serotonin (5-HT) have long been implicated in the development and treatment of neuropsychiatric disorders. Indeed, biomarkers of 5-HT deficiency have been identified in subpopulations of depression patients (4), and mutations within 5-HT-system genes have been associated with affective disorders, anxiety disorders, and alterations in stress sensitivity (3,(5)(6)(7)(8). In addition, most antidepressant drugs increase extracellular levels of brain 5-HT. However, whether brain 5-HT deficiency alters stress susceptibility or contributes to the development of aberrant emotional behavior remains largely unresolved. Here we examined the consequences of low levels of brai...

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Section: Resultsmentioning

confidence: 99%

Section: Social Avoidancementioning

confidence: 99%

Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress

Sachs¹,

Ni²,

Caron

2015

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

Self Cite

106

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“…Ethanol intake and preference increased in a knockin mouse line (Tph2KI) expressing a hypofunctional variant of the rate-limiting serotonin (5-HT) synthesis enzyme, tryptophan hydroxylase 2 (Sachs, Salahi, & Caron, 2014) (Table 4). Increased ethanol self-administration has also been reported in mice lacking 5-HT 1B receptors (Bouwknecht et al, 2000; Crabbe et al, 1996; Risinger, Doan, & Vickrey, 1999).…”

Section: Neurotransmitter Systemsmentioning

confidence: 99%

Genes and Alcohol Consumption

Mayfield

Arends

Harris

et al. 2016

International Review of Neurobiology

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In this chapter, we review the effects of global null mutant and overexpressing transgenic mouse lines on voluntary self-administration of alcohol. We examine approximately 200 publications pertaining to the effects of 155 mouse genes on alcohol consumption in different drinking models. The targeted genes vary in function and include neurotransmitter, ion channel, neuroimmune, and neuropeptide signaling systems. The alcohol self-administration models include operant conditioning, two- and four-bottle choice continuous and intermittent access, drinking in the dark limited access, chronic intermittent ethanol, and scheduled high alcohol consumption tests. Comparisons of different drinking models using the same mutant mice are potentially the most informative, and we will highlight those examples. More mutants have been tested for continuous two-bottle choice consumption than any other test; of the 137 mouse genes examined using this model, 97 (72%) altered drinking in at least one sex. Overall, the effects of genetic manipulations on alcohol drinking often depend on the sex of the mice, alcohol concentration and time of access, genetic background, as well as the drinking test.

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“…N ‐substituted cyclic imides may be used for regulating serotonin levels in humans . Such derivatives show antidepressant effects, being used for the treatment of disorders such as anxiety or as analgesics . The bicylo anthracene scaffold containing agent, 3‐(9,10‐dihydro‐9,10‐ethanoanthracene‐9‐yl) N ‐methylpropylamine (maprotiline) also shows antidepressant properties and imides incorporating this skeleton act as glucocorticoid receptor modulators .…”

Section: Introductionmentioning

confidence: 99%

9,10‐Dibromo‐N‐aryl‐9,10‐dihydro‐9,10‐[3,4]epipyrroloanthracene‐12,14‐diones: Synthesis and Investigation of Their Effects on Carbonic Anhydrase Isozymes I, II, IX, and XII

Göksu

Topal

Keskïn

et al. 2016

Archiv der Pharmazie

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N-substituted maleimides were synthesized from maleic anhydride and primary amines. 1,4-Dibromo-dibenzo[e,h]bicyclo-[2,2,2]octane-2,3-dicarboximide derivatives (4a-f) were prepared by the [4+2] cycloaddition reaction of dibromoanthracenes with the N-substituted maleimide derivatives. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects of the new derivatives were assayed against the human (h) isozymes hCA I, II, IX, and XII. All tested bicyclo dicarboximide derivatives exhibited excellent inhibitory effects in the nanomolar range, with Ki values in the range of 117.73-232.87 nM against hCA I and of 69.74-111.51 nM against hCA II, whereas they were low micromolar inhibitors against hCA IX and XII.

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

Cited by 26 publications

References 48 publications

Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress

Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress

Genes and Alcohol Consumption

9,10‐Dibromo‐N‐aryl‐9,10‐dihydro‐9,10‐[3,4]epipyrroloanthracene‐12,14‐diones: Synthesis and Investigation of Their Effects on Carbonic Anhydrase Isozymes I, II, IX, and XII

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