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Neuropharmacology of BZP
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Citation:   BilZ0r. "Neuropharmacology of BZP"., Nov 2003:
1-Benzylpiperazine (BZP) has a peripheral sympathomimetic action and a complex central action, both directly and indirectly acting upon on all monoamine1,2,3. There are few experiments investigating the nature of BZP's 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 α2 adrenoreceptor, and the second is on the noradrenergic uptake carrier. The α2-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 α2-adrenoreceptor1, thus negating negative feedback at the synapse, and causing a larger stimulation-evoked release of neurotransmitter [[which one?]]. This is the same process as yohimbine, though, BZP is some 10,000 times less potent, but possibly just as efficacious1. These results were found from experimenting on peripheral nerves, not central ones, and it is possible that BZP has no α2-antagonist properties in the CNS. I find it likely that BZP's central α2 action has limited effect on the subjective experience, and mediates things like blood pressure and rate increase. 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 NA1. Although the experiments which showed the stimulation-independent release of NA were done on peripheral nervous tissues, a study has been done to show that this action is probably exhibited in central nerves as well3. This amphetamine-like reuptake inhibition is probably BZP's noradrenergic action of most consequence in the CNS. In the peripheral nervous system, the α2-adrenoreceptor blockade is almost certainly responsible for most of the symptoms, as addition of clonidine (an α2 receptor agonist) blocks almost all of the effect of BZP in peripheral tissue1.

The action of BZP on the dopaminergic system is probably just restricted to the amphetamine-like reuptake inhibition and stimulation-independent release of dopamine (DA). This is supported by research that showed that in rats after 14 days of treatment with BZP, the amount of DA in subcortical cells is decreased, while the concentration of DA in the extracellular fluid is increased3.

The action of BZP on the serotonergic system is the most studied aspect of BZP's action, as one member of the team of experimenters who 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-HT3. 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-mediated2 (methergoline has similar pKi's for all 5ht2-receptor-subtypes). 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 amitriptyline3. Amitriptyline binds to the 5-HT reuptake carrier, probably blocking BZP's amphetamine-like action. Seeing that BZP can still exhibit a serotonergic action while the stimulation-independent release of 5-HT is blocked, 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-HT2, meaning that functionally, it is closer to an antagonist than an agonist.

When one compares the contribution of these different neurotransmitters 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 largely responsible for BZPs peripheral effects, as NA is the main mediator of the sympathetic nervous system.

The ability for BZP to induce dependence initially looks marked, as it has a pronounced central dopaminergic action3, but if one considers all the factors, this may not be so. Tolerance to BZP's central action will develop quickly, as it probably accumulates in synaptic vesicles in the same fashion as amphetamine, while tolerance to BZP's peripheral blockade of α2-adrenoreceptors will be limited or nonexistent. This will moderate the abuse potential, since 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 α2 receptor) would be intolerable.

In summary, BZP's action could be described as somewhere between amphetamine and MDMA including a yohimbine-like action as well, with limited to moderate abuse potential.

References #
  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, 78(3), 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.