Regulation of dorsal raphe nucleus function by serotonin autoreceptors: A behavioral perspective

McDevitt, Ross A.; Neumaier, John F.

doi:10.1016/j.jchemneu.2011.05.001

Cited by 79 publications

(78 citation statements)

References 216 publications

(288 reference statements)

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“…These increases in serotonin levels and antidepressant-like phenotypes have been seen previously in the ubiquitous 5-HT 1B R KO (Bechtholt et al, 2008;Jones and Lucki, 2005;Knobelman et al, 2001;Mayorga et al, 2001), but importantly, our genetic model allowed the dissociation of the role of 5-HT 1B autoreceptors from heteroreceptors. This advancement is significant since pharmacological dissection via local infusion of antagonists or agonists is not possible given the terminal localization of 5-HT 1B autoreceptors throughout the brain (McDevitt and Neumaier, 2011). The identification of a population of 5-HT 1B receptors involved in modulating anxiety and depression is important given the diverse physiological effects which 5-HT 1B Rs can cause depending on their localization.…”

Section: Discussionmentioning

confidence: 99%

“…Serotonin (5-HT) autoreceptors play a major role in regulating serotonergic tone and modulating the response to antidepressant pharmacotherapies (Richardson-Jones et al, 2010;Stamford et al, 2000). While the majority of research has focused on serotonin 1A (5-HT 1A ) autoreceptors, evidence also points to serotonin 1B (5-HT 1B ) autoreceptors as a major regulator of serotonin transmission and emotionality (Donaldson et al, 2014;McDevitt and Neumaier, 2011;Richardson-Jones et al, 2010). In rodent models, activation of 5-HT 1B receptors decreases serotonin levels through effects on release, synthesis, and reuptake (Hagan et al, 2012;Hjorth et al, 1995;Trillat et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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A Lack of Serotonin 1B Autoreceptors Results in Decreased Anxiety and Depression-Related Behaviors

Nautiyal

Tritschler

Ahmari

et al. 2016

Neuropsychopharmacol

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The effects of serotonin (5-HT) on anxiety and depression are mediated by a number of 5-HT receptors, including autoreceptors that act to inhibit 5-HT release. While the majority of anxiety and depression-related research has focused on the 5-HT 1A receptor, the 5-HT 1B receptor has a lesser known role in modulating emotional behavior. 5-HT 1B receptors are inhibitory GPCRs located on the presynaptic terminal of both serotonin and non-serotonin neurons, where they act to inhibit neurotransmitter release. The autoreceptor population located on the axon terminals of 5-HT neurons is a difficult population to study due to their diffuse localization throughout the brain that overlaps with 5-HT 1B heteroreceptors (receptors located on non-serotonergic neurons). In order to study the contribution of 5-HT 1B autoreceptors to anxiety and depression-related behaviors, we developed a genetic mouse model that allows for selective ablation of 5-HT 1B autoreceptors. Mice lacking 5-HT 1B autoreceptors displayed the expected increases in extracellular serotonin levels in the ventral hippocampus following administration of a selective serotonin reuptake inhibitor. In behavioral studies, they displayed decreased anxietylike behavior in the open field and antidepressant-like effects in the forced swim and sucrose preference tests. These results suggest that strategies aimed at blocking 5-HT 1B autoreceptors may be useful for the treatment of anxiety and depression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Lack of Serotonin 1B Autoreceptors Results in Decreased Anxiety and Depression-Related Behaviors

Nautiyal

Tritschler

Ahmari

et al. 2016

Neuropsychopharmacol

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“…Serotonin neurons in the DRN are thought to be essential in mood behavior and antidepressant responses (McDevitt and Neumaier, 2011), and express BDNF and its high-affinity receptor TrkB (Lunden and Kirby, 2013;Madhav et al, 2001). BDNF can directly influence serotonergic neurons by increasing serotonin synthesis and activity of these neurons Siuciak et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

TrkB Signaling in Dorsal Raphe Nucleus is Essential for Antidepressant Efficacy and Normal Aggression Behavior

