Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter

Thompson, Brent; Jessen, Tammy; Henry, L. Keith; Field, Julie R.; Gamble, Karen L.; Gresch, Paul J.; Carneiro, Ana M. D.; Horton, Rebecca E.; Chisnell, Peter; Belova, Yekaterina; McMahon, Douglas G.; Daws, Lynette C.; Blakely, Randy D.

doi:10.1073/pnas.1011920108

Cited by 49 publications

(99 citation statements)

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“…That is, the SSRIs were found to increase immobility in the tail suspension and forced swim tests in control I172 mice (5), which runs counter to the traditional view that SSRIs decrease immobility in these tests (18). As the authors speculate, this observation was most likely…”

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confidence: 50%

“…However, it may appear that the mutation contributes to SSRI nonresponsiveness. Either way, the outcome will help in the understanding of these SSRI effects in humans, who carry the I172 variant (5).…”

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confidence: 99%

“…The new transgenic mouse of Thompson et al (5) carries a modified copy of SERT that bears a single amino acid substitution, I172 > M172, proximal to the 5-HT binding site. The M172 substitution significantly reduces the potency of SSRIs to (i) reduce SERT affinity and 5-HT reuptake in vitro, (ii) reduce the 5-HT 1A receptor-dependent firing rate of serotonergic raphe neurons, (iii) reduce 5-HT clearance in vivo, (iv) increase extracellular 5-HT levels in vivo, and (v) affect depression-related behavioral symptoms.…”

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A mouse model to address unresolved antidepressant issues

Homberg

2011

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

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S elective serotonin reuptake inhibitors (SSRIs) are among the most widely used drugs in psychiatry. SSRIs were initially developed as antidepressant drugs, but-in analogy with the widespread central functions of serotonin (5-hydroxytryptamine; 5-HT) (1)-they are nowadays used in the treatment of a variety of psychiatric conditions, including autism spectrum disorders, obsessive compulsive disorder, and eating disorders. Besides their wide application, their popularity is presumably related to their limited side effects and relative safety in adults. However, there are also drawbacks related to SSRI use. Patients experience clinical effects only after several weeks of treatment (2), there are substantial individual differences in the response to SSRIs (3), and early life exposure to SSRIs may lead to hazardous developmental outcomes (4). Despite extensive research, underlying mechanisms have not yet been clarified, which hampers the design of faster, more effective, and safer antidepressant drugs. In PNAS, a new mouse model is presented (5) that offers the possibility to come closer to a resolution of these major questions in the field. The unique knockin mouse bears a mutation in the serotonin transporter (SERT) gene that eliminates high-affinity recognition of a variety of SSRIs, as well as cocaine.The new transgenic mouse of Thompson et al. (5) carries a modified copy of SERT that bears a single amino acid substitution, I172 > M172, proximal to the 5-HT binding site. The M172 substitution significantly reduces the potency of SSRIs to (i) reduce SERT affinity and 5-HT reuptake in vitro, (ii) reduce the 5-HT 1A receptor-dependent firing rate of serotonergic raphe neurons, (iii) reduce 5-HT clearance in vivo, (iv) increase extracellular 5-HT levels in vivo, and (v) affect depression-related behavioral symptoms. Importantly, the amino acid substitution does not affect the recognition of 5-HT itself. As a consequence, the animals show a normal growth, basal SERT protein and forebrain/midbrain 5-HT, dopamine, and norepinephrine levels are unchanged, and the transgenic animals do not differ from I172 control mice for each of the five parameters assessing SERT function (Table 1). This new mouse model shows that SERT is the sole target of SSRIs and, thereby, has heuristic value for dissecting the role of SERT and altered 5-HT signaling in the in vivo actions of SSRIs, and other SERT inhibitors.What other SERT models have been generated thus far? First, we have the SERT knockout mice and rats (6). Because of the absence of SERT, SSRI recognition is lost and extracellular 5-HT levels are constitutively increased. Thereby, they could be viewed as animal models for chronic SSRI exposure. However, rather than showing low levels of anxiety-and depression-like symptoms, they show increases, which are hypothesized to be attributed to a variety of compensatory changes (Table 1). Indeed, 5-HT receptor expression, sensitivity, and/or function is altered, neuroplastic changes have been noted, and the animals show metabolic (inc...

