Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Abstract

The novel antipsychotic aripiprazole requires high (490%) striatal D 2 receptor occupancy (D 2 RO) to be clinically active, but despite its high D 2 RO it does not show extrapyramidal symptoms. While most antipsychotics are active at nearly 65% D 2 RO, they show motor side effects when D 2 RO exceeds 80%. We investigated this discrepancy between D 2 RO, 5HT 2 receptor occupancy (5-HT 2 RO) and in vivo functional activity of aripiprazole in comparison to haloperidol (typical) and risperidone (atypical) in animal models. All three drugs showed dose-dependent D 2 RO. While risperidone clearly showed higher 5-HT 2 RO than D 2 RO, aripiprazole and haloperidol showed higher D 2 RO than 5-HT 2 RO at all doses. Haloperidol and risperidone induced catalepsy at doses producing 480% D 2 RO, while aripiprazole despite higher D 2 RO (490%) induced no catalepsy. Haloperidol and risperidone's ED 50 values for inhibition of conditioned avoidance response (CAR) and amphetamine-induced locomotor activity (AIL) corresponded to B60% D 2 RO. In contrast, aripiprazole showed a significant dissociation; while it blocked AIL at similar D 2 RO, a 23-fold higher dose (86% D 2 RO) was required to inhibit CAR. FOS expression in shell region of the nucleus accumbens was significant for all drugs at D 2 ROs that were effective in CAR. However, in the core region of the nucleus accumbens and dorsolateral striatum, aripiprazole differed from the others in that despite high D 2 RO it induced low FOS. Haloperidol and risperidone showed dose/occupancy-dependent prolactin elevations, while aripiprazole did not. Across models, haloperidol and risperidone show similar occupancy-functional antagonism of the D 2 system, while aripiprazole shows a clear dissociation. Partial agonism of aripiprazole offers a good explanation for this dissociation and provides a framework for understanding occupancy-functional relationships of partial D 2 agonist antipsychotics.

Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

“…The lower affinity to D 2 receptors compared to 5-HT 2 receptors partially explains NDMC's lack of significant occupancy at the D 2 receptors, 1 h after administration. The low D 2 RO of NDMC is consistent with its lack of catalepsy or prolactin elevation, as these measures have been closely linked to D 2 RO for other agents (Wadenberg et al, 2000b;Natesan et al, 2006). In the AIL model, NDMC had the least effects among the established antipsychotics tested.…”

“…The Fos expression induced by a dose of 60 mg/kg for NDMC does not exceed this threshold and could explain the lack of effect in CAR at early time points. The emergence of catalepsy is correlated with a certain threshold of Fos expression (430 counts) in the dorsolateral striatum among antipsychotic agents (Natesan et al, 2006). In the present study, only haloperidol exceeded this level of Fos expression, and showed catalepsy.…”

“…NDMC achieves this level of occupancy at a very high dose (100 mg/kg) and at time points much later (43%, 240-min post-drug administration) than that of clozapine. In the case of other D 2 antagonists/partial agonists, inhibition of AIL (ED 50 ) is seen at striatal D 2 occupancies B50-60% (Natesan et al, 2006). However, in the case of NDMC this level of occupancy is not achieved even at the high dose of 100 mg/kg observed up to 360-min post-treatment.…”

Reversal of Subchronic PCP-Induced Deficits in Attentional Set Shifting in Rats by Sertindole and a 5-HT6 Receptor Antagonist: Comparison Among Antipsychotics

“…The validity of the dose selection can be evaluated by comparison to doses effective in other rodent models of psychosis, by confirming clinically relevant plasma levels and/or DA D 2 receptor occupancies in vivo in the central nervous system. We selected dose ranges of haloperidol, olanzapine, and risperidone that did not produce behavioral disruption and that have been shown to induce DA D 2 receptor occupancies that correspond to therapeutically effective levels reported previously (Zhang and Bymaster, 1999;Natesan et al, 2006;LTB Brennum, H Lundbeck, unpublished), and induce marked behavioral effects in various animal models of psychosis (for review, see Arnt and Skarsfeldt, 1998). Clozapine has weaker DA D 2 in vivo binding potency, but the selected doses examined were within behaviorally active levels, and further dose increase leads to marked sedation (see Arnt and Skarsfeldt, 1998).…”

Repeated antipsychotic treatment progressively potentiates inhibition on phencyclidine-induced hyperlocomotion, but attenuates inhibition on amphetamine-induced hyperlocomotion: Relevance to animal models of antipsychotic drugs

“…Also, at the medium and high doses, both haloperidol and clozapine selectively disrupt avoidance responding-a validated behavioral index of antipsychotic activity (Li et al, 2004). The dose for amphetamine was 1.5 mg/kg, which is the common dose used in the literature (Arnt, 1995;Natesan et al, 2006;Sills et al, 2000).…”