I saw this posted on bluelight.com by yaesutom. I had a look through
https://www.thevespiary.org/rhodium/Rhodium/pharmacology/bzp.txt
, and didn't this article in there. I also had a check with the fse and didn't see it either.
Neuropharmacology of BZP
1-Benzylpiperazine (BZP) has a peripheral sympathomimetic action and a
complex central action, both directly and indirectly acting upon on all
monoamine[1, 2, 3]. There are few experiments investigating the nature of
BZPs mechanism of action, and they are mainly in vitro, and on peripheral
nerves. This article attempts to unify the existing research, to
extrapolate the results to an in vitro, central situation and, in light
of recent advances in pharmacology, clarify certain findings.
The action of BZP on the noradrenergic system has two main facets. The
first is the action on the a-2 adrenoreceptor, and the second is on the
noradrenergic uptake carrier. The a2-adrenoreceptor is the receptor that
mediates presynaptic negative feedback, both centrally and peripherally
in the adrenergic system. BZP has been shown to be an antagonist at the
a2-adrenoreceptor[1], thus negating negative feedback at the synapse, and
causing a larger stimulation evoked release of neurotransmitter. This is
the same process as yohimbine, though, BZP is some 10,000 times less
potent, but possibly just as efficacious[1]. These results were found
from experimenting on peripheral nerves, not central ones, and it is
possible that BZP has no a2-antagonist properties in the CNS. I find it
likely that BZPs central a2 action is extremely limited, especially at
recreational doses, but even if there is a significant a2-receptor
blockade, it does not effect the subjective experience, and is more
likely to effect things like blood pressure. BZP has also been shown to
inhibit the reuptake of noradrenaline (NA)[1, 3]. The reuptake inhibition
is amphetamine-like (a theme you will come to recognize), and hence also
causes the stimulation independent release of NA[1]. Although the
experiments which showed the stimulation independent release of NA was
done on peripheral nervous tissues, a study has been done to show that
this action is probably exhibited in central nerves as well[3]. This
amphetamine-like reuptake inhibition is probably BZPs noradrenergic
action of most consequence in the CNS. In the peripheral nervous system,
the a2-adrenoreceptor blockade is almost certainly responsible for most
of the symptoms, as addition of clonidine (an a2 receptor agonist) blocks
almost all of the effect of BZP in peripheral tissue[1].
The action of BZP on dopaminergic system is probably just restricted to
the amphetamine-like reuptake inhibition and stimulation independent
release of dopamine (DA). BZP has been shown increase the concentration
of DA in a cell free homogenate of subcortical rat brain, and decrease
the amount of DA found in cells after 14 days of treatment[3].
The action of BZP on the serotonergic system is the most studied aspect
of BZPs action, as one member of the team of experimenters that did most
of the research into BZP, was an employee of a drug company eager to
prove the serotoninomimetic action of BZP (as this indicates more action
as an antidepressant, and less possibility of abuse). Results show that
BZP increases the amount of serotonin (5-HT) in the extracellular fluid
surrounding subcortical neurons and decreases the amount of 5-HT in cells
after 14 days of treatment, indicating that BZP exhibits the now familiar
amphetamine-like inhibition of reuptake and stimulation independent
release of 5-HT[3]. On top of this central and probably peripheral
amphetamine-like action, BZP seems to be an agonist of the 5-HT2B
receptor. The logic behind the conclusion that BZP acts as a direct
agonist at the 5-HT2B receptor is as follows: When BZP is applied to
isolated rat stomach, it causes the smooth muscle to contract, and this
contraction is blocked by methergoline, indicating the process is
receptor mediated[2]. This could indicate that BZP is a direct 5-HT
receptor agonist, but it could also be explained by the fact that BZP
causes 5-HT to be released from nerves. BZP also causes hyperthermia in
rats at high ambient temperature an effect blocked by the 5-HT antagonist
cyproheptadine, but not by amitriptyline[3]. Amitriptyline binds to the
5-HT reuptake carrier, probably blocking BZPs amphetamine-like action.
Seeing that BZP can still exhibit a serotonergic action, while the
stimulation-independent release of 5-HT is blocked, shows that it must be
directly activating a 5-HT receptor, and seeing that it causes stomach
contraction, which is mediated by the 5-HT2B receptor, it must be a
direct agonist at the 5-HT2B receptor. The potency of BZP at the 5-HT2B
receptor must be at least 100,000 times less that 5-HT[2], meaning that
functionally, it is closer to an antagonist than an agonist.
When one compares the contribution of these different neurotransmitter to
the pharmacological action of BZP it is likely that 5-HT is the major
player, as BZP has the highest affinity for the 5-HT reuptake carrier
(IC50 2.9 x 10-6 mol/L). It is likely that NA and DA play a roughly equal
role centrally
(reuptake carrier IC50 2.8 x 10-5 mol/L and 1.3 x 10-5 mol/L
respectively)[3]. Peripherally, NA is the largely responsible for BZPs
peripheral effects, as NA is the main mediator of the sympathetic nervous
system.
The ability for BZP to induce dependance initially looks marked, as it
has a pronounced central dopaminergic action[3], but if one considers all
the factors, this may not be so. Tolerance to BZPs central action will
develop quickly, as it probably accumulates in synaptic vesicles in the
same fashion as amphetamine, while tolerance to BZPs peripheral blockade
of a2-adrenoreceptors will be limited or nonexistent. This will moderate
the abuse potential, as if dependence does develop it will occur along
with central tolerance, and if an individual tries to up the dose of BZP
to overcome the tolerance, the peripheral effects (mediated by the a2
receptor) would be intolerable.
In summary, BZPs action could be described as somewhere between
amphetamine and MDMA including a yohimbine like action as well, with
limited to moderate abuse potential.
[1] Magyar, K., Fekete, MIK., Tekes, K. and Török, TL. The action of
trelibet, a new antidepressive agent on [3H]noradrenaline release from
rabbit pulmonary artery. European Journal of Pharmacology. 130, 219-227,
1986.
[2] Malomvölgyi, B., Tóthfalusi, L., Tekes, K. and Magyar, K.
Comparison of serotonin agonistic and antagonistic activities of a new
antidepressant agent trelibet (EGYT-475) and its metabolite EGYT-2760 on
isolated rat fundus. Acta Physiologica Hungarica, 73), 201-209, 1991.
[3] Tekes, K., László, T., Malomvölgyi, B., Hermán, F. and Magyar, K.
Studies on the biochemical mode of action of EGYT-475, a new
antidepressant. Polish Journal of Pharmacology and Pharmacy. 39, 203-211,
1987.
ok, not the most exciting of things to post, but still might be useful.
