83 research outputs found
Regulation of 5-HT Receptors and the Hypothalamic-Pituitary-Adrenal Axis
Disturbances in the serotonin (5-HT) system is the neurobiological abnormality most consistently associated with suicide. Hyperactivity of the hypothalmic-pituitary-adrenal (HPA) axis is also described in suicide victims. The HPA axis is the classical neuroendocrine system that responds to stress and whose final product, corticosteroids, targets components of the limbic system, particularly the hippocampus. We will review resulsts from animal studies that point to the possibility that many of the 5-HT receptor changes observed in suicide brains may be a result of, or may be worsened by, the HPA overactivity that may be present in some suicide victims. The results of these studies can be summarized as follows: (1) chronic unpredictable stress produces high corticosteroid levels in rats; (2) chronic stress also results in changes in specific 5-HT receptors (increases in cortical 5-HT2A and decreases in hipocampal 5-HT1A and 5-HT1B); (3) chronic antidepressant administration prevents many of the 5-HT receptor changes observed after stress; and (4) chronic antidepressant administration reverses the overactivity of the HPA axis. If indeed 5-HT receptors have a partial role in controlling affective states, then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood. These data may also provide a biological understanding of how stressful events may increase the risk for suicide in vulnerable individuals and may help us elucidate the neurobiological underpinnings of treatment resistance.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73437/1/j.1749-6632.1997.tb52357.x.pd
A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials
Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD. © 2021, The Author(s).EU/EFPIA/Innovative Medicines Initiative 2 Joint Undertaking
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Effects of sigma receptor blockade on regional brain neurotensin concentrations
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Thyrotropin—releasing hormone and amphetamine: A comparison of pharmacological profiles in animals
1.
1. The pharmacological effects of TRH are compared to those produced by d-amphetamine in an attempt to elucidate the mechanisms underlying the activity of this endogenous peptide.
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2. Although numerous amphetamine-like actions have been attributed to TRH, several differences have been noted between these compounds and are discussed.
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3. At present, it is impossible to propose a single mechanism of action to explain the behavioral effects of TRH
Advances in the treatment of mood and anxiety disorders
Mood and anxiety disorders are prevalent in all countries and cultures, which becomes obvious when standardized diagnostic and evaluation techniques are utilized. It is estimated that ~450 million people worldwide suffer from psychiatric illness. In the United States alone, epidemiologic research has identified that tens of millions of Americans suffer from major depressive disorder (MDD) annually, with many of them being in the prime of their adult lives. In addition to medical, personal, and social costs, depression is also believed to have a significant impact on work productivity. Further epidemiologic research indicates that nearly half of all individuals meeting lifetime criteria for MDD also have met criteria for a comorbid anxiety disorder. With an average age of 16 years for the onset of any lifetime anxiety disorder, anxiety disorders appear to predispose affected individuals to a substantial lifetime risk for MDD. In order to improve outcomes in depression and anxiety disorders, clinicians must enhance the entire process of recognition, diagnosis, and treatment
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Neurotensin microinjection into the nucleus accumbens antagonizes dopamine-induced increase in locomotion and rearing
Neurotensin is an endogenous neuropeptide with neuronal perikarya or fibers distributed in the vicinity of the mesolimbic dopamine system. This observation, plus behavioral data showing that neurotensin injection into the nucleus accumbens blocks some behavioral effects of amphetamine, indicates that neurotensin may modulate the mesolimbic dopamine system. In this study it was shown that neurotensin given into the nucleus accumbens produces a dose-dependent blockade of locomotion and rearing initiated by dopamine injection into the nucleus accumbens. This effect is not mimicked by inactive neurotensin analogue nor some other endogenous neuropeptides. Since dopamine acts on postsynaptic dopamine receptors in the nucleus accumbens, neurotensin is acting, not on dopamine terminals, but on neurons or neuronal systems which are modulated by the mesolimbic dopamine system. This conclusion is supported by the facts that intra-accumbens injection of neurotensin does not alter accumbens levels of dopamine or its metabolites, nor does it affect the increase in dopamine metabolites produced by injection of neurotensin into the ventral tegmental area. Further, neurotensin was also found to block the dopamine-independent increase in locomotion and rearing produced by the injection of
d-Ala
2-Met-
5enkephalinamide into the nucleus accumbens.
These data indicate that neurotensin acts on neurons in the nucleus accumbens to counteract the motor stimulant effects of dopamine or enkephalin. Therefore, in the nucleus accumbens, neurotensin is not acting to modulate the mesolimbic dopamine system, but rather appears to antagonize behavioral hyperactivity, regardless of the neurochemical initiation
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Behavioral and neurochemical effects of neurotensin microinjection into the ventral tegmental area of the rat
The ventral tegmental area of the rat brain has been shown to possess high densities of neurotensin- and dopamine-containing neuronal perikarya. We recently demonstrated that microinjection of neurotensin into the ventral tegmental area produces behavioral hyperactivity similar to amphetamine-induced increase in exploratory behaviors, but lacking stereotypies. In this study, we report that the threshold dose for neurotensin-induced hyperactivity is 0.10–0.25 μg neurotensin/side. Either intracerebroventricular injection of haloperidol (5.0 μg/lateral ventricle) or destruction of the mesolimbic dopamine system by 6-hydroxydopamine abolishes the behavioral hyperactivity produced by intraventral tegmental injection of neurotensin (2.5 μg/side). Using high pressure liquid chromatography with electrochemical detection, we show that neurotensin injection into the ventral tegmental area increases the concentration of dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the nucleus accumbens and olfactory tubercles, but not in the striatum. This effect is especially profound in the nucleus accumbens where the threshold dose is less than 0.025 μg/side. The ratio of 3,4-dihydroxyphenylacetic acid to dopamine increased in the nucleus accumbens and olfactory tubercles in a dosedependent fashion (0.025 μg–2.50 μg/side). Neurotensin-induced behavioral hyperactivity correlates positively with neurotensin-induced changes in the ratio of 3,4-dihydroxyphenylacetic acid to dopamine.
This study indicates that neurotensin acts in the ventral tegmental area to activate the mesolimbic dopamine system. Further, this activation produces behavioral hyperactivity characterized by an increase in exploratory behaviors. The fact that both immunoreactive neurotensin and neurotensin receptors are found in high concentration in the ventral tegmental area supports the possible physiological significance of this peptide-catecholamine interaction
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