Panic disorder (PD) is a debilitating anxiety disorder that often reduces the quality of life and some of its symptoms are physical distress and fear. PD is often comorbid with other anxiety disorders and depressive disorders and also cardiovascular and respiratory illnesses. Pharmacotherapy and psychotherapy are the two most common treatment options for people with PD. A standard type of pharmacotherapy is selective serotonin reuptake inhibitors (SSRI) which in short work by increasing the level of serotonin in the brain and has been shown to be efficacious and safe. A vital brain structure that is closely linked to PD is the amygdala, and some of its functions are learning, emotional processing, and memory. There seems to be a functional and structural abnormality in the amygdala for people with PD compared to healthy individuals, for example, a smaller volume of gray matter and increased activity. The aim of the thesis is to conduct a systematic review on the effect of SSRIs on the functional alterations of the amygdala in patients suffering from PD. The present systematic review will try to answer the question: If SSRIs affect amygdala activation for PD patients compared to healthy individuals who are currently not undergoing any kind of pharmacotherapy. The results showed opposite findings; one study did not detect activation changes in the amygdala for PD patients using SSRIs, one detected higher activity in the right amygdala, whereas the other two showed a decrease in the left amygdala (one study did not specify left, bilateral, or right). More research regarding amygdala activation in PD patients using SSRIs is needed due to the small scale of studies currently available.

No description available.

10-15% of women take antidepressants during pregnancy. Selective serotonin reuptake inhibitors (SSRIs) are most commonly used for perinatal depression. Perinatal exposure to SSRIs has been shown to disrupt the development of serotonergic signaling pathways in the central nervous system (CNS); however, the effects on the developing enteric nervous system (ENS) remain relatively unexplored. We hypothesized that early life exposure to SSRIs would influence the structural development of the gastrointestinal (GI) tract. We further hypothesized that these structural changes could lead to clinically relevant functional outcomes, such as modifications in susceptibility to inflammation and altered GI motility. Female Wistar rats were given the SSRI, fluoxetine, or vehicle from 2 weeks prior to mating through gestation until weaning. At postnatal day 1 (P1), postnatal day 21 (P21; weaning) and 6 months of age (P6 months) intestines were harvested to assess for structural changes. At P6M, intestines were collected to assess motility in vitro and subsets of the offspring were treated with dextran sulfate sodium (DSS) to assess susceptibility to colitis. At P1, there was a significant decrease in serotonergic neurons in the female colon. At P21, there was a significant increase in serotonergic neurons of both sexes in the colon. At P6M, there was a significant increase in the frequency and velocity of long-distance contractions in the colon when both sexes were combined and an increase in ZO-1 in male colon. In conclusion, SSRI exposure in utero appears to have structural and functional consequences on the developing ENS in the SSRI exposed offspring. The structural consequences are seen in both sexes at P21 and although the structural changes to the ENS resolve by 6 months, motility in the colon continues to be significantly altered. There were no significant differences in chemical colitis, however, we did see difference of quantitative mRNA cytokines, chemokines and extracellular matrix components which may suggest differences in mucosal immune response. The mechanisms by which these changes occur remain to be explored. / Thesis / Master of Science (MSc)

Serotonin (5-HT) is a neurotransmitter in the central nervous system. Decrease in the brain 5-HT level could induce depression, showing a state of low mood, aversion to motion and feeling of worthlessness. About 12 million adults in the United States have depression. Antidepressants, such as monoamine oxidase inhibitors and selective serotonin reuptake inhibitors, can alleviate the depressive mood by increasing the brain's 5-HT activity, however they can also induce a potentially life-threatening side effect, namely 5-HT syndrome. This syndrome is manifested by neuromuscular hyperactivities, mental disorders and autonomic dysfunctions. Clinical studies have demonstrated that 5-HT2A receptor antagonists could effectively block severe symptoms of patients with the 5-HT syndrome. To understand the underlying mechanisms, in this study we examined the activity of the 5-HT2A receptor in rats with the 5-HT syndrome evoked by a combined injection of clorgyline, a monoamine oxidase inhibitor , and paroxetine, a selective 5-HT reuptake inhibitor. The major findings from my study were that: (1) Chronic clorgyline treatment significantly exacerbated 5-HT2A receptor-mediated symptoms of the 5-HT syndrome animals; (2) The 5-HT2A receptor-mediated symptoms were also aggravated when the 5-HT syndrome animals were housed in warm (32 ÀC) ambient temperature; (3) Blocking 5-HT2A receptors in the medial prefrontal cortex alleviated the 5-HT syndrome through a circuit between raphe serotonergic neurons and medial prefrontal cortex glutamatergic neurons. Taken together, my data demonstrate that the activity of 5-HT2A receptors may be enhanced by chronic antidepressant treatment and warm environmental temperature. / The sensitized 5-HT2A receptor in the medial prefrontal cortex may exacerbate the syndrome through a positive-feedback circuit between medial prefrontal cortex and raphe nuclei, which would result in excessive 5-HT in the brain. This study casts a new light on the underlying mechanisms of the 5-HT syndrome. / by Gongliang Zhang. / Thesis (Ph.D.)--Florida Atlantic University, 2010. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2010. Mode of access: World Wide Web.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 4 uppsatser.

