Altieri SC, Garcia-Garcia AL, Leonardo ED, Andrews AM. Rethinking 5-HT(1A) receptors: emerging modes of inhibitory feedback of relevance to emotion-related behavior. ACS Chem Neurosci 4: 72-83

Semel Institute for Neuroscience & Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine, Department of Chemistry and Biochemistry, and California NanoSystems Institute, University of California , Los Angeles, California 90095, United States.
ACS Chemical Neuroscience (Impact Factor: 4.36). 01/2013; 4(1):72-83. DOI: 10.1021/cn3002174
Source: PubMed


The complexities of the involvement of the serotonin transmitter system in numerous biological processes and psychiatric disorders is, to a substantial degree, attributable to the large number of serotonin receptor families and subtypes that have been identified and characterized for over four decades. Of these, the 5-HT(1A) receptor subtype, which was the first to be cloned and characterized, has received considerable attention based on its purported role in the etiology and treatment of mood and anxiety disorders. 5-HT(1A) receptors function both at presynaptic (autoreceptor) and postsynaptic (heteroreceptor) sites. Recent research has implicated distinct roles for these two populations of receptors in mediating emotion-related behavior. New concepts as to how 5-HT(1A) receptors function to control serotonergic tone throughout life were highlights of the proceedings of the 2012 Serotonin Club Meeting in Montpellier, France. Here, we review recent findings and current perspectives on functional aspects of 5-HT(1A) auto- and heteroreceptors with particular regard to their involvement in altered anxiety and mood states.

