Differential antagonism of cocaine self-administration and cocaine-induced disruptions of learning by haloperidol in rhesus monkeys

Abstract

Six rhesus monkeys responding under a three-component multiple schedule were administered haloperidol to determine its effects on cocaine self-administration and on cocaine's disruptive effects on the repeated acquisition and performance of response chains. In the absence of haloperidol, 0.0032-0.032 mg/kg/infusion of cocaine increased response rate and the number of infusions in the self-administration component when compared to saline administration, whereas 0.1-0.32 mg/kg/infusion decreased response rate and the number of infusions. When compared to saline administration, the two lowest infusion doses of cocaine had little or no effect on responding in the acquisition and performance components; however, higher infusion doses of cocaine dose-dependently decreased response rate in these components. In addition, the higher doses of cocaine also increased the percentage of errors in the acquisition and performance components. Pretreatment with haloperidol (0.0032 or 0.01 mg/kg, i.m.) antagonized the effects of low doses of cocaine on the number of infusions in the self-administration component, whereas only the 0.01-mg/kg dose antagonized the effects of high doses of cocaine on the number of infusions. Neither dose of haloperidol antagonized the rate-decreasing effects of cocaine on responding in the acquisition and performance components significantly; the highest dose of haloperidol alone decreased rates of responding in each component. Antagonism of cocaine's error-increasing effects by haloperidol was only evident at one dose of cocaine (0.032 mg/kg/infusion), and was more complete in the performance components than in the acquisition components. Together, these data show the limited suitability of haloperidol for selectively antagonizing cocaine self-administration in the context of a multiple schedule involving transition behavior, and show the lack of uniform antagonism across operant behaviors.

Fig 1

Drawing of the response panel used to test the subjects under the three-component multiple schedule of self-administration, repeated acquisition and performance.

Fig 2

Cumulative records from Monkey 79 showing the within-session effects of increasing infusion doses of cocaine in the self-administration component of the three-component multiple schedule. Each session began with a self-administration (SA) component and was followed by either a repeated-acquisition (A) or a performance (P) component depending on the session. In the self-administration components, the response pen stepped upward with every response and it was deflected downward for the duration of each cocaine infusion. In the acquisition and performance components, the response pen stepped upward with each correct response and it was deflected downward each time the five-response sequence was completed; every fourth downward deflection of the stepping pen a food pellet was delivered. The response pen reset at the edge of the paper or at the completion of each component. Downward deflections of the event pen (below each record) indicate timeouts in the self-administration components or incorrect responses in the acquisition and performance components. Each session terminated after four cycles of the multiple schedule.

Fig 3

Mean effects of haloperidol pretreatment on the average number of cocaine infusions obtained by 6 monkeys during the self-administration component of the multiple schedule. Each infusion dose of cocaine was tested alone before and after their combination with the 0.0032 or 0.01 mg/kg doses of haloperidol. Infusion doses of cocaine, both alone and in combination with a pretreatment of haloperidol, were available until the criterion was met (cf. Methods). The points and vertical lines above S indicate the mean and standard error of the mean (SEM) for the number of infusions to criterion during saline substitution or saline substitution after a pretreatment with each dose of haloperidol. The points and vertical lines above each unit dose of cocaine indicate the mean and SEM for the number of infusions to criterion after cocaine alone (open bars) or cocaine after a pretreatment with haloperidol (squares and triangles for 0.0032 and 0.01 mg/kg of haloperidol, respectively). Crosses (†) indicate a significant difference from the effects of cocaine alone as determined by a one-way ANOVA with repeated measures followed by Dunnetts post hoc tests, which were conducted after the two-way ANOVA identified main effects or a significant interaction (p < 0.05). The numbers in parentheses indicate the number of subjects represented by that data point when the number was less than 6.

Fig 4

Mean effects of haloperidol pretreatment on the overall response rate (top) and percentage of errors (bottom) of 6 monkeys responding under the three-component multiple schedule of self-administration, repeated acquisition and performance. The left-hand panels depict the effects obtained during the repeated-acquisition components, whereas the right-hand panels depict the effects obtained during the performance components. In both panels, the data points with vertical lines above S indicate mean and SEM for the sessions to criterion when saline was substituted for cocaine (circles), and the mean and SEM for saline substitution sessions that were preceded by a pretreatment of either 0.0032 (squares) or 0.01 (triangles) mg/kg of haloperidol. Data points with vertical lines in the dose-effect curves indicate the mean and SEM for the respective infusion dose of cocaine with or without haloperidol. Note that the percentage of errors was not included in the data analyses when response rate was less than 5 responses/min (0.083 responses/s). Asterisks (*) indicate a significant difference from the respective control data and crosses (†) indicate a significant difference from the effects of cocaine alone as determined by a one-way ANOVA with repeated measures followed by Dunnetts post hoc tests, which were conducted after the two-way ANOVA identified main effects or a significant interaction (p < 0.05). The numbers in parentheses indicate the number of subjects represented by that data point when the number was less than 6.

Fig 5

Cumulative records from Monkey 79 showing the within-session effects of a pretreatment of haloperidol, either 0.032 or 0.01 mg/kg, when saline was available in the self-administration component. The record in the top row represents the pattern of responding that occurred in the absence of a haloperidol pretreatment when saline was available in the self-administration component. For additional details, see legend for Fig. 1.

Fig 6

Cumulative records from Monkey 79 showing the within-session effects of 0.01 mg/kg of haloperidol when varying infusion doses of cocaine were available in the self-administration component. For additional details, see legend for Fig. 1.