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MDMA & PPI - Unique to Humans

phase_dancer

phase_dancer

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PPI or pre-pulse inhibition is the measure of startle response. PPI is reflective of cognitive and other responses, and is indicative in patients suffering Schizophrenia, obsessive/compulsive disorders and Huntingtons disease.

This paper looks at how humans respond to PPI tests after various pre-treatments followed by MDMA. What is very interesting is that humans are affected in the opposite way to rodents which seem to have reduced PPI when given MDMA.


Effects of MDMA (Ecstasy) on Prepulse Inhibition and Habituation of Startle in Humans after pretreatment with Citalopram, haloperidol, or Ketanserin

[From the Introduction]

Startle

The startle reflex is a contraction of the skeletal and facial musculature in response to a sudden intense stimulus, such as a loud noise. In humans, the eyeblink component of the startle reflex is measured using electromyography of the orbicularis oculi muscle. In rodents, a stabilimeter is used to register a whole-body flinch response. The startle reflex exhibits several forms of behavioral plasticity, such as prepulse inhibition

(PPI) and habituation, which are consistent phenomena across species. PPI refers to the normal suppression ofthe startle response when the startling stimulus is precededby a weak prestimulus. PPI is regarded as an operational measure of sensorimotor gating reflecting the ability to filter cognitive or sensory information. Habituation refers to the decrement of the startle response observed with repeated presentation of the stimulus and is considered to be the simplest form of learning and a prerequisite of selective attention. Both PPI and habituation deficits have been found in patients with schizophrenia (Bolino et al. 1994; Braff et al. 1992; Geyer and Braff 1982) and schizotypal personality disorder (Cadenhead et al. 1993). Deficits in PPI are also seen in obsessive–compulsive disorder(Swerdlow et al. 1993) and Huntington’s disease (Swerdlow et al. 1995).

....Little is known about the pharmacology of PPI in humans. Surprisingly, a recent study from our laboratory found that MDMA (1.7 mg/kg PO) increased PPI in healthy volunteers, thus having an opposite effect on sensorimotor gating in humans versus animals (Vollenweider et al. 1999a). Whether procedural or species-specific differences, including a different mechanism of action of MDMA, account for these findings is unclear. Therefore, the aims of the present study were several. First, the previous findings of an MDMA-induced increase in PPI should be confirmed. Second, three pretreatments—the highly selective serotonin uptake inhibitor citalopram,the D2antagonist haloperidol, and the 5-HT 2A/C antagonist ketanserin—were used in order to prevent MDMA effects on PPI to the extent that they depend on:
(1) MDMA-induced carrier-mediated release of presynaptic serotonin,
(2) D2 stimulation, or
(3)5-HT 2A/C stimulation.

It was hypothesized that citalopram would attenuate the effect of MDMA on PPI, based on the fact that selective serotonin uptake inhibitors reduce MDMA-induced serotonin release (Gudelsky and Nash 1996; Hekmatpanah and Peroutka 1990; Koch and Galloway 1997) and behavioral effects in animals (Callaway et al. 1990). Third, correlations should be assessed between differences in MDMA-induced psychological changes and changes in %habituation or %PPI.
Click to expand...
 
This seems interesting......wish I could fully get my head around it.
 
p_d, I know it's a long stretch and perhaps I'm simply being unrealistically hopeful...

But do you think that the difference in effects of MDMA on PPI in rodents/humans could be an indication that concluding neurotoxicity in humans exists is a syllogism perhaps not as credible as many believe?
 
Apollo, I don't think it's really a good indication. First of all, it's a well known fact that animals don't always have the same responses to drugs as humans. For example, opiates are depressants in humans, but they are stimulants in rats (one thing you notice when you give a rat morphine, for example, is that it starts running around with its tail sort of stiffly curved upwards - it's called a Straub tail). And, in fact, it is so well known that rodents in particular can react wildly differently than humans to drugs that, when testing new drugs, there's a rule that, before it gets to human trials, the drug has to be tested in at least three different species of animal, only one of which is allowed to be a rodent. Anyways, just because there was this discrepancy, doesn't mean the neurotoxicity models are inherently flawed.

One thing that did occur to me, though. If MDMA increases PPI, and PPI is decreased in schizophrenic (etc.) patients, then perhaps in the not too distant future (and in the pharmaceuticals world, that means about 20 years) we'll see MDMA analogues being used to treat these conditions... of course, the fact that MDMA screws with PPI could also be part of the reason that it can be psychotoxic (ie. it can induce conditions such as schizophrenia in sensitive people - generally people who are right on the edge of having it anyway). Either way, it'd be interesting to look into (give me something to do for my honours project :))
 
^^ Agreed
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Please keep us informed with any such project phantasmal.


In a rough attempt to offer a plausible explanation to possible behavioral expression differences between species.... 8(

Apollo I'm generalising here with a few guesses thrown, but don't forget the significant differences between higher and lower brain function in primates and humans compared to that with other animals. Defining intelligence, much of this can be explained by the relative density differences for various receptors, neurotransmitters etc in the human brain compared to the brains of animals.

It could well be said that because rodents operate primarily with lower brain function, they are sensitised to startle response, as awareness/reaction time equates to a greater chance of survival in lower species. In rodents, MDMA causes a stronger degree of lower brain response (compared to humans) resulting in decreased PPI (increased response time). For most animal species this would occur with any situation not familiar, which would be processed as being potentially dangerous.

Perhaps not in so much of a contrast, humans find their lower brain function comes more into play during moments of confusion, fear, anxiety tension, etc. But as MDMA causes the opposite with most people, it likely has a secondary affect of reducing lower brain function in humans (explains increased empathy/reduced sex drive). MDMA also disrupts memory processing. This must occur at a chemical level which does not (usually) stimulate an instinctive panic (fright/flight) reaction. Users feel safe.

PP reaction time is primarily a lower brain function. Fear and ultimate awareness can be distinguished as being opposite ends of the same ruler, involving lower & higher brain function respectively; Fear w/out confusion (initially) increases PP reaction time. In contrast is the schizophrenic who has learned to live with and even accept the condition of irregular and incomplete thought-memory processing. The patient may have subconsciously "learned" to endogenously control or restrict normal chemical response to situations in attempt to better manage themselves (survive). PP is either disrupted or possibly just not processed quickly enough (altered priority?) to cause an instant response.


These are just my thoughts on the matter. They fit with my limited knowledge of neuropharmacology but I have no experience in psychology other than a year or 2 of life observations. So please feel free to flame or completely ridicule.
 
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