Effects of Newer Antipsychotic Drugs on Apomorphine-Induced Climbing Behavior in Mice
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Chlorpromazine equivalence is used to chart the relative potencies of typical antipsychotic agents and is linearly related to the dopamine D2 receptor affinity. With the introduction of newer antipsychotic drugs, the roles of neurotransmitters other than dopamine have been emphasized, and it is difficult to attribute the diverse effects of these drugs to a common mechanism. Recently, several equivalent dose guidelines were published for newer antipsychotic drugs. The present study used the antagonism of apomorphine-induced climbing behavior to investigate the relationship between the clinically determined equivalent doses and behavioral effects measured using an animal model of several newer antipsychotic drugs. The antipsychotic drugs were administered 20 min before an apomorphine injection. After the apomorphine injection, climbing behavior was assessed visually for 20 min. The dose that inhibited 50% of the control group behavior was defined as the half-effective dose (HED) and was calculated from the regression line. The relationship between the HED and the published clinical minimum effective dose (MED) was investigated using linear regression analysis. All the antipsychotic drugs antagonized the apomorphine-induced climbing behavior in a dose-dependent manner. A statistically significant correlation between HED and MED was observed (Spearman’s rho=0.96, p <0.001), and a statistically significant linear relationship was also found (F =76.2, df=1, 4, p =0.001；r 2=0.950). Antipsychotics inhibit apomorphine-induced climbing behavior via D2 antagonism. Therefore, the result suggests that the common mechanism underlying the therapeutic effects of newer antipsychotics is related to dopamine D2 antagonism. However, the equivalent doses used in this study focused mainly on psychotic and behavioral symptoms, so they cannot embrace the multidimensional therapeutic effects of newer antipsychotics. Investigations of the relationship between the equivalent doses focusing on each symptom domain and the effects on diverse neurotransmitter systems would broaden our knowledge on the mechanisms of action in newer antipsychotics.
Abstract
Chlorpromazine equivalence is used to chart the relative potencies of typical antipsychotic agents and is linearly related to the dopamine D2 receptor affinity. With the introduction of newer antipsychotic drugs, the roles of neurotransmitters other than dopamine have been emphasized, and it is difficult to attribute the diverse effects of these drugs to a common mechanism. Recently, several equivalent dose guidelines were published for newer antipsychotic drugs. The present study used the antagonism of apomorphine-induced climbing behavior to investigate the relationship between the clinically determined equivalent doses and behavioral effects measured using an animal model of several newer antipsychotic drugs. The antipsychotic drugs were administered 20 min before an apomorphine injection. After the apomorphine injection, climbing behavior was assessed visually for 20 min. The dose that inhibited 50% of the control group behavior was defined as the half-effective dose (HED) and was calculated from the regression line. The relationship between the HED and the published clinical minimum effective dose (MED) was investigated using linear regression analysis. All the antipsychotic drugs antagonized the apomorphine-induced climbing behavior in a dose-dependent manner. A statistically significant correlation between HED and MED was observed (Spearman’s rho=0.96, p <0.001), and a statistically significant linear relationship was also found (F =76.2, df=1, 4, p =0.001；r 2=0.950). Antipsychotics inhibit apomorphine-induced climbing behavior via D2 antagonism. Therefore, the result suggests that the common mechanism underlying the therapeutic effects of newer antipsychotics is related to dopamine D2 antagonism. However, the equivalent doses used in this study focused mainly on psychotic and behavioral symptoms, so they cannot embrace the multidimensional therapeutic effects of newer antipsychotics. Investigations of the relationship between the equivalent doses focusing on each symptom domain and the effects on diverse neurotransmitter systems would broaden our knowledge on the mechanisms of action in newer antipsychotics.
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