2 replies to this topic

[birthdaysuit]

Adequate exercise, meditation, sufficient sleep and a healthy diet are important in regards to relieving anxiety, these are tasks I try to achieve everyday.

 

That being said, I have been taking picamilon for a few days now, which when taken orally is presumably suppose to cross the BBB and then hydrolyze into GABA and niacin. The released GABA in theory would activate GABA receptors. GABA is said to promote relaxation and better mood, but when I take picamilon I become lackadaisical and this often feeds the onset of panic because my volubility and verbal fluency decline. I feel quite dumbed down and unintelligent. However, I am more in control of these panicky feelings (like myo-inostiol) and I never feel like I’m going to depersonalize or lose control, which happens occasionally when I’m clearheaded. Picamilon is a GABA receptor agonist that affects the GABA-A receptor, similar to phenibut. Nevertheless. I definitely felt a sedative effect in dosages of 200-250mg. It doesn’t hyperpolarize the cell like alcohol does but it still has a depressant like effect. Also, I’m an angry drunk.

 

It is said that the reduced production of GABA-A sends false information to the amygdala which regulates the body's "fight or flight response" mechanism and in return, produces the physiological symptoms that lead to panic disorder. The “fight or flight response” is something I struggle with in social situations such as when I’m situated in a classroom, this is accompanied by increased sweating, piercing sounds, muscle tension/rapid muscle movement and intrusive thoughts. I’m also unable to look others in the eyes. I feel apprehension and impending doom. I certainly do not want to feel terror again! Hence, anxiety and fear responses are partly modulated by GABA type A receptor sites.  I’m just trying to figure out the connection between Picamilon and my panic. I know I’ve only been taking picamilon for a few days so I’ll continue to experiment for a few weeks.

 

Also, skullcap, valerian, l-theanine are GABA-A receptor Agonists. I also read that Taurine itself may have inhibitory effects, but it may also lead to increases in activity depending on administration. Also, L-Glutamine is a precursor to Glutamate, which is a precursor to GABA. So supplementing with that might help.

 

 

Phenibut is a GABAB receptor Agonist and Lemon balm, yet to try was identified as a potent inhibitor of GABA transaminase. The major compound responsible for GABA transaminase inhibition activity in lemon balm was then found to be rosemarinic acid.

 

Now, THC inhibits GABA, and boosts dopamine, malfunctioning in GABA signaling is associated with movement disorders (rapid muscle movement) as well as anxiety, schizophrenia, and addiction. This inhibition of GABA may be the reason cannabis consumption affects memory and movement and is therapeutic in cases such as Fibromyalgia. Now smoking strains high in THC, caused paranoia, social inhibition and panic attacks. Strains low in THC and high in CBD’s or just small inhales of 2nd hand smoke released the burden of anxiety and created a spontaneous, social, witty me. Also, after me panic induced cannabis attack I discovered that I have psoriasis throughout my hairline.

 

Inositol is a simple polyol precursor in a second messenger system important in brain myo-insitol, the natural isomer, which has been found to be therapeutically effective in depression, PANIC disorder, obsessive-compulsive disorder in double blind controlled trials and psoriasis. Now before I started taking this I panicked around people and had difficulty in situations were I was stuck on the phone for long periods of time. In general I was very uncomfortable in situations were I felt I could not escape. Inositol made it much easier for me to go with the flow; however, it also caused brain fog and short-term memory loss. Why is this? And what is the mechanism of action?

 

Inositol 'disruption' may be linked to depression, but that's surely when inositol gets too low, but because “myo-inostiol lowers testosterone levels” Zero concept of risk/reward process, motivational issues, sleeping beautifully, can't kick into gear on waking, can sleep whenever regardless of sleep had. So this could be a problem.

 

Pure fear with absence of any other emotions is felt as impending doom - a fear without a consciously known origin, these are feelings I struggle with in social situations and so badly want them to stop.

 

It is said that the emotion of pure fear can be induced chemically via kappa opioid receptor agonists.

 

Fear and motivation with no confidence is felt as anxiety->paranoia, these are feeling accompanied when smoking high THC-strains of cannabis. Dopamine increase and a motivation felt as paranoia. This does not include when I smoke strains low in THC and high in CBD. Something I have not done in over two years. 

 

Delta opioid network is in charge to reduce fear learning from perceived reward reduction and most probably to facilitate reward learning from perceived reward increase.

 

If there is enough delta opioid agonism, fear from failure to acquire predicted reward will not be learned, delta agonism will inhibit kappa opioid fear learning from reward prediction error.

