15 replies to this topic

[wannafulfill]

These studies interest me A LOT given our concern with nootropics that are mostly cholinergic in function. Let's please open the dialogue, as much as we dismiss Smart Drugs 2, there are some significant questions that I haven't gotten sufficient answers to. Namely, can we boost cholinergic function without adverse effects on mood and things like motivation? Does the following hypothesis for "affective psychoses" offer a valid frame for understanding, or even calling into question the indescriminate use of drugs like various forms of choline or cholinesterase inhibitors?

The cholinergic-adrenergic equilibrium
hypothesis of affective psychoses
by
Fritze J, Beckmann H
Psychiatrische Klinik und Poliklinik,
Universitat Wurzburg.
Fortschr Neurol Psychiatr 1988 Jan; 56(1):8-21

ABSTRACT
The biochemical effects of antidepressant drugs generated the hypothesis of disturbances in the noradrenergic system in the pathogenesis of affective disorders. However, interference with the cholinergic system also yields psychotropic sequelae. Central cholinomimetics revealed antimanic properties as opposed to antidepressant effects of anticholinergics. Therefore, in extension of the catecholamine hypothesis and again based on the paradigm of pharmacological isomorphism, a cholinergic-adrenergic balance hypothesis has been suggested for affective disorders. This postulates a cholinergic predominance relative to noradrenergic activity in depression and the converse in mania. Although there are indications of inverse behavioural effects of cholinergic as opposed to catecholaminergic stimulation in man and animal, there is only few evidence at the neurophysiological and biochemical level in favour of the net effects depending on such a balance. However, only the direct demonstration of a biochemical defect can prove the balance hypothesis. More probably, interindividually different defects must be expected. They need not necessarily involve the synaptic signal transduction directly. Strategies and findings which might demonstrate biochemical disturbances are presented and discussed.


Sodium valproate increases pupillary responsiveness
to a cholinergic agonist in responders with mania
by
DeMet EM, Sokolski KN
Mental Health Care Group,
Veterans Affairs Medical Center,
Long Beach, California 90822, USA.
Biol Psychiatry 1999 Aug 1; 46(3):432-6

ABSTRACT
BACKGROUND: The cholinergic hypothesis of affective disorders predicts that mania is a hypocholinergic state relative to monoaminergic activity. Treatments that increase cholinergic sensitivity are expected to improve manic symptoms. Valproic acid is an effective treatment for mania. Little, however, is known about the cholinergic effects of this agent. METHODS: Ten male hypomanic or manic patients were treated with valproic acid (1500-2000 mg) for 2 weeks. Cholinergic sensitivity was assessed before, and after treatment using graded concentrations of pilocarpine eyedrops (0.03-2.0%). Pupil size changes were quantified using an infrared pupillometer and ED50 values were referenced to maximal dilation with 0.5% tropicamide. RESULTS: Valproate treatment decreased Bech mania ratings and ED50 values (p < .0001). Improvements in mania after treatment were closely correlated with decreases in ED50 (r = .76; p < .01). This relationship was indistinguishable from one previously observed after lithium treatment. CONCLUSIONS: These results provide support for the cholinergic-adrenergic hypothesis. Moreover, similar pupillary reactions to valproic acid and lithium treatments suggest that these agents may share a common action on muscarinic receptors.

[wannafulfill]

From the review of Smart Drugs 2 here http://www.nootropics.com/index.html


"So what's the catch? One problem, to which not all authorities on nootropics give enough emphasis, is the complex interplay between cognition and mood. Great care should be taken before tampering with the noradrenaline/acetylcholine axis. Thought-frenzied hypercholinergic states, for instance, are characteristic of one "noradrenergic" sub-type of depression. A predominance of forebrain cholinergic activity, frequently triggered by chronic uncontrolled stress, can lead to a reduced sensitivity to reward, an inability to sustain effort, and behavioural suppression."

[johnmk]

A predominance of forebrain cholinergic activity, frequently triggered by chronic uncontrolled stress, can lead to a reduced sensitivity to reward, an inability to sustain effort, and behavioural suppression."

This sounds disturbingly like me, though things have been improving lately.

