An investigation of the behavioral mechanisms of antipsychotic action using a drug–drug conditioning paradigm

Abstract

Antipsychotic drugs at noncataleptic doses selectively suppress conditioned avoidance response in rats. In our previous study, we had used a two-way active avoidance response paradigm to show that the antipsychotic-induced interoceptive state is one of the mechanisms underlying the avoidance-disruptive effect of antipsychotics. In this study, we sought to further examine this mechanism using a novel drug–drug conditioning procedure. We made use of the fact that both the typical neuroleptic haloperidol and the atypical neuroleptic olanzapine disrupt conditioned avoidance responding, whereas chlordiazepoxide (an anxiolytic) does not. We reasoned that if the antipsychotic interoceptive state is important in causing a disruption on avoidance responding (an index of antipsychotic efficacy), pairing chlordiazepoxide (a cueing drug conditional stimulus) with haloperidol or olanzapine (a cued drug unconditional stimulus) should engender chlordiazepoxide to exhibit this property and behave like an antipsychotic drug. Chlordiazepoxide exhibited an acquired antipsychotic-like property in disrupting avoidance responding after being repeatedly paired with haloperidol, but not with olanzapine. In contrast, it significantly attenuated the antiavoidance efficacy of olanzapine but not haloperidol after being repeatedly paired with these drugs. This study suggests that the haloperidol-induced interoceptive drug state is directly involved in its antiavoidance action, and chlordiazepoxide may attenuate the antiavoidance efficacy of antipsychotics (especially olanzapine). To the extent that the antiavoidance effect predicts clinical effects of antipsychotic treatment, this study suggests that the antipsychotic-induced interoceptive drug state may be an important behavioral mechanism mediating the clinical effects of antipsychotic treatments.

Olanzapine Sensitization and Clozapine Tolerance: From Adolescence to Adulthood in the Conditioned Avoidance Response Model

“…The answer to both questions is yes. We demonstrated that OLZ sensitization and CLZ tolerance could be induced in adolescent rats using the same procedure (ie, an induction phase followed by a challenge test) as employed in adult rats (Li et al, 2004;Li et al, 2007;Li et al, 2009a;Li et al, 2009b;Li et al, 2010;Mead and Li, 2010;Li et al, 2012;Zhang and Li, 2012). They mainly manifested in the avoidance response (a behavioral measure of antipsychotic activity) and/or intertrial crossing (a behavioral measure of motor function/sedation), but not in the 22 kHz USV (an index of anxiolytic property), suggesting that they are behaviorally specific (Stewart and Badiani, 1993).…”

“…Using such a paradigm, we show that repeated treatment of haloperidol and olanzapine (OLZ) induce a sensitization effect in both the induction and expression phases (Li et al, 2009b;Li et al, 2009a;Sun et al, 2009;Li et al, 2010;Mead and Li, 2010;Zhao et al, 2012). In contrast, repeated treatment of clozapine (CLZ) does not cause an apparent sensitization or tolerance during the induction phase (Sun et al, 2009;Li et al, 2010).…”

Adolescent olanzapine sensitization is correlated with hippocampal stem cell proliferation in a maternal immune activation rat model of schizophrenia

“…Olanzapine (OLZ) 0.5, 1.0, and 2.0 mg/kg (subcutaneous [sc]; gifts from the NIMH drug supply program) were dissolved in distilled sterile water with 1.0–1.5% glacial acetic acid. The 1.0 and 2.0 mg/kg OLZ acutely inhibit CAR without inducing catalepsy based on our previous work (Feng et al , 2013; Li et al , 2004, 2007, 2009; Mead and Li, 2010; Qiao et al , 2013a, 2013b; Sun et al , 2009; Zhang and Li, 2012; Zhao and Li, 2010). The lower challenge dose of 0.5 mg/kg OLZ has been successfully used in our previous studies (Mead and Li, 2010; Qiao et al , 2013a; Sparkman and Li, 2012; Swalve and Li, 2012; Zhang and Li, 2012) and prevents the floor effect (i.e.…”

Parametric studies of antipsychotic-induced sensitization in the conditioned avoidance response model

“…In recent years, we have used the conditioned avoidance response (CAR) model, a well-established animal model with high predictive validity for antipsychotic action (Wadenberg and Hicks, 1999), to investigate the long-term effects of repeated antipsychotic treatment (Li et al ., 2004b, 2007, 2009a, 2009b, 2010; Mead and Li, 2010). We showed that repeated treatment with haloperidol (HAL; a typical antipsychotic), olanzapine (OLZ), and risperidone (atypical antipsychotics) produces a progressively-enhanced disruption of avoidance responding over 7 days (Li et al ., 2007).…”