Effects of antipsychotic drugs on MK-801-induced attentional and motivational deficits in rats

Abstract

Background: Attentional deficits that accompany schizophrenia are not effectively treated by available antipsychotic medications. Disruption of NMDA receptor function is often used to model aspects of this disorder in rodents. We used the 5-choice serial reaction time task (5CSRTT) to characterize attentional deficits caused by acute administration or withdrawal from chronic administration of the NMDA receptor antagonist MK-801, and determine if they are ameliorated by haloperidol or clozapine.

Methods: Acute studies involved tests in the presence of MK-801: rats were administered haloperidol (0.008-0.125 mg/kg, SC) or clozapine (0.16-2.5 mg/kg, SC) in combination with MK-801 (0.25 mg/kg, IP) prior to daily test sessions. Chronic studies involved tests in the absence of MK-801: following daily tests, rats were administered MK-801 (0.5 mg/kg, IP) and tested 24 h later in the absence or presence of haloperidol or clozapine.

Results: Acute MK-801 disrupted performance: it decreased accuracy while increasing omissions, premature responses, and magazine entries. Haloperidol reduced disruptive effects associated with increased activation, whereas it exacerbated other deficits. Clozapine dose-dependently attenuated several of the MK-801-induced performance deficits. Withdrawal from chronic MK-801 progressively increased omissions and response latencies and decreased premature responding, suggesting an amotivational state. Neither haloperidol nor clozapine ameliorated these performance deficits.

Discussion: Acute administration and withdrawal from chronic MK-801 administration produced distinct behavioral profiles in the 5CSRTT. Acute MK-801 impaired attention and impulse control whereas chronic MK-801 withdrawal caused signs consistent with amotivation. Haloperidol and clozapine were more effective at attenuating deficits caused by acute MK-801 administration.

Figure 1

Effect of haloperidol pretreatment on behavioral deficits induced by acute MK-801 administration. Haloperidol (0.0-0.063 mg/kg, SC) was administered 60 min prior to testing and MK-801 (0.25 mg/kg, IP) was administered 30 min prior to testing. MK-801 administration (grey bar) reduced accuracy (a), increased omissions (b), premature responses (c), and magazine entries (d), but did not affect correct response latencies (e) or reward retrieval latencies (f). Haloperidol significantly attenuated the MK-801-induced increase in premature responses and magazine entries, but it exaggerated the MK-801-induced increase in omissions and reward retrieval latencies. Significantly different from 0.0 mg/kg MK-801 + 0.0 mg/kg Haloperidol, *P < 0.05, **P < 0.01, Fisher's protected t-tests. Significantly different from MK-801 (0.25 mg/kg) + Haloperidol (0.0 mg/kg), ˆP < 0.05, ˆˆP < 0.01, Fisher's protected t-tests.

Figure 2

Effect of clozapine pretreatment on behavioral deficits induced by acute MK-801 administration. Clozapine (0.0-1.25 mg/kg, SC) was administered 60 min prior to testing and MK-801 (0.25 mg/kg, IP) was administered 30 min prior to testing. MK-801 administration (grey bar) reduced accuracy (a), increased omissions (b), premature responses (c), magazine entries (d), and correct response latencies (e). Clozapine attenuated MK-801-induced behavioral deficits. Significantly different from 0.0 mg/kg MK-801 + 0.0 mg/kg Clozapine), *P < 0.05, **P < 0.01, Fisher's protected t-tests. Significantly different from MK-801 (0.25 mg/kg) + Clozapine (0.0 mg/kg), ˆP < 0.05, ˆˆP < 0.01 Fisher's protected t-tests.

Figure 3

Effects of chronic MK-801 withdrawal on 5CSRTT performance. Because data from the haloperidol and clozapine groups did not differ on days when antipsychotics were not administered, these data were pooled for statistical analyses. Beginning after baseline was established, MK-801 (0.5 mg/kg, IP) was administered 30 min after daily test sessions; tests were conducted 23.5 hr later. Chronic MK-801 withdrawal decreased accuracy of responding (a), premature responses (c) and, magazine entries (d) while it increased omissions (b), correct response latencies (e), and reward retrieval latencies (f) relative to baseline. Solid black bar in (a) represents period of chronic MK-801 administration and the grey dashed bar (a) represents time period of acute intermittent antipsychotic treatment. Baseline scores were the average of the 3 test sessions preceding the initiation of MK-801 administration. Significantly different from baseline, *P < 0.05, **P < 0.01, Fisher's protected t-tests.

Figure 4

Ability of haloperidol pretreatment to attenuate performance deficits caused by exposure to a regimen of chronic MK-801 administration. MK-801 (0.5 mg/kg, IP) was administered 30 min after daily training sessions; testing occurred 23.5 hr later. On days 6, 8, 10 and 12 of MK-801 administration, haloperidol (0.0-0.016 mg/kg, SC) was administered 60 min prior to testing. Exposure to MK-801 administration alone (grey bar) did not affect accuracy (a), but it impaired accuracy in combination with haloperidol (0.004-0.016 mg/kg). Exposure to MK-801 increased omissions (c) and reward retrieval latencies (f), and decreased premature responses (c) and magazine entries (d). These effects were not altered by haloperidol (0.004-0.016 mg/kg). Exposure to MK-801 increased correct response latencies (e), and haloperidol (0.008-0.016 mg/kg) potentiated this effect. Significantly different from baseline, *P < 0.05, **P < 0.01, Fisher's protected t-tests. Significantly different from chronic MK-801 + haloperidol (0.0 mg/kg), ˆˆP < 0.01, Fisher's protected t-tests.

Figure 5

Ability of clozapine pretreatment to attenuate performance deficits caused by exposure to a regimen of chronic MK-801 administration. MK-801 (0.5 mg/kg, IP) was administered 30 min after daily training sessions; testing occurred 23.5 hr later. On days 6, 8, 10 and 12 of MK-801 administration, clozapine (0.08-0.63 mg/kg, SC) was administered 60 min prior to testing. Exposure to MK-801 administration alone (grey bar) did not affect accuracy (a), but it impaired accuracy in combination with clozapine (0.08-0.32 mg/kg). Exposure to MK-801 administration increased omissions (b) and correct response latencies (e), but decreased magazine entries (d). These effects were not altered by clozapine (0.08-0.32 mg/kg). Exposure to MK-801 did not affect premature responses (c), but it increased reward retrieval latencies, an effect attenuated by clozapine (0.08 mg/kg). Significantly different from baseline, *P < 0.05, **P < 0.01, Fisher's protected t-tests.