[wannafulfill]

Lifemirage I would like to know what you think if and when you get a chance. Thank-you very much!

[pinballwizard]

can someone translate this into basic-speak? in maybe a sentence or 2?

[wannafulfill]

The hypothesis, which has quite a bit of support, is that a cholinergic (such as acetylcholine) - adrenergic (such as dopamine, noradrenaline) balance system is involved in the regulation of drive and mood. This is supported by the fact that cholinomimetics have acute depressiogenic and antimanic properties and, conversely, anticholinergics have some acute euphoriant activity.

From what I understand the implications are important. Supplementing with things like choline donors, cholinesterase inhibitors, and other drugs which upregulate the cholinergic system (centrophenoxine, hydergine, racetams) could possibly cause an imbalance in the cholinergic-adrenergic balance.

I suspect supporters of these nootropics will stress the point in the first abstract, that "only the direct demonstration of a biochemical defect can prove the balance hypothesis." However, this same truth can potentially be put to the argument that demonstration of a biochemical defect should be a prerequisite for altering cholinergic activity.

I want to avoid reductionism here, because I would theoretically like a debate and the bringing of more knowledge to bear on the subject. However, my observation that various members of the forums interested in and taking nootropics have experiences with depression or lack of motivation, and have not expressed a concern with mania or milder dispositions approximating it much at all. This fact, combined with other members' comments have lead me to suspect that some people may already have an imbalance in this purported axis towards choline. [While it is a matter of the autonomic system, it is hypothesized that people with allergies (for reasons I'm looking into) have just that imbalance.] I, for one, have enough information to rule out such supplements and drugs in my own regimen.

Not all nootropics affect choline systems and things like deprenyl may be more useful in some people.

My concern, at the base, is that certain forums spread the attitude that advocates the indescriminate use of certain supplements for a one dimensional, simple effect such as "huperzine = better memory" or "Alpha-glycerylphosphorylcholine = improved cognitive function." While I realize many people have used these drugs without associated pathologies reported, I suggest a more comprehensive and cautionary approach.

Edited by wannafulfill, 20 July 2005 - 08:20 AM.

[wannafulfill]

...and allergies:


Allergy and depression: a neurochemical threshold
model of the relation between the illnesses
by
Marshall PS
Department of Psychiatry,
Hennepin County Medical Center,
Minneapolis, Minnesota 55415.
Psychol Bull 1993 Jan; 113(1):23-43

ABSTRACT
Empirical studies suggest a very high prevalence of atopic disorder in people with depression. Research indicates that individuals with allergy have cholinergic hyperresponsiveness and beta-adrenergic hyporesponsiveness in the autonomic nervous system. Evidence is reviewed that similar imbalances in central nervous system cholinergic-adrenergic activity play a casual role in depression behaviors. It is hypothesized that the allergic state or allergic reactions can accentuate cholinergic-adrenergic activity imbalances in the central nervous system of a small subgroup of people at risk for endogenous depression thereby producing depression symptomatology.

Eur Respir J 1995; 8: 752-754
Copyright © ERS Journals Ltd 1995


--------------------------------------------------------------------------------

Original Articles

Chronic allergen exposure enhances cholinergic neurotransmission in sensitized guinea-pigs
N Kageyama, A Igarashi, M Ichinose, M Miura, H Yamauchi, M Tomaki, J Ishikawa, Y Sasaki, and K Shirato


Airway hyperresponsiveness in asthmatic patients may be related to cholinergic hyperresponsiveness. In this study, we examined whether chronic allergen exposure induces cholinergic hyperresponsiveness in ovalbumin (OA) sensitized guinea-pig airways. Three weeks after active sensitization, ovalbumin (0.03%, for 3 min, challenged group) or saline inhalation (control group) was repeated every day for 4 weeks. Cholinergic responses were assessed by isometric tracheal contraction after electrical field stimulation (EFS) or exogenously applied acetylcholine (ACh). The contractions were expressed as a percentage of the maximum response to ACh (10(-3) M) (AChmax). We calculated the effective frequencies producing 25% of AChmax (EF25) from frequency-response curves. EFS-induced contractile responses were significantly enhanced in the challenged group (logEF25 = 0.66 +/- 0.08 (mean +/- SEM)) compared with the control group (logEF25 = 1.12 +/- 0.16). In contrast, exogenous ACh-mediated contractile tracheal responses were almost the same in both groups. We conclude that repeated allergen inhalation causes cholinergic airway hyperresponsiveness, presumably due to the facilitation of cholinergic neurotransmission. This mechanism may be involved in the airway hyperresponsiveness in asthmatic airways.


