Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction, and the thoughtful regulation of attention, action, and emotion. For example, schizophrenia, depression, long COVID, and Alzheimer's disease are all associated with dlPFC dysfunction, with neuropathology often being focused in layer III. The dlPFC has extensive top-down projections, e.g., to the posterior association cortices to regulate attention and to the subgenual cingulate cortex via the rostral and medial PFC to regulate emotional responses. However, the dlPFC is particularly dependent on arousal state and is very vulnerable to stress and inflammation, which are etiological and/or exacerbating factors for most mental disorders. The cellular mechanisms by which stress and inflammation impact the dlPFC are a topic of current research and are summarized in this review. For example, the layer III dlPFC circuits that generate working memory-related neuronal firing have unusual neurotransmission, depending on NMDA receptor and nicotinic α7 receptor actions that are blocked under inflammatory conditions by kynurenic acid. These circuits also have unusual neuromodulation, with the molecular machinery to magnify calcium signaling in spines needed to support persistent firing, which must be tightly regulated to prevent toxic calcium actions. Stress rapidly weakens layer III connectivity by driving feedforward calcium-cAMP (cyclic adenosine monophosphate) opening of potassium channels on spines. This is regulated by postsynaptic noradrenergic α_2A adrenergic receptor and mGluR3 (metabotropic glutamate receptor 3) signaling but dysregulated by inflammation and/or chronic stress exposure, which contribute to spine loss. Treatments that strengthen the dlPFC via pharmacological (the α_2A adrenergic receptor agonist, guanfacine) or repetitive transcranial magnetic stimulation manipulation provide a rational basis for therapy.

2022-05-01·European Journal of Pharmacology3区 · 医学

Tasipimidine—the pharmacological profile of a novel orally active selective α2A-adrenoceptor agonist

3区 · 医学

Article

作者: Aspegren, John ; Unkila, Kaisa ; Lehtimäki, Jyrki ; Haapalinna, Antti ; Pesonen, Ullamari ; Jalava, Niina

The pharmacological profile of tasipimidine, a novel orally active α₂-adrenoceptor agonist developed for situational anxiety and fear in dogs, was studied in various in vitro and in vivo models. In the cell assays, tasipimidine demonstrated binding affinity and full agonism on the human α_2A-adrenoceptors with a pEC50 of 7.57, while agonism on the α_2B-and α_2C-adrenoceptors and the rodent α_2D-adrenoceptor was weaker, resulting in pEC50 values of 6.00, 6.29 and 6.56, respectively. Tasipimidine had a low binding affinity on the human α₁-adrenoceptors. It had no functional effects in the LNCaP cells expressing endogenously the human α_1A-adrenoceptors but was a weak agonist in the Chem-1 cells coexpressing Gα15 protein and α_1A-adrenoceptors. In the recombinant CHO cells, although tasipimidine was a weak partial agonist in the inositol monophosphate accumulation assay, it was a full agonist in the intracellular [Ca²⁺] assay. No functional effects were observed on the human α_1B-adrenoceptor, whereas in the rat α_1A and α_1B-adrenoceptors, tasipimidine was a weak partial agonist. In the rat vas deferens preparations, tasipimidine was a full agonist on the α_2D-adrenoceptor but weak partial agonist on the α₁-adrenoceptor. The receptor profile of tasipimidine indicated few secondary targets, and no functional effects were observed. Sedative effects of tasipimidine were demonstrated in vivo by the reduced acoustic startle reflex in rats with subcutaneous doses and decreased spontaneous locomotor activity in mice with subcutaneous and higher oral doses. It may be concluded that tasipimidine is an orally active and selective α_2A-adrenoceptor agonist.

2021-03-01·Research in Veterinary Science3区 · 农林科学

Hippocampal monoamine changes in the Flinders sensitive line rat: A case for the possible use of selective α2C-AR-antagonists in stress and anxiety disorders in companion animals

3区 · 农林科学

Article

作者: Brian H. Harvey ; Leith C.R. Meyer ; Francois P. Viljoen ; Quixi Sonntag ; Madeleine M. Uys ; Mohammed Shahid

Non-selective α₂-adrenoreceptor (AR) stimulation delivers favourable sedative, analgesic, muscle relaxant and anxiolytic actions in companion animals, but is associated with cardiovascular and respiratory side effects. Anxiety conditions underscore monoamine disturbances amenable to α₂-AR modulation. We investigated sub-chronic (14 day s.c.) treatment with the selective α_2C-AR antagonist, ORM-10921 (0.03, 0.1, 0.3 mg/kg/d) on hippocampal noradrenaline (NA), dopamine (DA), serotonin (5-HT) and their turnover levels in stress sensitive Flinders Sensitive Line (FSL) rats versus Flinders Resistant Line (FRL) controls, using high performance liquid chromatography. The effects of ORM-10921 were compared to the non-selective α₂-AR antagonist, idazoxan (IDAZ; 3 mg/kg/d), and to imipramine (IMI; 15 mg/kg/d), a reference antidepressant in this model. FSL rats displayed significantly reduced 5-HT (p = 0.03) and DA (p = 0.02) levels vs. FRL controls, while NA levels showed a similar trend. ORM-10921 significantly increased NA (all doses p ≤ 0.02), 5-HT (0.1 and 0.3 mg/kg p ≤ 0.03) and DA levels (all doses p ≤ 0.03), which correlated with decreased monoamine turnover. In contrast, IDAZ significantly elevated NA (p < 0.005) and DA (p < 0.004) but not 5-HT levels. IMI also significantly increased 5-HT (p < 0.009), with a tendency to increase NA (p = 0.09) but not DA. ORM-10921 exerts similar albeit broader effects on hippocampal monoamines than IDAZ, explaining earlier established efficacy associated with α_2C-AR antagonism in animal models of depression and cognitive dysfunction. These and the current studies encourage application of ORM-10921 in depression in humans, as well as raise the intriguing possibility that selective α_2C-AR antagonists may be beneficial in anxiety and stress-related disorders in companion animals. Both warrant further study.

100 项与 α2A-AR antagonists(Institute of Organic Chemistry & Biochemistry AS CR v.v.i) 相关的药物交易

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