Dopaminergic and ligand-independent activation of steroid hormone receptors

Postmarketing experience has shown that diarrhea may be a sign of drug-induced microscopic colitis , primarily lymphocytic colitis . In these cases diarrhea has usually been moderate to severe, watery, and non-bloody, at times associated with dehydration, abdominal pain, weight loss, and hypokalemia. In the majority of cases, diarrhea and other colitis-related symptoms resolved or significantly improved when Comtan treatment was stopped. In some patients with biopsy confirmed colitis, diarrhea had resolved or significantly improved after discontinuation of Comtan but recurred after retreatment with Comtan.

The ventral tegmental area and substantia nigra pars compacta receive inputs from other neurotransmitters systems, including glutaminergic inputs, GABAergic inputs, cholinergic inputs, and inputs from other monoaminergic nuclei. The VTA contains 5-HT 1A receptors that exert a biphasic effects on firing , with low doses of 5-HT 1A receptor agonists eliciting an increase in firing rate, and higher doses suppressing activity. The 5-HT 2A receptors expressed on dopaminergic neurons increase activity, while 5-HT 2C receptors elicit a decrease in activity. [26] The mesolimbic pathway, which projects from the VTA to the nucleus accumbens, is also regulated by muscarinic acetylcholine receptors . In particular, the activation of muscarinic acetylcholine receptor M2 and muscarinic acetylcholine receptor M4 inhibits dopamine release, while muscarinic acetylcholine receptor M1 activation increases dopamine release. [27] GABAergic inputs from the striatum decrease dopaminergic neuronal activity, and glutaminergic inputs from many cortical and subcortical areas increase the firing rate of dopaminergic neurons. Endocannabinoids also appear to have a modulatory effect on dopamine release from neurons that project out of the VTA and SNc. [28] Noradrenergic inputs deriving from the locus coeruleus have excitatory and inhibitory effects on the dopaminergic neurons that project out of the VTA and SNc. [29] [30] The excitatory orexinergic inputs to the VTA originate in the lateral hypothalamus and may regulate the baseline firing of VTA dopaminergic neurons. [31] [32]

The most important reward pathway in brain is the mesolimbic dopamine system, composed of the VTA (ventral tegumental area) and NAc (nucleus accumbens). This (VTA-NAc) circuit is a key detector of a rewarding stimulus. Under normal conditions, the circuit controls an individual's responses to natural rewards, such as food, sex, and social interactions, and is therefore an important determinant of motivation and incentive drive. In simplistic terms, activation of the pathway tells the individual to repeat what it just did to get that reward. It also tells the memory centers in the brain to pay particular attention to all features of that rewarding experience, so it can be repeated in the future. Not surprisingly, it is a very old pathway from an evolutionary point of view. The use of dopamine neurons to mediate behavioral responses to natural rewards is seen in worms and flies, which evolved ~1 billion years ago.

Dopaminergic and ligand-independent activation of steroid hormone receptors

dopaminergic and ligand-independent activation of steroid hormone receptors

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