 

“The evolutionary hypothesis based on the functional co-option of fear conditioning mechanisms into those subserving adjustment to incentive loss (Papini, 2003) requires some specificity as to the nature of those functions for the opioid system. In relation to fear conditioning, the opioid system has been suggested to play a role in modulating (1) the intensity of the shock-induced pain and signal-induced fear (Fanselow & Bolles, 1979), (2) the magnitude of the error- correction mechanism involved in fear acquisition and extinction (McNally, in press), and (3) the consolidation of the fear memory (McGaugh & Roozendaal, 2008).”

Delta opioids reduce acute frustration from reward failure - in short. They stop the induction of the current frustrated state to be analyzed and recorded by the brain as a fear cue - they stop fear cue learning that would result from reward failure.

 

The opioids latch onto to key nerual circuit points to recognize success in dopaminergic intent. They also latch onto noradrenaline neurons to determine failure in dopaminergic intent – which results in innate frustration before the fear response takes over. The opioids latch onto pain senses to recognize pain and numb it in response. Certainty of use is first learned for own body, moving hands and legs. Then for external objects like sword or steering wheel and in the end people as objects or even social concepts!

 

Fear is invoked each time certainty of action and reaction is doubted, engages the learning/challenge mode to learn the new context and remove threats, learn most effortless/painless use of reality. Learning certainty provides reward until 100% certainty is achieved after which there is no reward – this is in fact the mechanism that causes drug tolerance. After certainty is learned one can only feel fear when certainty of use comes in question. The drugs cause the user to learn more certainty than possible in reality, which causes fear-doubt depression in withdrawal. It also explains the PARANOIA created by dopaminergic drugs.

 

 

Moreover, a conditioned fear is often measured with freezing (a period of watchful immobility) or fear potentiated startle (the augmentation of the startle reflex by a fearful stimulus). Changes in heart rate, breathing and muscle responses via electromyography can also be used to measure conditioned fear.

 

Now, beta blockers block the action of endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) -in particular on adrenergic beta receptors, of the sympathetic nervous system, which mediates the “fight-or-flight response.” Something I struggle with in social situations. I tense up, sweat and often want to leave the area in hopes to find solitude. I’ll also feel intense sensations of impending doom when someone asks me a question or speaks my name. This can simply be paying for groceries, (some days worse than others.)

 

Passionflower stops the physical panic. I heard that L-Arginine and Hawthorne, Indian Snakeroot, coleus are good substitutes for betablockers, I just want a natural, holistic medicine.

 

PLEASE HELP!

Edited by birthdaysuit, 15 September 2015 - 07:55 PM.

[Junk Master]

If it's just too bad to deal with try a short course of low dose Clonazepam.

[gamesguru]

Interactions of a standardized flavonoid fraction from Tilia americana with Serotoninergic drugs in elevated plus maze.
Tilia americana var. mexicana (Schltdl) Hardin (Tiliaceae) aerial parts (bracts and flowers) are used in the traditional Mexican medicine to treat nervous disorders, as sedative and to treat insomnia. A fraction of this species called FC1 (organic fraction from this plant) was proposed, described as anxiolytic and characterized by the presence of flavonoids. In the present work, this fraction was standardized, and its interaction with different serotonergic drugs was tested. We used the elevated plus maze model as anxiety test and the open field test so as to observe a possible effect on mice׳s motor behavior.
HPLC technique was used to quantify the flavonoids contained in a fraction called F1C. Different doses of F1C were administered to ICR mice (12.5, 25, 37.5 and 50mg/kg, oral pathway) then they were exposed to elevated plus maze or open field test. After, each dose of F1C fraction was co-administered with different drugs, in order to evaluate the animal׳s behavior: DOI agonist (2.0mg/kg) and KET antagonist (0.03mg/kg) of 5-HT2A receptors; 8-OH-DPAT (0.1mg/kg) selective agonist and WAY100635 (0.5mg/kg) antagonist of 5HT1 receptors.
The HPLC quantitative analysis revealed the F1C composition (mg/g of extract): tiliroside (28.56), glucoside of quercetin (16.25), quercitrin (7.96), rutin (3.93), Kaempferol (2.83). The Emax for F1C curve was 80.6% for time to open arms with an ED50 of 15.09 mg/kg. The combination of F1C with DOI gives a significant increase of the flavonoids' anxiolytic effect, while KET blocks it completely (Emax=12.25% and ED50=2.4 mg/kg). The administration of F1C with 8-OH-DPAT does not generate significant changes on the time to open arms, although it does induce a decrement in F1C potency (Emax=83.3% and ED50=33.3mg/kg). When F1C and WAY-100365 are combined, the anxiolytic activity of the fraction decreases (Emax=33.3% and ED50=102.10mg/kg).
The medicinal use attributed to Tilia americana for their effect on central nervous system, could be in part in the flavonoid fraction (F1C) with anxiolytic activity which is dose dependent, and has the ability to interact with the serotonergic system. It is necessary to advance in the study of the mechanism of action, using other techniques such in vitro analysis.

