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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 14 of 14. This is the beginning of the thread.
Posted by B2chica on December 11, 2008, at 13:10:56
i have a question regarding phasic vs. tonic inhibitory currents.
do psychotropic medications effect or adjust for the neurotransmitter currents?
origianally i was reading about GABAergic inhibition and it was talking about its tonic properties.
and i was wondering about the medications that we are on.
do they effect the 'natural' (flawed or not) current of transmitters?b2c.
Posted by B2chica on December 11, 2008, at 13:28:14
In reply to phasic vs. tonic inhibitory currents/psych med, posted by B2chica on December 11, 2008, at 13:10:56
found a study re effects of vigabatrin (which inhibits GABA transaminase)
first Gabapentin increased a tonic inhibitory conductance.
next they found that High-affinity GABAa receptors (which generate the tonic current) may detect small increases in the 'ambient' concentration of neurotransmitter caused by gabapentin.So GABAa receptors were 'insensitive to the acute application of gabapentin, wheraes chronic treatment increased the amplitude of the tonic current threefold.'
the meds that come to mind are:
Depakote, Nardil (gaba increase -gaba transaminase inhibition
Topomax, gabaA receptor enhancement
and what about provigil since it is a GABA decrease?any input appreciated.
thanks
b2c.
Posted by Phillipa on December 11, 2008, at 13:36:33
In reply to Re: phasic vs. tonic inhibitory currents/psych med, posted by B2chica on December 11, 2008, at 13:28:14
Mind if I follow as seriously don't understand. But would like to learn since believe gaba is my problem? Love Phillipa
Posted by desolationrower on December 11, 2008, at 14:47:32
In reply to Re: phasic vs. tonic inhibitory currents/psych med, posted by B2chica on December 11, 2008, at 13:28:14
hm, this is an interesting topic. I was unaware of particular phasic/tonic effects with gaba, but it does happen in many other systems. USually it is tonic activation, often of extrasynaptic autoreceptors, which controls phasic levels released. I'll try to look into this when i have some time. What was the context you were thinking abotu this in?
-d/r
Posted by B2chica on December 11, 2008, at 15:35:06
In reply to Re: phasic vs. tonic inhibitory currents/psych med, posted by desolationrower on December 11, 2008, at 14:47:32
well i know that psych meds obviously effect certain neurotransmitter in a manner of agonist, inhibitor, but didn't know if they effect the current as well?
since GABA is tonic, my theory goes that
when emotionally normal, normal GABA is tonic, when in a manic phase the current somehow becomes phasic and thats why some meds may not effect mania, because they effect the NT themselves and not the current which in some cases may be the only 'disorder' if you will.i was also thinking then that 'normal' serotonin levels would be phasic, and when a person becomes depressive the serotonin takes on a tonic attribute. thus why some AD's make you manic, not needing a serotonin LEVEL adjustment, but just need a 'current adjustment'...
i'm not saying tonic/phasic across the board mind you. i'm just thinking outloud. and that maybe Some peoples issue may not be the level of neurotransmitter but the current of it.
*****************
and keep in mind i just learned about these tonic/phasic variables in nt today, so i really don't know much about it, thats why the inquiry.
but i'm very excited to learn more about this...thanks for checking on your end too!
b2c.
Posted by B2chica on December 11, 2008, at 15:38:48
In reply to phasic vs. tonic inhibitory currents/psych med, posted by B2chica on December 11, 2008, at 13:10:56
some meds that brought me to this thinking were the Gaba related meds.
Gabapentin
Nardil
Depakote
Topomax
all GABA inhibitor transanamise
and provigil GABA decreasethese all effect GABAa or b
*********************
but now i'm not "looking" at certain drugs, more the theory of 'phasic/tonic intervention'.
Posted by B2chica on December 11, 2008, at 15:44:23
In reply to Re: phasic vs. tonic inhibitory currents/psych med » B2chica, posted by Phillipa on December 11, 2008, at 13:36:33
of course follow alone. but keep in mind that i used GABA as an example because thats the study that i could find talking about tonic attributes. (GABA is known tonic in mammals)
but i'm also talking across the board of effects on all NT. definately looking at serotonin and dopamine.
Posted by B2chica on December 11, 2008, at 15:57:24
In reply to phasic vs. tonic inhibitory currents/psych med, posted by B2chica on December 11, 2008, at 13:10:56
Some interesting tidbits from an article.
"Receptors with Different Affinities Mediate Phasic and Tonic GABAA
Conductances in Hippocampal Neurons"
-the last paragraph you kind of have to sort through to get the good info from. but it wasn't clear unless i copied it all here.