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A mouse model to address unresolved antidepressant issues

Homberg

2011

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

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“…We recently developed a knock-in mouse strain (SERT I172M) that results in significantly reduced sensitivity to multiple SSRIs. 132 The SERT I172 M model may be useful in pursuing this question.…”

Section: Acs Chemical Neurosciencementioning

confidence: 99%

A Dialogue between the Immune System and Brain, Spoken in the Language of Serotonin

Baganz

Blakely

2012

ACS Chem. Neurosci.

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Neuropsychiatric disorders have long been linked to both immune system activation and alterations in serotonin (5-HT) signaling. In the CNS, the contributions of 5-HT modulate a broad range of targets, most notably, hypothalamic, limbic and cortical circuits linked to the control of mood and mood disorders. In the periphery, many are aware of the production and actions of 5-HT in the gut but are unaware that the molecule and its receptors are also present in the immune system where evidence suggests they contribute to the both innate and adaptive responses. In addition, there is clear evidence that the immune system communicates to the brain via both humoral and neuronal mechanisms, and that CNS 5-HT neurons are a direct or indirect target for these actions. Following a brief primer on the immune system, we describe our current understanding of the synthesis, release, and actions of 5-HT in modulating immune function, including the expression of 5-HT biosynthetic enzymes, receptors, and transporters that are typically studied with respect to the roles in the CNS. We then orient our presentation to recent findings that pro-inflammatory cytokines can modulate CNS 5-HT signaling, leading to a conceptualization that among the many roles of 5-HT in the body is an integrated physiological and behavioral response to inflammatory events and pathogens. From this perspective, altered 5-HT/immune conversations are likely to contribute to risk for neurobehavioral disorders historically linked to compromised 5-HT function or ameliorated by 5-HT targeted medications, including depression and anxiety disorders, obsessive-compulsive disorder (OCD), and autism. Our review raises the question as to whether genetic variation impacting 5-HT signaling genes may contribute to maladaptive behavior as much through perturbed immune system modulation as through altered brain mechanisms. Conversely, targeting the immune system for therapeutic development may provide an important opportunity to treat mental illness.

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“…Furthermore, in vitro experiments with transfected cells formed the basis for many genetic mutations that were later engineered in mice, which now serve for in vivo investigations of psychoactive drugs or as preclinical models of mental disorders (Henry et al, 2006;Mazei-Robison et al, 2008;Prasad et al, 2005). For example, in vitro experiments allowed the construction of a transgenic mouse model with a 5-hydroxytryptamine (5-HT [serotonin]) transporter (SERT) mutation for the in vivo assessment of SERT-mediated effects of antidepressants or cocaine (Prosser et al, 2014;Thompson et al, 2011) or to shed light on functional abnormalities of the DAT variant Val559, which is being investigated as a potential mouse model of attention-deficit hyperactivity disorder (Mergy et al, 2014).…”

Section: Methods For Studying Transporter and Receptor Pharmacology Imentioning

confidence: 99%

Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells

Simmler

Liechti

2016

Neuropharmacology of New Psychoactive Substances (NPS)

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Pharmacological assays carried out in transfected cells have been very useful for describing the mechanism of action of cathinone new psychoactive substances (NPS). These in vitro characterizations provide fast and reliable information on psychoactive substances soon after they emerge for recreational use. Well-investigated comparator compounds, such as methamphetamine, 3,4-methylenedioxymethamphetamine, cocaine, and lysergic acid diethylamide, should always be included in the characterization to enhance the translation of the in vitro data into clinically useful information. We classified cathinone NPS according to their pharmacology at monoamine transporters and receptors. Cathinone NPS are monoamine uptake inhibitors and most induce transportermediated monoamine efflux with weak to no activity at pre-or postsynaptic receptors. Cathinones with a nitrogen-containing pyrrolidine ring emerged as NPS that are extremely potent transporter inhibitors but not monoamine releasers. Cathinones exhibit clinically relevant differences in relative potencies at serotonin vs. dopamine transporters. Additionally, cathinone NPS have more dopaminergic vs. serotonergic properties compared with their non-β-keto amphetamine analogs, suggesting more stimulant and reinforcing properties. In conclusion, in vitro pharmacological assays in heterologous expression systems help to predict the psychoactive and toxicological effects of NPS.

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Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter

Cited by 49 publications

References 58 publications

A mouse model to address unresolved antidepressant issues

A mouse model to address unresolved antidepressant issues

A Dialogue between the Immune System and Brain, Spoken in the Language of Serotonin

Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells

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