Magnolol enhances pentobarbital-induced sleeping behaviors: possible involvement of GABAergic systems.
This study was performed to investigate whether magnolol enhances pentobarbital-induced sleeping behaviors through the GABAergic systems. Magnolol prolonged the sleeping time induced by pentobarbital. In addition, magnolol increased chloride influx in primary cultured cerebellar granule cells. The expression of the GABA(A) receptor alpha-subunit was increased selectively by magnolol, but magnolol had no effect on the abundance of beta- or gamma-subunits. The expression of glutamic acid decarboxylase (GAD) was not influenced by magnolol. It is suggested that magnolol may enhance pentobarbital-induced sleeping behaviors through the activation of GABAergic systems.

Falcarindiol Allosterically Modulates GABAergic Currents in Cultured Rat Hippocampal Neurons Abstract

 

"the effects on the amplitude of mIPSC and of the currents evoked by low [GABA] suggest an upregulation of agonist binding."

Falcarindiol (1), a C-17 polyacetylenic diol, shows a pleiotropic profile of bioactivity, but the mechanism(s) underlying its actions are largely unknown. Large amounts of 1 co-occur in water hemlock (Oenanthe crocata) along with the convulsant polyacetylenic toxin oenanthotoxin (2), a potent GABA_A receptor (GABA_AR) inhibitor. Since these compounds are structurally and biogenetically related, it was considered of interest to evaluate whether 1 could affect GABAergic activity, and for this purpose a model of hippocampal cultured neurons was used. Compound 1 significantly increased the amplitude of miniature inhibitory postsynaptic currents, accelerated their onset, and prolonged the decay kinetics. This compound enhanced also the amplitude of currents elicited by 3 μM GABA and accelerated their fading, reducing, however, currents evoked by a saturating (10 mM) GABA concentration. Moreover, kinetic analysis of responses to 10 mM GABA revealed that 1 upregulated the rate and extent of desensitization and slowed the current onset and deactivation. Taken together, these data show that 1 exerts a potent modulatory action on GABA_ARs, possibly by modulating agonist binding and desensitization, overall potentially decreasing the toxicity of co-occurring GABA-inhibiting convulsant toxins.

Chronic Caffeine Alters the Density of Adenosine, Adrenergic, Cholinergic, GABA, and Serotonin Receptors and Calcium Channels in Mouse Brain

1. Chronic ingestion of caffeine by male NIH strain mice alters the density of a variety of central receptors.

2. The density of cortical A₁ adenosine receptors is increased by 20%, while the density of striatal A_2A adenosine receptors is unaltered.

3. The densities of cortical β₁ and cerebellar β₂ adrenergic receptors are reduced by ca. 25%, while the densities of cortical α₁ and α₂ adrenergic receptors are not significantly altered. Densities of striatal D₁ and D₂ dopaminergic receptors are unaltered. The densities of cortical 5 HT₁ and 5 HT₂ serotonergic receptors are increased by 26–30%. Densities of cortical muscarinic and nicotinic receptors are increased by 40–50%. The density of cortical benzodiazepine-binding sites associated with GABA_A receptors is increased by 65%, and the affinity appears slightly decreased. The density of cortical MK-801 sites associated with NMDA-glutaminergic receptors appear unaltered.

4. The density of cortical nitrendipine-binding sites associated with calcium channels is increased by 18%.

5. The results indicate that chronic ingestion of caffeine equivalent to about 100 mg/kg/day in mice causes a wide range of biochemical alterations in the central nervous system.

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Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation
Stress is a major risk factor for the development of mood and anxiety disorders; elucidation of novel approaches to mitigate the deleterious effects of stress could have broad clinical applications. Pharmacological augmentation of central endogenous cannabinoid (eCB) signaling may be an effective therapeutic strategy to mitigate the adverse behavioral and physiological consequences of stress. Here we show that acute foot-shock stress induces a transient anxiety state measured 24 h later using the light–dark box assay and novelty-induced hypophagia test. Acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), reverses the stress-induced anxiety state in a cannabinoid receptor-dependent manner. FAAH inhibition does not significantly affect anxiety-like behaviors in non-stressed mice. Moreover, whole brain anandamide levels are reduced 24 h after acute foot-shock stress and are negatively correlated with anxiety-like behavioral measures in the light–dark box test. These data indicate that central anandamide levels predict acute stress-induced anxiety, and that reversal of stress-induced anandamide deficiency is a key mechanism subserving the therapeutic effects of FAAH inhibition. These studies provide further support that eCB-augmentation is a viable pharmacological strategy for the treatment of stress-related neuropsychiatric disorders.

Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the ‘runner’s high’
Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the ‘runner’s high’, which may function to encourage habitual aerobic exercise. Endocannabinoids (eCBs) are endogenous neurotransmitters that appear to play a major role in generating these rewards by activating cannabinoid receptors in brain reward regions during and after exercise. Other species also regularly engage in endurance exercise (cursorial mammals), and as humans share many morphological traits with these taxa, it is possible that exercise-induced eCB signaling motivates habitual high-intensity locomotor behaviors in cursorial mammals. If true, then neurobiological rewards may explain variation in habitual locomotor activity and performance across mammals. We measured circulating eCBs in humans, dogs (a cursorial mammal) and ferrets (a non-cursorial mammal) before and after treadmill exercise to test the hypothesis that neurobiological rewards are linked to high-intensity exercise in cursorial mammals. We show that humans and dogs share significantly increased exercise-induced eCB signaling following high-intensity endurance running. eCB signaling does not significantly increase following low-intensity walking in these taxa, and eCB signaling does not significantly increase in the non-cursorial ferrets following exercise at any intensity. This study provides the first evidence that inter-specific variation in neurotransmitter signaling may explain differences in locomotor behavior among mammals. Thus, a neurobiological reward for endurance exercise may explain why humans and other cursorial mammals habitually engage in aerobic exercise despite the higher associated energy costs and injury risks, and why non-cursorial mammals avoid such locomotor behaviors.

 

 

"Hossainet al. (2002) showed that catechin and epicatechin, as well as their 3-gallate derivatives, possessed negative modulatory action at α1β2 GABAA receptors"

 

Plant-derived flavanol (-)epicatechin mitigates anxiety in association with elevated hippocampal monoamine and BDNF levels, but does not influence pattern separation in mice.
Flavanols found in natural products such as cocoa and green tea elicit structural and biochemical changes in the hippocampus, a brain area important for mood and cognition. Here, we evaluated the outcome of daily consumption of the flavanol (-)epicatechin (4 mg per day in water) by adult male C57BL/6 mice on measures of anxiety in the elevated plus maze (EPM) and open field (OF). Furthermore, pattern separation, the ability to distinguish between closely spaced identical stimuli, considered to be mediated by the hippocampal dentate gyrus (DG), was tested using the touchscreen. To investigate mechanisms through which (-)epicatechin may exert its effects, mice were injected with bromodeoxyuridine (50 mg kg(-1)) to evaluate adult hippocampal neurogenesis. In addition, monoaminergic and neurotrophin signaling pathway proteins were measured in tissue derived from subject cortices and hippocampi. Flavanol consumption reduced anxiety in the OF and EPM. Elevated hippocampal and cortical tyrosine hydroxylase, downregulated cortical monoamine oxidase-A levels, as well as increased hippocampal brain-derived neurotrophic factor (BDNF) and pro-BDNF support the flavanol's anxiolytic effects. In addition, elevated pAkt in hippocampus and cortex was observed. (-)Epicatechin ingestion did not facilitate touchscreen performance or DG neurogenesis, suggesting a non-neurogenic mechanism. The concurrent modulation of complementary neurotrophic and monoaminergic signaling pathways may contribute to beneficial mood-modulating effects of this flavanol.

Chronic Administration of Catechin Decreases Depression and Anxiety-Like Behaviors in a Rat Model Using Chronic Corticosterone Injections
Previous studies have demonstrated that repeated administration of the exogenous stress hormone corticosterone (CORT) induces dysregulation in the hypothalamic-pituitary-adrenal (HPA) axis and results in depression and anxiety. The current study sought to verify the impact of catechin (CTN) administration on chronic CORT-induced behavioral alterations using the forced swimming test (FST) and the elevated plus maze (EPM) test. Additionally, the effects of CTN on central noradrenergic systems were examined by observing changes in neuronal tyrosine hydroxylase (TH) immunoreactivity in rat brains. Male rats received 10, 20, or 40 mg/kg CTN (i.p.) 1 h prior to a daily injection of CORT for 21 consecutive days. The activation of the HPA axis in response to the repeated CORT injections was confirmed by measuring serum levels of CORT and the expression of corticotrophin-releasing factor (CRF) in the hypothalamus. Daily CTN administration significantly decreased immobility in the FST, increased open-arm exploration in the EPM test, and significantly blocked increases of TH expression in the locus coeruleus (LC). It also significantly enhanced the total number of line crossing in the open-field test (OFT), while individual differences in locomotor activities between experimental groups were not observed in the OFT. Taken together, these findings indicate that the administration of catechin prior to high-dose exogenous corticosterone significantly improves helpless behaviors, possibly by modulating the central noradrenergic system in rats. Therefore, CTN may be a useful agent for the treatment or alleviation of the complex symptoms associated with depression and anxiety disorders.

