Behavioral evidence of depolarization block of dopamine neurons after chronic treatment with haloperidol and clozapine

Abstract

Electrophysiological studies have shown that chronic treatment with haloperidol causes depolarization block (DB) of dopamine cells in anesthetized and paralyzed rats. It has been proposed that the emergence of DB underlies the therapeutic and side effects of this drug. However, the relevance of DB to the clinical actions of haloperidol has been questioned on the grounds that chronic drug-induced DB has not yet been demonstrated in freely moving animals. In this study, responding for rewarding electrical brain stimulation was used to assess the occurrence of DB in rats chronically treated with haloperidol or clozapine. The time course of the effects of acute haloperidol (7.8-500 microg/kg) and clozapine (5-40 mg/kg) and of withdrawal from chronic drug treatment on reward and performance measures were also characterized. Haloperidol and clozapine dose-dependently attenuated reward and performance, haloperidol producing a predominant suppression of performance, and clozapine preferentially attenuating reward. Chronic (21 d) treatment with haloperidol (500 microg/kg) caused responding to cease in the six rats tested, and repeated injection with apomorphine restored the behavior in all of them; such an effect of apomorphine was observed in only two of six rats treated acutely with the same dose of haloperidol. Chronic treatment with clozapine (20 mg/kg) increased reward thresholds, an effect that was reversed by apomorphine in chronically, but not acutely, treated rats. The times at which chronic haloperidol-treated rats resumed responding was positively correlated with indices of behavioral supersensitivity after withdrawal, suggesting that the effect of apomorphine was not caused by direct stimulation of upregulated postsynaptic receptors. These findings constitute the first behavioral evidence of DB in unanesthetized, freely moving animals treated chronically with antipsychotics. They also demonstrate that the neural substrates mediating reward and performance are functionally independent and differentially sensitive to haloperidol and clozapine.

Fig. 1.

Time course of changes in reward thresholds (a) and maximal response rates (b) after treatment with haloperidol [7.8 μg/kg (○), 15.63 μg/kg (▵), and 31.25 μg/kg (■)] and vehicle (▾), as a function of time after injection. Each point (n = 6) is expressed as percent of baseline and represents the mean ± SEM. Threshold and response rate data obtained from the vehicle (control) group are the same in this figure and Figure 2. Although the test session in the vehicle control condition lasted 630 min, rats treated with the three lowest doses of haloperidol were tested only for 270 min because of the short time course of the effects of these doses. For clarity, only data collected between 0 and 270 min after vehicle injection are illustrated. For ease of comparison between reward thresholds and response rates, in all the figures, changes in the latter are also plotted on a semilogarithmic scale. †p < 0.05, 7.8 μg/kg versus vehicle; *p < 0.05, 15.63 μg/kg versus vehicle; #p < 0.05, 31.25 μg/kg versus vehicle; Dunnett's tests.

Fig. 2.

Time course of changes in reward thresholds (○,top) and maximal response rates (▵,bottom) after treatment with haloperidol (62.5, 125, and 500 μg/kg) and vehicle (▾), as a function of time after injection. Numbers above or below eachpoint indicate the number of rats responding at each time interval. Each point (n = 6) is expressed as percent of baseline and represents the mean ± SEM.Filled symbols in the drug conditions indicate values that lie beyond the 95% confidence interval of the vehicle curve (p < 0.05).

Fig. 3.

Time course of changes in reward thresholds (a) and maximal response rates (b) after treatment with clozapine [5 mg/kg (○), 10 mg/kg (▵), 20 mg/kg (■), and 40 mg/kg (⋄)] and vehicle (▾), as a function of time after injection. Each point (n = 6) is expressed as percent of baseline and represents the mean ± SEM. †p < 0.05, 10 mg/kg versus vehicle; *p < 0.05, 20 mg/kg versus vehicle; #p < 0.05, 40 mg/kg versus vehicle; Dunnett's tests.