"A nondesensitizing receptor with high affinity for GABA located extrasynaptically would be ideal for mediating tonic currents. It is therefore possible that different kinetics and binding affinities of the different subpopulations of GABAARs underlying tonic and phasic conductances cause them to respond differently when exposed to competitive antagonists.""The binding mechanisms of agonists and competitive antagonists are fundamentally distinct (Jones et al., 2001) and have been shown to be unrelated for GABA and the competitive GABAAR antagonist SR95531 (gabazine) on _- and _-subunit-containing receptors (Wafford et al., 2001). Receptors containing either of these two mutually exclusive subunits (Araujo et al., 1998) have similar affinities for SR95531 (Wafford et al., 2001), but _-subunit containing receptors have a 50-fold higher affinity for GABA than _-subunit-containing receptors (Saxena and Macdonald, 1996).
Therefore, because of their different GABA affinities, a nonsaturating concentration of a competitive antagonist with the appropriate properties would more likely prevent GABA binding and thus block _-subunit-containing receptors to a greater extent than _-subunit-containing receptors. The Kon and Koff values for SR95531 are 4.28 _ 107 M-1 sec -1 and 9.1 sec_1, respectively (Jones et al., 1998), indicating that the binding affinity and off rate are sufficient to differentially affect high- and low-affinity GABAARs. If tonic inhibition recorded in dentate gyrus granule cells is primarily mediated by GABAARs with a higher affinity for GABA than receptors mediating phasic inhibition, then there should be a concentration of SR95531 that will barely block tonic inhibition but considerably antagonize phasic inhibition. Furthermore, very high concentrations of this antagonist should outcompete GABA at both receptors and completely block both conductances. We have previously demonstrated these predictions with a kinetic model of tonic and phasic inhibition using a nondesensitizing, high GABA-affinity receptor"
Posted by Phillipa on December 11, 2008, at 19:58:55
In reply to Re: phasic vs. tonic inhibitory currents/psych med » Phillipa, posted by B2chica on December 11, 2008, at 15:44:23
Thanks very complicated to me. Phillipa
Posted by desolationrower on December 12, 2008, at 2:22:36
In reply to Re: phasic vs. tonic inhibitory currents/psych med » desolationrower, posted by B2chica on December 11, 2008, at 15:35:06
> well i know that psych meds obviously effect certain neurotransmitter in a manner of agonist, inhibitor, but didn't know if they effect the current as well?
> since GABA is tonic, my theory goes that
> when emotionally normal, normal GABA is tonic, when in a manic phase the current somehow becomes phasic and thats why some meds may not effect mania, because they effect the NT themselves and not the current which in some cases may be the only 'disorder' if you will.I think they operate on a much more frequent level, every second there is phasic activation of many gabaergic neurones...hm, theres a lot on this, but i think there can be a link, normally when i think of tonic/phasic i think of role in modulating the orchestration of neurones into sysmtes in the brain, and the information processing stuff. i liked maths but reading calculus and statistics is just too much for me to remember. but tied in with bipolar, it could be analogus to epilepsy kindling, at least thats what i think of when i think of improper gaba neurone patterns, the improper synchronizing of neurones in the brain.
> i was also thinking then that 'normal' serotonin levels would be phasic, and when a person becomes depressive the serotonin takes on a tonic attribute. thus why some AD's make you manic, not needing a serotonin LEVEL adjustment, but just need a 'current adjustment'...
i think something like this might be the case with the locus caeruleus and norepinephrine... i think phasic activation is reduced by methylphenidate, so behaviour is less activated, tonic is increased, more attentive to surroundings...
> i'm not saying tonic/phasic across the board mind you. i'm just thinking outloud. and that maybe Some peoples issue may not be the level of neurotransmitter but the current of it.
>
> *****************
> and keep in mind i just learned about these tonic/phasic variables in nt today, so i really don't know much about it, thats why the inquiry.
> but i'm very excited to learn more about this...
>
> thanks for checking on your end too!
>
> b2c.good to bring this up, instead of just 'more vs. less' of a transmitter...it all matters, circuits/location, pattern of activation, interplay with immune system, etc.
-d/r
Posted by B2chica on December 12, 2008, at 7:47:36
In reply to Re: phasic vs. tonic inhibitory currents/psych med » Phillipa, posted by B2chica on December 11, 2008, at 15:44:23
Posted by B2chica on December 12, 2008, at 7:53:12
In reply to Re: phasic vs. tonic inhibitory currents/psych med, posted by desolationrower on December 12, 2008, at 2:22:36
> i think something like this might be the case with the locus caeruleus and norepinephrine... i think phasic activation is reduced by methylphenidate, so behaviour is less activated, tonic is increased, more attentive to surroundings...
this is very interesting. i've been on methylphenidate for several years, initially for ADD, but honestly it helps SO much with my depression. infact at one period (about four months) i was only on ritalin for my depression.-i ended up needing much more, but just had to mention.