 

but it could also cause anxiety:
(-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons.
Emerging evidence suggests that the cellular actions of flavonoids relate not simply to their antioxidant potential but also to the modulation of protein kinase signalling pathways. We investigated in primary cortical neurons, the ability of the flavan-3-ol, (-)epicatechin, and its human metabolites at physiologically relevant concentrations, to stimulate phosphorylation of the transcription factor cAMP-response element binding protein (CREB), a regulator of neuronal viability and synaptic plasticity. (-)Epicatechin at 100-300 nmol/L stimulated a rapid, extracellular signal-regulated kinase (ERK)- and PI3K-dependent, increase in CREB phosphorylation. At micromolar concentrations, stimulation was no longer apparent and at the highest concentration tested (30 mumol/L) (-)epicatechin was inhibitory. (-)Epicatechin also stimulated ERK and Akt phosphorylation with similar bell-shaped concentration-response characteristics. The human metabolite 3'-O-methyl-(-)epicatechin was as effective as (-)epicatechin at stimulating ERK phosphorylation, but (-)epicatechin glucuronide was inactive. (-)Epicatechin and 3'-O-methyl-(-)epicatechin treatments (100 nmol/L) increased CRE-luciferase activity in cortical neurons in a partially ERK-dependent manner, suggesting the potential to increase CREB-mediated gene expression. mRNA levels of the glutamate receptor subunit GluR2 increased by 60%, measured 18 h after a 15 min exposure to (-)epicatechin and this translated into an increase in GluR2 protein. Thus, (-)epicatechin has the potential to increase CREB-regulated gene expression and increase GluR2 levels and thus modulate neurotransmission, plasticity and synaptogenesis.
AMPA receptor GluR2, but not GluR1, subunit deletion impairs emotional response conditioning in mice.
Deletions of gria1 or gria2 genes encoding alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic-acid-receptor subunits differ in their effects on appetitive conditioning. The authors investigated whether similar differences would occur in an aversive conditioning test. The ability of a discrete stimulus paired with footshock to subsequently inhibit food-maintained operant responding (conditioned emotional response) was examined in mice with deletions of gria1 or gria2 genes. Whereas gria1 knockout (KO) mice performed normally compared with wild-type (WT) controls, gria2 KO mice displayed no reduction in response rates when the shock-paired stimulus was presented. Nevertheless, gria2 KOs displayed evidence of freezing in a footshock-paired context, indicating that aversive learning could occur. In addition, gria1 KO mice showed some evidence of increased anxiety, and gria2 KOs showed reduced anxiety, in the elevated plus-maze.

and watch out for mania if predisposed:
The Role of Hippocampal GluR1 and GluR2 Receptors in Manic-Like Behavior
The cellular basis underlying the complex clinical symptomatology of bipolar disorder and the mechanisms underlying the actions of its effective treatments have not yet been fully elucidated. This study investigated the role of hippocampal synaptic AMPA receptors. We found that chronic administration of the   antimanic agents lithium and valproate (VPA) reduced synaptic AMPA receptor GluR1/2 in hippocampal neurons   in vitro and in vivo. Electrophysiological studies confirmed that the  AMPA/NMDA ratio was reduced in CA1 regions of hippocampal slices from lithium-treated animals . Reduction in GluR1 phosphorylation at its cAMP-dependent protein kinase A site by the synthetic peptide TAT-S845, which mimics the effects of lithium or VPA, was sufficient to attenuate surface and synaptic GluR1/2 levels in hippocampal neurons in vitro and in vivo. Intrahippocampal infusion studies with the AMPA-specific inhibitor GYKI 52466 [4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine hydrochloride], a GluR1-specific TAT-S845 peptide, showed that GluR1/2 was essential for the development of manic/hedonic-like behaviors such as amphetamine-induced hyperactivity. These studies provide novel insights into the role of hippocampal  GluR1/2 receptors in mediating facets of the manic syndrome and offer avenues for the development of novel therapeutics   for these disorders. 

Edited by gamesguru, 17 September 2015 - 06:21 PM.