12 replies to this topic

[medievil]

PDE10

Only very recently, PDE10-Is have become a target for CNS research, especially concerning the cognitive deficits related to schizophrenia (Schmidt et al. 2008). In the next section, a summary of the available literature on PDE10-Is and cognition will be given; a more detailed overview can be found in Table 7.


Table 7

Overview of effects of PDE10-Is on cognition
Chronic treatment with the PDE10-I papaverine impaired spatial memory and reversal learning in unimpaired mice in the Morris water maze (Hebb et al. 2008). Administration of TP-10 did not have an effect on information processing in a prepulse inhibition task in unimpaired and MK-801-impaired mice (Schmidt et al. 2008). However, TP-10 reversed the auditory gating deficit caused by d-amphetamine in rats (Schmidt et al. 2008). Papaverine improved attention in the attention shifting task in rats that were impaired by subchronic phenylcyclohexylpiperidine (PCP) treatment, a model of schizophrenia, whereas no effect was found in unimpaired rats (Rodefer et al. 2005).

Several studies also used KO models to study the role of PDE10 in cognition. It was shown that PDE10A knockout in a DBA1LacJ background had no effect on learning and memory in the passive avoidance and water escape task in mice (Siuciak et al. 2006, 2008b). In addition, these mice showed the same conditioned avoidance response as wild-type mice; however, these KO mice required more training to reach the performance of wild-type animals (Siuciak et al. 2006, 2008b). On the other hand, PDE10A KO mice with a C57BL/6N background were unable to reach the performance of the wild-type mice in this task (Siuciak et al. 2008b).

The data discussed in the previous paragraphs showed that PDE10-Is can improve cognition in impaired animals, but can also induce a cognitive impairment in healthy animals. There are several explanations that might account for these contradictory findings. First, the cognitive impairment in healthy animals caused by papaverine was the result of a subchronic treatment, which was not found after acute treatment in impaired animals. Secondly, different aspects of cognition were addressed in these studies. In the healthy animals, learning and memory were studied, whereas in the impaired animals, information processing and attention were investigated. Thirdly, improving cognition of a healthy individual is not the same as restoring impaired cognition; the underlying processes, and thus the effect of a compound, may differ.

So it appears that in impaired conditions like shizophrenia they are helpfull without impairment while they kick the alpha mice in the ass.
now since there are reasons to beleive that AVPD; ADHD; OCD relate to shizophrenia i wonder wheter they will be therapeutic for those conditions.

And after i suspected this i found a patent talking about PDE10 inhibitors for shizo; anxiety; OCD and ADHD so maybe im onto something.

There's one thats easy to get; papaverine

[medievil]

To probe negative symptoms, we ran the compounds in a
model that evaluates social behaviors in rodents, known as
the SASA model (Moy et al., 2004; Sankoorikal et al., 2006).
Because social interaction in rodents can be impaired by
NMDA antagonism and PDE10A inhibition normalizes
NMDA antagonist effects in other models, we reasoned that
these compounds might enhance social behaviors. Moreover,
a recent report found increased social interaction in
PDE10A2 knockout mice (Sano et al., 2008). In the SASA
model, both PDE10A inhibitors increased the amount of time
spent by the BALB/c mice on the social side of the test
chamber compared with vehicle treatment. This intriguing
finding supports further investigation of PDE10A inhibitors
in other assays modeling negative symptom domains, such as
NMDA antagonist-induced anhedonia. This is an active area
of our current research. Together with the efficacy in antipsychotic and cognition models, these data also suggest that
PDE10A inhibition has the potential to be a true broadspectrum agent for the treatment of schizophrenia.

http://jpet.aspetjou.../2/574.full.pdf

[medievil]

D2-like receptors are often stimulated by tonic levels of DA release,
457 whereas D1-like receptors are stimulated primarily during phasic
458 DA release (Goto et al., 2007).

PDE10 Inhibitors lower tonic D2 and potentiate D1 i cant help but think i may be onto something but well see...
http://zaldlab.psy.v...ns/mtt10nbr.pdf

That paper explains the neurobiology behind anhedonia.

The similarities and differences between the behavioral effects of the PDE10A inhibition and D2 receptor blockade may be explained by contrasting their effects on striatal function. The striatum is the primary site of midbrain dopaminergic and cortical glutamatergic input to the basal ganglia, a subcortical circuit that functions as a cortical feedback loop. Within the striatum, cortically driven response options are reinforced according to coincident dopaminergic regulation of two functionally opposed striatal projections referred to as the direct and indirect pathways (Cheer et al., 2007). Direct pathway MSNs selectively express D1 receptors positively coupled to adenylyl cyclase. Phasic, D1 receptor-mediated increases in cAMP enhance the activity of direct pathway MSN to facilitate ongoing behaviors. Although the indirect pathway functions to tonically inhibit behavior, the MSNs forming these projections express D2 receptors negatively coupled to adenylyl cyclase hence their activity is inhibited by dopamine (see Surmeier et al., 2007). Thus, appropriately timed increases in dopamine release can facilitate behavior by simultaneously enabling direct pathway activity and inhibiting indirect pathway activity. In contrast, behavioral patterns coincident with reduced dopaminergic signaling are deselected due to decreased direct pathway activity and increased indirect pathway activity.

