Dopamine antagonistBlocking dopamine DA D 2 receptors is the sine qua non blocckade antipsychotic activity. However, it is this same glukokortikosteroid adalah that accounts for their liability to produce extrapyramidal symptoms EPS and hyperprolactinemia. Haloperidol dopamine blockade remains unclear, though, blockaed there are other negative consequences that might result from DA D 2 blockade. For example, previous research has demonstrated a robust relationship between DA and both cognition and haloperidol dopamine blockade. The present study was designed to evaluate the impact of DA D 2 antagonism on each of these domains.
Impact of haloperidol, a dopamine D2 antagonist, on cognition and mood. - PubMed - NCBI
Two techniques are commonly used to measure antipsychotic induced dopamine D 2 occupancy in animals: While both of these techniques have been used in the past, there is no direct and systematic comparison.
This seven-fold difference in the sensitivity of the two techniques to measure antipsychotic-induced D 2 occupancy explains discrepancies in the previous studies which have used these two methods and also suggest that for future studies the 3 H-raclopride method is a more sensitive and, likely, a more valid reflector of true receptor occupancy.
The blockade of receptors by antipsychotics is a crucial parameter for understanding their pharmacological actions. Slight differences in receptor blockade can have important functional consequences.
Similar findings have been reported in animal studies where a few percent shift in occupancy was associated with a significant appearance of catalepsy Kapur et al. Therefore, the determination of receptor occupancy with precision and reliability is of great importance.
In animal studies two techniques have been commonly used for the determination of drug-receptor occupancy in vivo. One technique referred to here as the radiotracer method relies on the competition between a selective reversible radiotracer and the antipsychotic, in vivo , to measure occupancy 3 H-raclopride or 3 H-spiperone are common choices for the dopamine D 2 receptor Kohler et al. The other technique relies on the competition between an irreversible ligand which inactivates the receptors, and the antipsychotic, in vivo.
Alkylating agent N-ethoxycarbonylethoxy-1,2-dihydroquinoline EEDQ is the most common choice for the dopamine D 2 receptor Meller et al. There has been no direct comparison of the two, even though the results and inferences from the two methods are often used interchangeably. The purpose of this experiment was to compare these two commonly used methods in their ability to measure haloperidol-induced dopamine D 2 receptor occupancy.
Adult male Sprague-Dawley rats — g were used for this study. The animals were treated with stratified doses of haloperidol 0. In the radiotracer group, the animals were first given a dose of haloperidol 0. The animals were sacrificed at 2 h after the injection of haloperidol.
The ratio of specific striatal minus cerebellar to non-specific binding cerebellar at the time of sacrifice was taken as a measure of the available dopamine D 2 receptors. Occupancy, in haloperidol-treated animals, was calculated as: This approach and the equation is similar to the method used in humans to obtain D 2 occupancy using PET Kapur et al. Thus by measuring the amount of protection from inactivation afforded by an antipsychotic one can obtain a measure of antipsychotic receptor occupancy Meller et al.
As in past studies, three groups of animals were needed in this case. A second group was treated with haloperidol vehicle and EEDQ VE and provided the number of D 2 receptors when there was no drug occupancy i. The animals were sacrificed 24 h later in keeping with previous studies using this method Meller et al.
The striata were dissected in each of the three groups and the B max and K d of the dopamine D 2 receptors were obtained using 3 H-Spiperone and a Scatchard analysis as described previously Seeman and Van Tol The D 2 occupancy was obtained using the formula: There was a substantial difference in the sensitivity of the two techniques as illustrated in Figure 1. The radiotracer method revealed a much higher occupancy by haloperidol at all the doses, with the difference particularly remarkable at lower doses.
While both methods showed an orderly dose-response, on theoretical grounds one would expect the dose-occupancy data to conform to a saturating hyperbola i. Relationship between dose and D 2 occupancy as determined by the two methods. The radiotracer method using 3 H-raclopride shows a seven-fold higher sensitivity for detecting haloperidol induced D 2 occupancy in vivo.
This difference in the sensitivity of the two methods explains significantly disparate estimates of drug potencies in previous reports using these two different techniques Kohler and Karlsson-Boethius ; Saller et al. A higher sensitivity does not by itself mean greater validity, but the 3 H-raclopride data show several other features that enhance its validity: An important limitation of the current study is the use of different radioligands to measure in vivo receptor occupancy raclopride and the number of receptors protected by EEDQ spiperone.
Our choice of ligands was in keeping with the practice of past studies using these two methods Meller et al. While differences between these two ligands have been reported before, these differences are unlikely to be an explanation for the observed difference. First, even though spiperone is used in the EEDQ method, the method is based on the competition protection between EEDQ and haloperidol, and not spiperone and haloperidol. Despite these theoretical reasons, a complex three-way interaction i.
The precise reason for this substantial difference cannot be inferred from our results. However, a few possibilities need to be considered. While it has been shown that haloperidol shows a dose-dependent competition with EEDQ, it has yet to be shown that both haloperidol and EEDQ vie for the same site on the receptor in a simple competitive fashion.
Furthermore, the determination of protection after EEDQ is done ex vivo after a h delay. This is a standard in all previous studies and is observed to make sure that the challenge drug, haloperidol in this study, has exited the system and is not directly competing with the ex vivo ligand.
Since observed results show a lesser occupancy with EEDQ, receptor recovery in the 24 h is unlikely to be an explanation for this difference. In summary, the in-vivo method for determining D 2 occupancy is substantially more sensitive than the EEDQ method. Until the reasons for the observed discrepancy are better understood, caution is advised in using EEDQ-derived dopamine D 2 occupancy estimates since they may represent a serious underestimate of the true in vivo situation.
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Adv Exp Med Biol Chronic haloperidol affects striatal D2-dopamine receptor reappearance after irreversible receptor blockade. Dopamine receptor occupancy in vivo: Deriving the therapeutic concentrations for clozapine and haloperidol: Eur J Pharmacol H-C Guan for their expert technical assistance. Correspondence to Shitij Kapur. To obtain permission to re-use content from this article visit RightsLink.
Skip to main content. Abstract Two techniques are commonly used to measure antipsychotic induced dopamine D 2 occupancy in animals: Main The blockade of receptors by antipsychotics is a crucial parameter for understanding their pharmacological actions. Figure 1 Relationship between dose and D 2 occupancy as determined by the two methods.
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