Adachi

Autry

Mahgoub

et al. 2016

Neuropsychopharmacol

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Brain-derived neurotrophic factor (BDNF) and its high affinity receptor, tropomyosin receptor kinase B (TrkB), have important roles in neural plasticity and are required for antidepressant efficacy. Studies examining the role of BDNF-TrkB signaling in depression and antidepressant efficacy have largely focused on the limbic system, leaving it unclear whether this signaling is important in other brain regions. BDNF and TrkB are both highly expressed in the dorsal raphe nucleus (DRN), a brain region that has been suggested to have a role in depression and antidepressant action, although it is unknown whether BDNF and TrkB in the dorsal raphe nucleus are involved in these processes. We combined the adeno-associated virus (AAV) with the Cre-loxP site-specific recombination system to selectively knock down either Bdnf or TrkB in the DRN. These mice were then characterized in several behavioral paradigms including measures of depression-related behavior and antidepressant efficacy. We show that knockdown of TrkB, but not Bdnf, in the DRN results in loss of antidepressant efficacy and increased aggression-related behavior. We also show that knockdown of TrkB or Bdnf in this brain region does not have an impact on weight, activity levels, anxiety, or depression-related behaviors. These data reveal a critical role for TrkB signaling in the DRN in mediating antidepressant responses and normal aggression behavior. The results also suggest a non-cell autonomous role for BDNF in the DRN in mediating antidepressant efficacy.

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“…Complicating the situation is the finding that serotonin release is tightly regulated by autoreceptors that control it via negative-feedback inhibition. Indeed, increasing autoreceptor function is anxiolytic, which is presumably associated with reduced serotonergic function and, as our data suggest, reduced HA (McDevitt & Neumaier, 2011). Overall, it appears that our current understanding of serotonin release, and the mechanism of action of SSRIs, is still in its infancy, and further investigations will be needed to determine the precise relationship between serotonin and HA.…”

Section: Discussionmentioning

confidence: 66%

Dorsal raphe nucleus and harm avoidance: A resting-state investigation

Meylakh

Henderson

2016

Cogn Affect Behav Neurosci

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The temperament dimension of harm avoidance defines an individual's biological tendency to exhibit altering levels of anxious, inhibiting, and cautious behavior. High harm avoidance and anxiety are highly comorbid, likely due to activity in similar neural circuitries involving the dorsal raphe nucleus. Despite the many investigations that have explored personality factors and brain function, none have determined the influence of ongoing activity within dorsal raphe networks on harm avoidance. The aim of this study was to explore such a relationship. In 62 healthy subjects, a series of 180 functional magnetic resonance images covering the entire brain were collected, and each subject completed the 240-item TCI-R questionnaire. Independent component analyses were performed to define the dorsal raphe network and then to determine the regions significantly correlated with harm avoidance. The independent component analyses revealed three signal intensity fluctuation maps encompassing the dorsal raphe nucleus, showing interactions with regions of the amygdala, hippocampus, nucleus accumbens, and prefrontal, insular, and cingulate cortices. Within these systems, the resting signal intensity was significantly coupled to harm avoidance in the bilateral basal amygdala, bilateral ventral hippocampus, bilateral insula, bilateral nucleus accumbens, and medial prefrontal cortex. Note that we could not measure serotonergic output, but instead measured signal changes in the dorsal raphe that likely reflect synaptic activity. These data provide evidence that at rest, signal intensity fluctuations within the dorsal raphe networks are related to harm avoidance. Given the strong relationship between harm avoidance and anxiety-like behaviors, it is possible that ongoing activity within this identified neural circuitry can contribute to an individual developing anxiety disorders.

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Regulation of dorsal raphe nucleus function by serotonin autoreceptors: A behavioral perspective

Cited by 79 publications

References 216 publications

A Lack of Serotonin 1B Autoreceptors Results in Decreased Anxiety and Depression-Related Behaviors

A Lack of Serotonin 1B Autoreceptors Results in Decreased Anxiety and Depression-Related Behaviors

TrkB Signaling in Dorsal Raphe Nucleus is Essential for Antidepressant Efficacy and Normal Aggression Behavior

Dorsal raphe nucleus and harm avoidance: A resting-state investigation

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