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Animal models are crucial for understanding the mechanism of action of antipsychotics. However, the dose of an antipsychotic in animal studies is often arbitrarily chosen, with haloperidol 1 mg/kg being a rather common standard. Recent clinical positron emission tomography (PET) studies in patients show all antipsychotics to block dopamine D 2  receptors, and most are effective at doses that lead to 60% to 80% D 2  occupancy. When occupancy exceeds 80%, the incidence of side effects rises sharply. To use this “bedside” information to inform the “bench,” we measured D 2  occupancy in rats using a method similar in principle to the [ 11  C]-raclopride PET method in humans. We found that: 1) as in humans, haloperidol is effective in animal models of antipsychotic action when D 2  occupancy &gt; 70% and leads to effects in models of extrapyramidal side effects when D 2  occupancy is &gt; 80%; 2) very low doses, 0.06 mg/kg/sc, cause acute D 2  occupancy of 75%; 3) and even doses that acutely saturate D 2  receptors give little D 2  occupancy after 24 hours due to the very short half-life of haloperidol in rats (2.5 hours versus 24 hours in humans). We conclude that most previous animal studies of antipsychotics have used doses giving rise to inappropriately high acute D 2  occupancy and inappropriately low D 2  occupancy between doses. We exemplify how this dosing confounder could lead to inappropriate conclusions. Data from the bedside translated to the bench—using D 2  occupancy as a mediating variable—will lead to more valid animal models.

Are Animal Studies of Antipsychotics Appropriately Dosed?: Lessons from the Bedside to the Bench