>
> good to bring this up, instead of just 'more vs. less' of a transmitter...it all matters, circuits/location, pattern of activation, interplay with immune system, etc.Exactly my thoughts.
thanks for your input.
b2c.
Posted by desolationrower on December 18, 2008, at 0:03:47
In reply to Re: phasic vs. tonic inhibitory currents/psych med » desolationrower, posted by B2chica on December 12, 2008, at 7:53:12
Hm, here are a few things I came across that may be of some interest. Didn't see anything that made me go wow tho.
Good overview of physiology -> http://www.ion.ucl.ac.uk/~dkullman/TiNSTonic.pdf
Involved in getting pissed ->
Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity
ABSTRACT
Neuronal mechanisms underlying alcohol intoxication are unclear. We find that alcohol impairs motor coordination by enhancing tonic inhibition mediated by a specific subtype of extrasynaptic GABAA receptor (GABAR), alpha6beta3delta, expressed exclusively in cerebellar granule cells. In recombinant studies, we characterize a naturally occurring single-nucleotide polymorphism that causes a single amino acid change (R100Q) in alpha6 (encoded in rats by the Gabra6 gene). We show that this change selectively increases alcohol sensitivity of alpha6beta3delta GABARs. Behavioral and electrophysiological comparisons of Gabra6 100R/100R and Gabra6 100Q/100Q rats strongly suggest that alcohol impairs motor coordination by enhancing granule cell tonic inhibition. These findings identify extrasynaptic GABARs as critical targets underlying low-dose alcohol intoxication and demonstrate that subtle changes in tonic inhibition in one class of neurons can alter behavior.PMDD link -> http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2012942
GAbapentin/vigabatrin work by reversing GABA transport by changing transport gradient setpoint, gabapentin increases transports expression, vigabatrin only enhances tonic inhibition. wonder if same for gabati like phenelzine metabolite? Also tonic activated extrasynaptic receptors don't downregualte? hm. if alcohol works by that, explains lack of significatn alcohol tolerance (other than the ETOH metabolizing enzyme stuff)
http://jn.physiology.org/cgi/reprint/90/3/1363.pdf
PMID: 12966170oooh, and then i found this->
Chronic intermittent ethanol-induced switch of ethanol actions from extrasynaptic to synaptic hippocampal GABAA receptors.
Liang J, Zhang N, Cagetti E, Houser CR, Olsen RW, Spigelman I.
ABSTRACT
Alcohol withdrawal syndrome (AWS) symptoms include hyperexcitability, anxiety, and sleep disorders. Chronic intermittent ethanol (CIE) treatment of rats with subsequent withdrawal of ethanol (EtOH) reproduced AWS symptoms in behavioral assays, which included tolerance to the sleep-inducing effect of acute EtOH and its maintained anxiolytic effect. Electrophysiological assays demonstrated a CIE-induced long-term loss of extrasynaptic GABAA receptor (GABAAR) responsiveness and a gain of synaptic GABAAR responsiveness of CA1 pyramidal and dentate granule neurons to EtOH that we were able to relate to behavioral effects. After CIE treatment, the alpha4 subunit-preferring GABAAR ligands 4,5,6,7 tetrahydroisoxazolo[5,4-c]pyridin-3-ol, La3+, and Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5alpha][1,4]benzodiazepine-3-carboxylate) exerted decreased effects on extrasynaptic currents but had increased effects on synaptic currents. Electron microscopy revealed an increase in central synaptic localization of alpha4 but not delta subunits within GABAergic synapses on the dentate granule cells of CIE rats. Recordings in dentate granule cells from delta subunit-deficient mice revealed that this subunit is not required for synaptic GABAAR sensitivity to low [EtOH]. The profound alterations in EtOH sensitivity and alpha4 subunit localization at hippocampal GABAARs of CIE rats suggest that such changes in these and other relevant brain circuits may contribute to the development of tolerance to the sleep-inducing effects and long-term dependence on alcohol.link to epilepsy->http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1176385
Tonic GABAergic Inhibition of Sympathetic Preganglionic Neurons: A Novel Substrate for Sympathetic Control
ABSTRACT
The sympathetic tone is primarily defined by the level of activity of the sympathetic preganglionic neurons. We report a novel inhibitory influence on sympathetic activity, that of tonic GABAergic inhibition which could have a profound global effect on sympathetic outflow. Recording from identified SPNs in the intermediolateral cell column (IML) of rat spinal cord slices, application of the GABA receptor antagonist bicuculline, but not gabazine, elicited a change in voltage that lasted for the duration of application. This response was mediated by a direct effect on SPNs since it persisted in tetrodotoxin and low Ca2+/high Mg2+ and the amplitude of responses were related to Cl concentration in patch solutions. Such tonic inhibitory responses were not observed in interneurons, the other neuronal type in the IML, although ongoing IPSPs were antagonized in these neurons. The effects of bicuculline were enhanced by diazepam but not zolpidem or the GABA modulators THIP and THDOC suggesting a role for {alpha}5 subunits. PCR using primers for the {alpha}5 and {delta} subunits indicated the presence of {alpha}5, but not {delta} subunits in the IML. Firing rates of SPNs were enhanced by bicuculline and decreased by diazepam indicating that this tonic inhibition has a profound effect on the excitability of SPNs. These data indicate a novel influence for controlling the activity of SPNs regardless of their function.hm, how does this relate to tonic levles?-> GABATransporterDeficiencyCausesTremor,Ataxia,
Nervousness,andIncreasedGABA-InducedTonic
ConductanceinCerebellum
http://orphanin.caltech.edu/~lester/world/Reprints%20from%20our%20lab/2005/Chiu-JNS-2005.pdf
Reduced anxiety and depression-like behaviors in mice lacking GABA transporter subtype 1.