Cross-sectional associations of asthma, hay fever, and other allergies with major depression and low-back pain among adults aged 20-39 years in the United States
by
Hurwitz EL, Morgenstern H
Department of Epidemiology,
UCLA School of Public Health,
Los Angeles, CA, USA.
Am J Epidemiol 1999 Nov 15; 150(10):1107-16

ABSTRACT
Although low-back pain and depression are common comorbidities, the mechanisms responsible for their association remain unclear. The effects of proinflammatory cytokines on the hypothalamic-pituitary-adrenal (HPA) axis lead to the hypothesis that allergic reactions, as markers for inflammation-associated activation of the HPA axis, result in aberrant responses to subsequent stressors. Data from 6,836 US adults 20-39 years old from the Third National Health and Nutrition Examination Survey (1988-1994) were used. Subjects responded to questions regarding low-back pain in the past 12 months and history of asthma, hay fever, and other allergies. The history and onset of major depression were obtained from the Diagnostic Interview Schedule. Logistic regression modeling was used to estimate the associations between allergies and depression and low-back pain. Subjects with a history of any allergy were more likely to report low-back pain (odds ratio = 1.51; 95% confidence interval: 1.16, 1.96), to be diagnosed with major depression (odds ratio = 1.58; 95% confidence interval: 1.13, 2.21), and much more likely to have both major depression and low-back pain (odds ratio = 3.03; 95% confidence interval: 1.32, 6.92). Hypersensitivity reactions may prime the HPA axis to respond aberrantly to stressors, resulting in physical and behavioral consequences.

Edited by wannafulfill, 28 June 2005 - 05:53 AM.

[wannafulfill]

can someone translate this into basic-speak?  in maybe a sentence or 2?

It may be that I am not on to anything. After all, I came across this page the other day and actually learned something [bl:)] :

http://faculty.washi...ler/introb.html

[wannafulfill]

bump, I am still intensely interested in the questions I pose in the 6th post down from the top.

[mnosal]

Couldn't a daily dose of L-tyrosine say 3-4g help in keeping the Adrenergic/Cholinergic balance? As a precursor to the adrenergic neurotransmitters, Tyrosine should theoreticaly provide an excess in the same way Aplha-GPC or CDP choline provide an abundance of Acetylcholine.

[johnmk]

Would taking l-tyrosine be less (or not at all) neurotoxic compared to levodopa? I eat a high-ish protein diet, around 80 total grams per day. Sufficient for maintenance and some minor muscle building. Is this ample intake, i.e. might I already get plenty of l-tyrosine just from my food?

[mitkat]

da_sense, have you got any links/studies on that? I'm going to do some searching, but if you can remember where you saw that, lemme know, cause this topic has peaked my concern.

[scottl]

tyrosine in larger daily amounts could be toxic.

??? How can an amino acid be toxic?

Powerdrive and neurostim each contain several grams of tyrosine.

http://www.pdrhealth.../lty_0256.shtml

ADVERSE REACTIONS
L-tyrosine is generally well tolerated. There are some reports of those taking supplemental L-tyrosine experiencing insomnia and nervousness.

DOSAGE AND ADMINISTRATION
Those who use supplemental L-tyrosine typically take 500 to 1500 mg daily.


http://home.caregrou...ts/Tyrosine.htm
side effects/toxicity: L-Tyrosine has very low toxicity. There have been very few reports of toxicity.

About the only thing I can find is:

http://www.ncbi.nlm....st_uids=9125148
The toxicity of tyrosine metabolites has been suggested, but not proven, to play a role in the ethiopathogenesis of hepatic alterations observed in **hereditary tyrosinemia type I ** (prob not common)