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Available from: Alvaro L Garcia-Garcia, Jan 13, 2014
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    • "Only tandospirone was registered but only in Japan for generalized anxiety disorder. Notwithstanding the lack of effective anxiolytics acting via 5-HT 1A receptor modulation, considerable evidence has accumulated showing the involvement of 5-HT 1A receptors in anxiety (and depression) both in preclinical and clinical studies (Akimova et al., 2009; Altieri et al., 2013; Savitz et al., 2009; Garcia-Garcia et al., 2014). As already mentioned, 5-HT 1A receptors represent as two main populations in the CNS, autoreceptors and heteroreceptors that function by coupling to G i /G 0 proteins controlling different intracellular signaling cascades like inhibition of cAMP formation, inactivation of calcium channels and activation of potassium channels (Barnes and Sharp, 1999). "
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    ABSTRACT: The neurotransmitter serotonin is an evolutionary ancient molecule that has remarkable modulatory effects in almost all central nervous system integrative functions, such as mood, anxiety, stress, aggression, feeding, cognition and sexual behavior. After given a short outline of the serotonergic system (anatomy, receptors, transporter) the author's contributions over the last 40 years in the role of serotonin in depression, aggression, anxiety, stress and sexual behavior is outlined. Each area delineates the work performed on animal model development, drug discovery and development. Most of the research described has started from an industrial perspective, aimed at developing animals models for psychiatric diseases and leading to putative new innovative psychotropic drugs, like in the cases of the SSRI fluvoxamine, the serenic eltoprazine and the anxiolytic flesinoxan. Later research mainly focused on developing translational animal models for psychiatric diseases and implicating them in the search for mechanisms involved in normal and diseased brains and finding new concepts for appropriate drugs. Copyright © 2014. Published by Elsevier B.V.
    European Journal of Pharmacology 11/2014; 753. DOI:10.1016/j.ejphar.2014.10.031 · 2.53 Impact Factor
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    • "A number of preclinical studies have elucidated mechanisms by which the dorsal raphe serotonergic system is modulated. Medial prefrontal cortex (mPFC) glutamatergic projections to the dorsal raphe have been described in detail (Celada et al., 2001; Altieri et al., 2012). Thus, stimulation of the mPFC causes release of serotonin in the dorsal raphe via activation of glutamatergic-releasing pyramidal layer V neurons. "
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    ABSTRACT: First-line treatment of major depression includes administration of a selective serotonin reuptake inhibitor (SSRI), yet studies suggest that remission rates following two trials of an SSRI are less than 50%. The authors examine the putative biological substrates underlying “Treatment Refractory Depression (TRD)” with the goal of elucidating novel rationales to treat TRD. We look at relevant articles from the preclinical and clinical literature combined with clinical exposure to TRD patients. A major focus was to outline pathophysiological mechanisms whereby the serotonin (5-HT) system becomes impervious to the desired enhancement of 5-HT neurotransmission by SSRI’s. A complementary focus was to dissect neurotransmitter systems, which serve to inhibit the dorsal raphe. We propose, based on a body of translational studies, TRD may not represent a simple 5-HT deficit state but rather an excess of midbrain peri-raphe 5-HT and subsequent deficit at key fronto-limbic projection sites, with ultimate compromise in 5-HT-mediated neuroplasticity. Glutamate, 5-HT, noradrenaline and histamine are activated by stress and exert an inhibitory effect on 5-HT outflow, in part by “flooding” 5-HT1A autoreceptors by 5-HT itself. Certain factors putatively exacerbate this scenario- presence of the short arm of the serotonin transporter gene, early life adversity and comorbid bipolar disorder- each of which has been associated with SSRI-treatment resistance. By utilizing an incremental approach, we provide a system for treating the TRD patient based on a strategy of rescuing 5-HT neurotransmission from a state of SSRI-induced dorsal raphe stasis. This calls for “stacked” interventions, with an SSRI base, targeting, if necessary, the glutamatergic, serotonergic, noradrenergic and histaminergic systems, thereby successively eliminating the inhibitory effects each are capable of exerting on 5-HT neurons. Future studies are recommended to test this biologically based approach for TRD.
    Frontiers in Behavioral Neuroscience 05/2014; 8:189. DOI:10.3389/fnbeh.2014.00189 · 3.27 Impact Factor
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    • "Importantly, changes in the activity of the brain's 5-HT system have been implicated in a wide range of behavioral disorders, including anxiety. In addition, the 5-HT 1A receptor has been reputed as a modulator of anxiety in its normal and pathological forms (Altieri et al., 2013; Popova and Naumenko, 2013). "
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    ABSTRACT: Interactions between the prelimbic cortex and the basolateral amygdala underlie fear memory processing, mostly through acquiring and consolidating the learning of a conditioned fear. More recently, studies highlighted the role of the dorsal periaqueductal gray (DPAG) in the modulation of learning fear responses. In addition, extensive data in the literature have signaled the importance of serotonin (5-HT) on fear and anxiety. In the present study, the role of 5-HT neurotransmission of the prelimbic cortex, basolateral amygdala or the DPAG on the unconditioned and conditioned fear responses in rats previously selected as low- (LA) or high-anxious (HA) were assessed through local infusions of 5-HT itself (10 nmol/0.2 μl) or the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT - 0.3 μg/0.2 μl). Behavioral analysis was conducted using the fear-potentiated startle procedure. Dependent variables recorded were the latency and amplitude of the unconditioned startle response and fear-potentiated startle. Our findings suggest that, on the prelimbic cortex, 5-HT modulate the expression of conditioned fear response in HA rats and this modulation is dependent on 5-HT1A receptors. This is not true, however, for the basolateral amygdala or the DPAG. In these regions LA but not HA rats were susceptible to the anxiolytic-like effect of 5-HT1A receptor activation. It is thought that the expression of conditioned fear in HA subjects may be dependent on other 5-HT receptors, as the 5-HT1B subtype, and/or changes in other systems such as the GABA and glutamate neurotransmitters. These results increase our understanding of the rostrocaudal influence of 5-HT on the unconditioned and conditioned fear response in LA and HA subjects and, to some extent, are in disagreement with the theoretical current that emphasizes the role of 5-HT on anxiety, mainly at the subcortical and midbrain levels.
    Neuroscience 03/2014; 268. DOI:10.1016/j.neuroscience.2014.03.005 · 3.36 Impact Factor
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