Liu GX, Cai GQ, Cai YQ, Sheng ZJ, Jiang J, Mei Z, Wang ZG, Guo L, Fei J.
ABSTRACT
Gamma-aminobutyric acid (GABA) transporter subtype 1 (GAT1), which transports extracellular GABA into presynaptic neurons, plays an important regulatory role in the function of GABAergic systems. However, the contributions of the GAT1 in regulating mental status are not fully understood. In this paper, we observed the behavioral alterations of GAT1 knockout (GAT1(-/-)) mice using several depression- and anxiety-related models (eg, the forced-swimming test and the tail-suspension test for testing depression-related behaviors; the open-field test, the dark-light exploration test, the emergence test, and the elevated plus maze (EPM) test for anxiety-related behaviors). Here we found that GAT1(-/-) mice showed a lower level of depression- and anxiety-like behaviors in comparison to wild-type mice. Furthermore, GAT1(-/-) mice exhibited measurable insensitivity to selected antidepressants and anxiolytics such as fluoxetine, amitriptyline, buspirone, diazepam, and tiagabine in the tail-suspension test and/or the EPM test. Moreover, the basal level of corticosterone was found to be significantly lower in GAT1(-/-) mice. These results showed that the absence of GAT1 affects mental status through enhancing the GABAergic system, as well as modifying the serotonergic system and the hypothalamic-pituitary-adrenal (HPA) activity in mice.sleep-> Extrasynaptic GABAA receptors of thalamocortical neurons: a molecular target for hypnotics.
ABSTRACT
Among hypnotic agents that enhance GABAA receptor function, etomidate is unusual because it is selective for beta2/beta3 compared with beta1 subunit-containing GABAA receptors. Mice incorporating an etomidate-insensitive beta2 subunit (beta(2N265S)) revealed that beta2 subunit-containing receptors mediate the enhancement of slow-wave activity (SWA) by etomidate, are required for the sedative, and contribute to the hypnotic actions of this anesthetic. Although the anatomical location of the beta2-containing receptors that mediate these actions is unknown, the thalamus is implicated. We have characterized GABAA receptor-mediated neurotransmission in thalamic nucleus reticularis (nRT) and ventrobasalis complex (VB) neurons of wild-type, beta2(-/-), and beta(2N265S) mice. VB but not nRT neurons exhibit a large GABA-mediated tonic conductance that contributes approximately 80% of the total GABAA receptor-mediated transmission. Consequently, although etomidate enhances inhibition in both neuronal types, the effect of this anesthetic on the tonic conductance of VB neurons is dominant. The GABA-enhancing actions of etomidate in VB but not nRT neurons are greatly suppressed by the beta(2N265S) mutation. The hypnotic THIP (Gaboxadol) induces SWA and at low, clinically relevant concentrations (30 nM to 3 microM) increases the tonic conductance of VB neurons, with no effect on VB or nRT miniature IPSCs (mIPSCs) or on the holding current of nRT neurons. Zolpidem, which has no effect on SWA, prolongs VB mIPSCs but is ineffective on the phasic and tonic conductance of nRT and VB neurons, respectively. Collectively, these findings suggest that enhancement of extrasynaptic inhibition in the thalamus may contribute to the distinct sleep EEG profiles of etomidate and THIP compared with zolpidem.-d/r
Posted by B2chica on December 18, 2008, at 8:02:41
In reply to Re: phasic vs. tonic inhibitory currents/psych med, posted by desolationrower on December 18, 2008, at 0:03:47
thanks, that's some good searchin. i had read two of the articles posted, but i liked the rest. unfortunately, like you said...nothings sticking out.
i'm going to read further into your links and additional.thanks so much for this!
b2c.
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