Antagonism of the amphetamine cue by both classical and atypical antipsychotic drugs

Rats were trained to discriminate the stimulus properties of 1 mg/kg of d-amphetamine sulphate (AMPH) from saline in a two-lever task in which correct responding was reinforced with water under a fixed ratio (FR 32) schedule. Classical antipsychotic drugs from different chemical classes were all able to block the AMPH cue. Doses (mg/kg) inhibiting the cueing effect to 50% (ID50) were 0.035 (haloperidol), 0.04 (spiroperidol), 0.09 (cis(Z)-flupenthixol), 0.12 (trifluperazine), 0.15 (perphenazine), 0.92 (chlorpromazine) and 1.40 (pimozide). The AMPH cue was also antagonized by antipsychotic drugs that are considered atypical due to their relative lack of activity in conventional animal models or inability to produce extrapyramidal symptoms in the clinic. The following ID50 values were obtained: 0.88 (molindone), 1.22 (clozapine), 5.48 (metoclopramide), 15.4 (thioridazine) and 52.8 [-)-sulpiride). In addition, the AMPH cue was blocked by the D-1 selective dopamine (DA) antagonist, SCH 23390 (ID50 = 0.014 mg/kg). The abilities of these drugs to block the AMPH cue were unrelated to the drugs' effect upon the rate of responding. For example, some drugs (e.g. haloperidol, spiroperidol and SCH 23390) blocked the AMPH cue completely without any effect on the response rate. Furthermore, the non-antipsychotic phenothiazine, promethazine (2.5-12.5 mg/kg) failed to affect the AMPH cue although the drug strongly suppressed the response rate. However, the potent DA agonists, apomorphine (0.05-0.33 mg/kg) and lisuride (0.02-0.08 mg/kg), and the DA and norepinephrine agonist, DPI (0.4 and 0.8 mg/kg), did not mimic the AMPH cue or did so only partially. These results suggest that the 1 mg/kg AMPH cue depends on (DA) systems other than those involved in the stereotyped motor behavior commonly produced by high doses of AMPH or DA agonists. Low-dose AMPH discrimination may thus serve as a new model for studying antipsychotic drug action.