The regulation and modulation of the serotonergic system is clinically significant in humans. Abnormally low levels of serotonin can result in depression and conditions like panic disorder, obsessive-compulsive disorder, social anxiety disorder, sudden infant death syndrome, and eating disorders. The mechanistic role of serotonin (5-HT) on the neural circuits related with these diseases is not definitively known. Drosophila is a simple model system that provides an advantage over vertebrates to modify genetically and for electrophysiological studies on identifiable cells. In this organism the sensory-CNS-motor circuit is modulated by 5-HT, octopamine (OA), and dopamine (DA), which gives one insight that these neuromodulators are playing a role in central neuronal circuits. The role of 5-HT in the behavior and development of Drosophila melanogaster larvae is being studied. p-CPA (para-chlorophenylalanine) blocks the synthesis of 5-HT by inhibiting tryptophan hydroxylase. The development, behavior and physiology in 3rd instar larvae are affected after feeding this drug. MDMA (3,4 methylenedioxyamphetamine), an analog of methamphetamine is a drug of abuse that has been shown to cause depletion of 5-HT from nerve terminals. It causes the 5-HT transporter to work in reverse. Thus, a dumping of 5-HT results. In Drosophila 3rd instar larva development, physiology and behavior are effected when MDMA is fed throughout their development period. Also at the fly neuromuscular junction, (NMJ) MDMA is causing more evoked vesicular release of glutamate from the presynaptic nerve terminal. Also using anti-sense expression of the 5-HT2dro receptor, role of 5-HT and one of its receptors is studied on development, physiology and behavior. Knock down of 5-HT2dro resulted in developmental delay. Physiology and behavior were also abnormal in these animals.

No description available.

Determination of the physiologic roles of serotonin (5-HT) has long been hampered by the lack of compounds specific for certain of the 5-HT receptor subtypes. The objective of this dissertation was to characterize vascular serotonin receptors in certain arteries and to develop functional assays for the putative 5-HT₁(A) and 5-HT₂ receptors in vascular tissue to test novel compounds. Although 5-HT₁(A) receptor involvement in the 5-HT contraction of the canine basilar artery was previously reported, the 8-OH-DPAT (5-HT₁(A) specific agonist) EC₅₀ values in the canine, rabbit, guinea pig, and bovine basilar arteries studies were not consistent with the presence of 5-HT₁(A) receptors. Studies examining the 5-HT₂ selective antagonist ketanserin, several novel aryltryptamines with a range of affinities, and enantiomers of spiroxatrine, in the 5-HT-contracted rat aorta showed a good correlation between the aorta affinities and the affinities of these compounds at the [³H] ketanserin binding site (defined as 5-HT₂) in the rat frontal cortex. Comparison of the affinities of several known and novel compounds in the rat aorta and the rabbit femoral artery to the [³H] ketanserin site affinities in the frontal cortices of both species showed that the rabbit femoral artery 5-HT₂-like receptor was similar but not identical to either the rat aorta or the CNS sites from either species. The rabbit aorta and the rat femoral artery were then examined to determine if the 5-HT₂ receptor heterogeneity was species or vascular bed specific. The results from all four vascular tissues showed that no two tissues had identical responses to the compounds studied. The rat aorta appeared unique in the lack of agonist activity of RU24969 and the non-competitive antagonism of 5-HT by methysergide, but correlated to the CNS site for the affinities of all compounds. The major finding of the dissertation was the definitive evidence for vascular 5-HT₂ receptor heterogeneity; this subtype was previously thought to be homogeneous. Development of more selective compounds for 5-HT receptor subtypes may lead to greater understanding of the physiological roles of serotonin.

Recent approaches in depression therapeutics include triple reuptake inhibitors, drugs that target three monoamine systems. Using in vivo electrophysiological and microdialysis techniques, the effects of 2- and 14-day treatments of escitalopram, nomifensine and the co-administration of these two drugs (TRI) were examined in male Sprague-Dawley rats. Short- and long-term TRI administration decreased NE firing and had no effect on DA neurons. Normal 5-HT firing rates were maintained after 2-day TRI administration compared to the robust inhibitory action of selective serotonin reuptake inhibitors (SSRIs). Escitalopram treatment enhanced the tonic activation of the 5-HT1A receptors given the increase in firing observed following WAY100635 administration. Nomifensine treatment enhanced tonic activation of the α2–adrenoceptors following idazoxan administration. TRI treatment caused a robust increase in extracellular DA levels that was in part mediated by a serotonergic contribution. Therapeutic effects of the drugs examined in this study may be due to the enhancement of 5-HT, NE and/or DA neurotransmission.

Antidepressants are generally believed to exert their clinical efficacy by enhancing 5-HT transmission. Interestingly, sustained administration of selective serotonin (5-HT) reuptake inhibitors (SSRIs) strongly suppresses in the first few days the firing activity of 5-HT neurons in the dorsal raphe nucleus (DRN), thereby severely hampering the increase of 5-HT in target regions. Remarkably, the firing activity of 5-HT neurons gradually recovers over the time course of treatment and this recovery is believed to be accounted for by the desensitization of 5-HT1A somatodendritic autoreceptors. Here, we sought to investigate whether additional mechanisms might contribute to the dynamic regulation of excitability of 5-HT neurons during the course of SSRI treatments. Borrowing from the well-described homeostatic strengthening of glutamatergic synapses onto cortical pyramidal neurons following prolonged periods of inactivity, we hypothesized that a similar homeostatic-like regulation of synaptic strength might be operant on 5-HT cells during an SSRI treatment. To test this possibility, we used whole-cell electrophysiological recordings on acute midbrain slices to monitor glutamatergic synapses onto 5-HT neurons. We found that a two-day treatment with the SSRI citalopram induced a robust reduction in both the amplitude and frequency of AMPAR-mediated mEPSCs. We also show that this depression in synaptic strength, induced by an SSRI, is transient since excitatory drive onto 5-HT neurons was enhanced by 7 days of treatments. Altogether, these results document a dynamic regulation of glutamatergic synaptic transmission during the time course of a prolonged treatment with an SSRI. Further elucidation of the cellular and molecular mechanisms driving this synaptic plasticity might identify novel pharmacological target to shorten the delay of antidepressant action.