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- Borroto-Escuela, DO, et al.
(author)
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Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia-Relevance for Mental Diseases
- 2021
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In: Cells. - : MDPI AG. - 2073-4409. ; 10:8
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Journal article (peer-reviewed)abstract
- The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1–15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.
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- Cantero-Garcia, N, et al.
(author)
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The Combination of Galanin (1-15) and Escitalopram in Rats Suggests a New Strategy for Alcohol Use Disorder Comorbidity with Depression
- 2022
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In: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:2
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Journal article (peer-reviewed)abstract
- Alcohol use disorder (AUD) is highly prevalent, and over 50% of AUD patients also suffer major depressive disorders. Selective 5-HT reuptake inhibitors (SSRIs) can reduce rodent ethanol drinking but exert modest clinical efficacy in alcoholic individuals. Finding new pharmacological strategies that could modulate alcohol consumption and depression is necessary. We have analyzed the effect of Galanin (1–15) [GAL(1–15)] on escitalopram (ESC)-mediated effect in alcohol consumption using the alcohol self-administration test, the nuclei involved in the effect, and whether GAL(1–15) + ESC modulated the response in despair or anxiety tests in animals under chronic alcohol intake. GAL(1–15) + ESC combination substantially reduced alcohol intake in the alcohol self-administration test and, moreover, enhanced the reduction of reward capacity of ESC on different reinforcers such as sucrose or saccharine. GAL(1–15) + ESC coadministration significantly decreases the number of C-Fos-IR TH cell bodies in the VTA, and PCA analysis suggests that one functional network, including VTA, RMTg and DR, is involved in these effects. Significantly in rats with chronic alcohol consumption, GAL(1–15) reversed adverse ESC-mediated effects in the depression-related behavioural test and forced swimming test. The results open up the possibility of using GAL(1–15) in combination with the SSRI Escitalopram as a novel strategy in AUD comorbidity with depression.
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- Diaz-Cabiale, Z., et al.
(author)
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Long-term modulation by postnatal oxytocin of the α2-adrenoceptor agonist binding sites in central autonomic regions and the role of prenatal stress
- 2004
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In: Journal of neuroendocrinology (Print). - : Wiley. - 0953-8194 .- 1365-2826. ; 16:3, s. 183-190
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Journal article (peer-reviewed)abstract
- The aim of this work was to evaluate whether oxytocin administered in male rats subcutaneously early in life in the absence or presence of food restriction during pregnancy has life-long effects on the α2-agonist binding sites in the nucleus of the solitarii tract (NTS), in the hypothalamus and the amygdala, as evaluated by quantitative receptor autoradiography. Maternal food restriction alone increased the affinity of the α2-agonist [3H]UK14.304 binding sites exclusively in the NTS. In offspring from ad libitum fed dams, oxytocin treatment significantly increased the density of α2-agonist binding sites in the NTS and in the hypothalamus. The Kd value of the α2-agonist binding sites in the hypothalamus of these rats, but not in the other regions studied, was also significantly increased. In offspring from food-restricted dams, oxytocin treatment produced a significant increase of the Bmax values in the hypothalamus and the amygdala and the Kd value of the α2-agonist binding sites in the NTS of these rats also was selectively and significantly increased. These results suggest that a postnatal, oxytocin-induced increase of regional α2-adrenoceptor function can be seen in adulthood by a persistent, regionally selective increase in the density of central α2-adrenoceptor agonist binding sites, in the absence of an affinity change in the NTS. Such a regional increase of α2-adrenoceptor signalling in adulthood may contribute to the anti-stress action of postnatal oxytocin. By contrast, after prenatal stress, the potential increase in α2-adrenoceptor signalling takes place via selective increases of density with no changes of affinity of the α2-agonist binding sites in the hypothalamus and the amygdala.
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- Diaz-Cabiale, Z, et al.
(author)
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Oxytocin/alpha(2)-Adrenoceptor interactions in feeding responses
- 2000
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In: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 71:3, s. 209-218
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Journal article (peer-reviewed)abstract
- The modulation of α<sub>2</sub>-adrenoceptor-induced food intake by oxytocin has been evaluated in studies on food intake and by quantitative receptor autoradiography in the hypothalamus and the amygdala of the rat. The effects of lateral intracerebroventricular administration of clonidine and oxytocin were evaluated on food intake in satiated animals. Food consumption was measured at 30, 90, 240 min and 22 h (1,320 min) after injection. The coinjection of oxytocin and clonidine was found to counteract the increase in food intake produced by clonidine (p < 0.001) in satiated rats. Receptor autoradiographic experiments showed that oxytocin significantly increased the K<sub>d</sub> values of [<sup>3</sup>H]<i>p</i>-aminoclonidine α<sub>2</sub>-agonist-binding sites in the hypothalamus. Effective oxytocin concentrations ranged between 0.3 and 1 n<i>M</i> (p < 0.05) with a maximal action of 250% at 1 n<i>M</i>. The B<sub>max</sub> value was significantly increased (p < 0.05) for all concentrations of oxytocin. In the amygdala, oxytocin also increased both the K<sub>d</sub> of [<sup>3</sup>H]<i>p</i>-aminoclonidine-binding sites by about 190% at 1 n<i>M</i> and the B<sub>max</sub> values at 1 and 3 n<i>M</i> (p < 0.05). Oxytocin (1 n<i>M</i>) also significantly and substantially (p < 0.01) increased the K<sub>d</sub> and B<sub>max</sub> values of the [<sup>3</sup>H]UK 14.304 α<sub>2</sub>-agonist-binding sites in the hypothalamus and amygdala in agreement with the results obtained with the other agonist of the α<sub>2</sub>-adrenoceptor [<sup>3</sup>H]<i>p</i>-aminoclonidine. This effect was partially blocked by the presence of the specific oxytocin receptor antagonist, CAP. These findings suggest the existence of an antagonistic oxytocin/α<sub>2</sub>-receptor interaction in the hypothalamus and amygdala that may be of relevance for the demonstrated modulation of α<sub>2</sub>-adrenoceptor-induced feeding responses by oxytocin.
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