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Sunday, September 14, 2014

All About "GABA" - Interactions, Analysis and Conclusions

        GABA is the primary inhibitory (calming) neurotransmitter in the Mammmalian / Human nervous system, in most areas it acts to inhibit glutamate release, and efflux of noradrenaline and dopamine(1).

                                                GABAergic Inhibition of Glutamate

However, GABA also has additional effects and in some instances may be mildly stimulating. GABA acts to regulate a number of other neurotransmitters, specifically decreasing serotonergic firing, and can be considered an additional factor in the neuroendocrine inhibition of cortisol, ACTH and prolactin(2) (3) (4) (5). Thus GABA deficiencies may result in stress related disorders, "simulated" stress responses and elevated prolactin levels. GABA also plays a role in growth hormone release, mainly increasing it(6).

GABA, like other neurotransmitters and neuromodulators can bind to a receptor to exert it's effects. In the case of GABA, there are two main receptor groups - GABA-A and GABA-B.

GABA-B seems to have a strong neuroendocrine role, and affects stress related responses, as well as having peripheral effects on muscle relaxation and contraction.

GABA-A has many sites, the target of drugs mainly being benzodiazepine sites - which help to produce relaxation (both neurological and muscular). GABA also has gamma,beta and alpha subtype sites, and neurosteroids play a large role in regulating these sites(7).

Pregnenolone, Cortisol, Opioids, Androgens and Estrogen..and many other hormones regulate GABA activity.

Cortisol seems to increase GABA at mild concentrations, whereas at higher concentrations it inhibits GABA activity (8) (9).

Allopregnenolone (a neurosteroid) affects GABA and acts to increase GABA-ergic opening and potentiation of Chloride influx, and thus may enhance the relaxing effects of GABA. However, pregnenolone itself may act to negatively modulate GABA in certain brain areas(10)(11).

Vitamin D also regulates GABA transmission, primarily to inhibit it in many brain regions(12) (13), but may yet increase it in others - mainly by indirect actions on serotonin by Vitamin D and it's steroidal metabolites(14)

Opioids and opioid agonists act primarily to inhibit and decrease GABA activity - thus if your question lies in why opioids cause anxiety - this may represent an important part of it(15).

Being that endogenous and exogenous opioid activity affects GABA in a negative manner, and yet also disturbs other neuroendocrine systems, such as sex hormone release and causing prolactin increases - opioid activity may in other ways decrease GABA as well - making opioids both an indirect and direct antagonist of GABA activity(16) (17).

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