Edited by medievil, 02 June 2012 - 09:52 AM.

[medievil]

Administration of a concentration (100 μM) of dipyridamole that blocks PDE8 inhibited ecto-phosphodiesterase activity (by 44%). However, a lower concentration of dipyridamole (3 μM) that blocks PDE9, PDE10, and PDE11, but not PDE8, did not inhibit ecto-phosphodiesterase activity.

This shit we may be looking for.

[medievil]

Hmm

High dose curcumin for PDE2 and 4 inhibition
High dose luteolin for PDE2;4 and 5 inhibition
Some kind of lasting form of papaverine
Forskolin

Potentially perfectly modulates dopaminergic activity for people with ADHD; AVPD; OCD; Anhedonia and shizophrenia?
Its just a wild gues but ive been reading fucking papers all night; PDE may be the key for negative symptions.

If not meh lets stay at amp.

The hypothesis that PDE10A inhibition will produce an
antipsychotic response in the clinic is supported by the behavioral effects of TP-10. In particular, TP-10 reduced exploratory locomotor activity, activity stimulated by the uncompetitive NMDA antagonist PCP, and that resulting from
the administration of amphetamine. PCP models a hypoglutamatergic state and is reported to produce behavioral effects
similar to the positive, negative, and cognitive symptoms of
schizophrenia in humans (Johnson and Jones, 1990; Jentsch
and Roth, 1999), whereas amphetamine mimics the hyperdopaminergic state believed to contribute to the generation of
psychotic symptoms

Ive been reading articles like that non stop the past day shit if this shit doesnt induce neurogenesis like learning should do i dont know what will. Time to watch porn.

Edited by medievil, 02 June 2012 - 10:37 PM.

[medievil]

Im back in belguim; ill go get some papaverine today and add it to my combo of a stim, prami and ginseng and see what it does, it likely wont be intresting for non impaired people as it probably makes them worse.

[Nattzor]

So this would be really compatible with CILTEP?

[medievil]

It may be, the issue is that PDE10 inhibition impairs memory in healthy animals so it can only help those with mental issues.

I ended up forgetting to get papaverine before i went back to the UK so cant really report back unfortionally, any idea wheter its otc in the UK?

[medievil]

Ill go get some papaverine if there'rs any way to use it therapeutically, seems to come in ampoules to inject in your dick or other places? can you drink some fluid? and how much is a normal dose?

I know the half life is shit but wonna know what it does?
it looks extremely interesting, and now that im back in belguim might give it a try, with candlefat can make timerelease.

[medievil]

For got sake shit to inject in your dick is otc but viagra needs a script.

[medievil]

"PAPAVERINE HOUD AMP INJ 100MG"

Biol Psychiatry. 1976 Apr;11(2):217-25.
Effect of oral papaverine on cerebral blood flow in normals: evaluation by the xenon-133 inhalation method.

Wang HS, Obrist WD.

Abstract

Several issues related to the use of vasoactive drugs in the treatment of neuropsychiatric disorders secondary to cerebrovascular insufficiency remain unresolved due to lack of a practical method for the quantitative measurement of cerebral blood flow (CBF). The present report concerns the use of a noninvasive CBF method in the evaluation of a commonly used vasoactive drug (oral papaverine). Series CBF measurements were made by the Xe133 inhalation method in 21 healthy young adults, using a double-blind crossover experimental design. The findings show that oral papaverine (300 mg b.i.d.) significantly increases blood flow under conditions of both normal breathing and hyperventilation, the latter being used to induce cerebral vasoconstriction. There were large variations in individual response to the drug, and the average increase in CBF (6 to 9%) was smaller than that observed by other investigators using intravenous papaverine. No adverse reactions or alterations in blood pressure were encountered.

So can anyone confirm, would it be safe to drink a ampoules and note what effects it has, as 100mg is around the oral dose?

[medievil]

http://contraceptin....t&product_id=29

Stuff seems to be cheap online, but can i try the ampoules as the doses in them are far less so it prob wont work? its otc here so could just give it a try.

Not that im too bothered got a bit tired of trying shit but bored as hell and stuff can work like viagra if im correct.

Edited by medievil, 27 January 2013 - 12:56 AM.

[lourdaud]

Interesting!

Anyone know where to get luteolin or rolipram btw??