Fig. 4.

Time course of changes in reward thresholds (a) and maximal response rates (b) after treatment with cumulative doses (12.7, 25.4, 50.8, 101.7, and 203.3 μg/kg) of APO or VEH in CVEH-treated rats. Values are expressed as percent of baseline and are plotted as a function of time since the 21st injection of vehicle. Each point (n = 6) represents the mean ± SEM. Arrows indicate times of APO or VEH injection. Thresholds: ●, CVEH+APO; ○, CVEH+VEH. Response rates: ▴, CVEH+APO; ▵, CVEH+VEH. **p< 0.01; Tukey tests.

Fig. 5.

Time course of changes in reward thresholds (●) and maximal response rates (▴) after administration of APO to rats treated with CHAL (500 μg/kg). Data obtained from individual animals are shown. Values are expressed as percent of baseline and are plotted as a function of time since the 21st injection of haloperidol.Arrows indicate times of APO injection. NO SS, No self-stimulation.

Fig. 6.

Time course of changes in reward thresholds (●) and maximal response rates (▴) after administration of VEH to rats treated with CHAL (500 μg/kg). Data obtained from individual animals are shown. Values are expressed as percent of baseline and are plotted as a function of time since the 21st injection of haloperidol.Arrows indicate times of VEH injection. NO SS, No self-stimulation.

Fig. 7.

Time course of changes in reward thresholds (●) and maximal response rates (▴) after administration of APO to rats treated with CVEHH (chronic vehicle for 20 d plus 500 μg/kg haloperidol on day 21). Data obtained from individual animals are shown. Values are expressed as percent of baseline and are plotted as a function of time since injection of haloperidol. Arrowsindicate times of APO injection. NO SS, No self-stimulation.

Fig. 8.

Time course of changes in reward thresholds (●) and maximal response rates (▴) after administration of VEH to rats treated with CVEHH (chronic vehicle for 20 d plus 500 μg/kg haloperidol on day 21). Data obtained from individual animals are shown. Values are expressed as percent of baseline and are plotted as a function of time since injection of haloperidol. Arrowsindicate times of VEH injection. NO SS, No self-stimulation.

Fig. 9.

Percentage of animals in each drug condition that resumed responding (on at least 2 consecutive passes) before the end of the test session (open bars) and the times at which this occurred (hatched bars; bar heights represent mean ± SEM). *p < 0.05; χ² test.

Fig. 10.

Left, Time course of changes in reward thresholds (a) and maximal response rates (b) after administration of APO or VEH to rats treated with CCLOZ (20 mg/kg). Thresholds: ●, CCLOZ+APO; ○, CCLOZ+VEH. Response rates: ▴, CCLOZ+APO; ▵, CCLOZ+VEH.Right, Time course of changes in reward thresholds (c) and maximal response rates (d) after administration of APO or VEH to rats treated with CVEHC (chronic vehicle for 20 d plus 20 mg/kg clozapine on day 21). Thresholds: ●, CVEHC+APO; ○, CVEHC+VEH. Response rates: ▴, CVEHC+APO; ▵, CVEHC+VEH. Values are expressed as percent of baseline and are plotted as a function of time after injection of clozapine. Eachpoint (n = 6) represents the mean ± SEM. Arrows indicate times of APO or VEH injection. *p < 0.05; **p < 0.01; Tukey tests.

Fig. 11.

Time course of changes in reward thresholds (a) and maximal response rates (b) after withdrawal from CHAL (○), CCLOZ (■), and CVEH (▴) treatment. Values are expressed as percent of baseline and are plotted as a function of days after drug withdrawal. Each point (n = 12) represents the mean ± SEM. *p < 0.05; Dunnett's tests.

Fig. 12.

Correlation between time (in minutes) of resumed responding in the six animals treated with CHAL+APO in experiment 2 and their highest degree of behavioral supersensitivity (percent of increase in maximal response rates) in experiment 3.