ReviewEffects of citalopram on serotonin and CRF systems in the midbrain of primates with differences in stress sensitivity☆
Highlights
► Monkeys were characterized as stress-sensitive or stress-resilient by their ovulatory response during metabolic and psychosocial stress. ► Stress-sensitive monkeys showed an improvement in ovarian function after 15 weeks of citalopram treatment. ► Stress-sensitive monkeys have reduced gene expression of Fev, TPH2, SERT and 5HT1A compared to stress-resilient monkeys. ► Citalopram treatment did not improve Fev, TPH2, SERT or 5HT1A gene expression in stress-sensitive monkeys. ► Stress-sensitive monkeys have greater CRF fiber density and less CRF-R2 expression in the raphe compared to stress-resilient monkeys. ► Citalopram treatment decreased CRF fiber density and increased CRF-R2 expresssion in the dorsal raphe of stress-sensitive monkeys.
Section snippets
Fev
Fev (a homolog of Pet1 in rats) is an ETS domain transcription factor that determines whether a neuron is serotonergic; and it functions specifically in the differentiation and maintenance of serotonin neurons. Fev is absolutely necessary for a neuron to become serotonergic and it is not expressed in any other neurons of the CNS. Indeed, the rodent homolog of Fev marks and is restricted to, the entire rostral-caudal extent of the rat serotonergic hindbrain raphe complex (Hendricks et al., 1999
TPH2
TPH2 is the rate limiting or committal enzyme in the overall synthesis of serotonin in the brain and it converts the precursor, tryptophan to 5-hydroxytryptophan, which is then converted to 5-hydroxytryptamine or serotonin. Hence, the level or activity of this pivotal enzyme plays a role in the concentration of serotonin achieved in cell bodies. It appears that newly synthesized 5-HT is preferentially released. However, the release of 5-HT is dependent on neuronal activity, and it is not always
SERT
The primary means by which serotonergic neurons control extracellular serotonin concentrations is via the serotonin reuptake transporter (SERT), which acts to reduce the concentration of serotonin in the synaptic cleft (Blakely et al., 1994). Removal of serotonin from the extracellular space and terminating serotonin neurotransmission are the major tasks of SERT (Blakely et al., 1994). The SERT proteins are predominantly located presynaptically at serotonin nerve terminals (Hoffman et al., 1998
5HT1A
The most widely studied of the 5HT autoreceptors is the 5HT1A receptor. The 5HT1A autoreceptor subtype is of significant importance because it inhibits serotonin neural firing (Sprouse and Aghajanian, 1986), which leads to a suppression of serotonin synthesis, serotonin turnover and the release of serotonin in diverse projection areas (Bohmaker et al., 1993, Sharp et al., 1993, Singh and Lucki, 1993). A characteristic of compounds with medium to high efficacy for blocking 5HT1A receptors is an
CRF fiber density
The knowledge of CRF innervation of the serotonergic raphe nuclei (Sakanaka et al., 1987, Ruggiero et al., 1999) coupled with the detection of CRF receptors in the raphe (Chalmers et al., 1995, Van Pett et al., 2000) forged the link between the CRF and serotonin systems. Subsequently, the opposing effects of CRF and UCN on serotonin were established in rodents. Administration of CRF directly into the DRN inhibits serotonergic activity, and CRF-R1 antagonists block this effect (Price et al., 1998
UCN1 fiber density
UCN1 decreases feeding behavior, and also participates in the stress response (Spina et al., 1996, Oki and Sasano, 2004, Pan and Kastin, 2008). UCN1 binds to CRF-R2 with greater affinity than CRF suggesting that UCN1 preferentially binds CRF-R2. Both UCN1 knockout mice and CRF-R2 knockout mice exhibit increased anxiety-like behavior (Pan and Kastin, 2008). Thus, it has been generalized that activation of CRF-R1 by CRF increases anxiety-like behavior whereas activation of CRF-R2 by UCN1
CRF-R2
CRF receptors have been detected in the raphe of rodents (Chalmers et al., 1995, Van Pett et al., 2000) and primates (Sanchez et al., 2010). The opposing effects of CRF and UCN on serotonin were established in rodents. As mentioned earlier, there are two types of CRF receptors, CRF-R1 and CRF-R2. Administration of CRF directly into the DRN inhibits serotonergic activity, and CRF-R1 antagonists block this effect (Price et al., 1998). CRF also has opposing effects on serotonin activity depending
Overview and correlations
The neurobiological basis of individual differences in stress sensitivity and the potential pharmacological remediation is an important issue in obvious fields such as psychiatry and immunology. A large body of clinical research has found that individuals may be stress-sensitive or stress-resilient, and that stress-sensitive individuals have an increased incidence of mood and anxiety disorders. More recently, gynecologists have recognized that individual differences in stress sensitivity play a
Acknowledgements
We are very grateful for the dedicated work of J.A. Bytheway, S. Guay, D. Kerr, and N. Rockcastle for the performance of the physiological studies treating monkeys with citalopram. We are also indebted to the collaboration with D.A. Axelson and J.M. Perel in the Dept. of Psychiatry at the University of Pittsburgh who measured blood citalopram levels. We thank S.R. Ojeda (Division of Neuroscience, ONPRC) for his help with the non-isotopic in situ hybridization procedure. Technical assistance
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