Detailed analysis of food-reinforced operant lever pressing distinguishes effects of a cannabinoid CB1 inverse agonist and dopamine D1 and D2 antagonists

Abstract

Overt similarities exist between the effects of systemic cannabinoid CB1 inverse agonists and dopamine (DA) antagonists on appetitive behavior. The present set of studies was undertaken to apply a fine-grained analysis of food-reinforced operant lever pressing in rats in order to compare the pattern of effects produced by administration of the CB1 inverse agonist AM 251 and those induced by the DA D1 antagonist SKF 83566, and the D2 antagonist raclopride. Three groups of rats were trained on a fixed-ratio 5 (FR5) schedule and administered these compounds over a range of doses expected to suppress responding. All three drugs produced a dose-related suppression of total lever pressing. In addition to main effects of dose, regression analyses were performed to determine which of several response timing- and rate-related variables correlated most strongly with overall responding in each group. It was found that total session time spent pausing from responding was significantly better at predicting responding in the AM 251 group, while both DA antagonists produced significantly stronger regression coefficients (versus AM 251) from fast responding measures. These results suggest that, while several similarities exist, CB1, D1, and D2 antagonists are not identical in their pattern of suppression of food-maintained lever pressing.

Figure 1

Linear regression plots between total pause time (TPT) and overall responding. The slope produced by AM 251 was significantly more negative than those produced by either DA antagonist, which did not differ from one another. **p < .01 difference between AM 251 and both SKF 83566 and raclopride. Regression equations: AM 251: Y = 2093.3 – 1.26 X. SKF 83566: Y = 1828.3 – 1.04 X. Raclopride: Y = 1687.3 – 0.952 X.

Figure 2

Least-squares regression lines predicting responding from the percent of IRTs which were pauses (IRTs > 5s). AM 251 and SKF 83566 produced a significantly stronger slope than raclopride. **p < .01 difference between raclopride and both SKF 83566 and AM 251. Regression equations: AM 251: Y = 1582.4 - 114.8 X. SKF 83566: Y = 1683.7 – 86.8 X. Raclopride: Y = 1400.6 – 51.6 X.

Figure 3

Linear regression predicting overall responding from Bin 1, the first, shortest IRT bin as a percent of all IRTs. AM 251 produced a significantly lower slope than either DA antagonist. *p < .05 difference between AM 251 and both SKF 83566 and raclopride. Regression equations: AM 251: Y = 601.3 + 16.61 X. SKF 83566: Y = 363.7 + 31.69 X. Raclopride: Y = 239.7 + 34.82 X.

Figure 4

Lines of best fit predicting overall responding from the second-shortest IRT bin, expressed as a percent of all IRTs. As with the relationship between Bin 1 and responding, both DA antagonists were better at producing a relationship between Bin 2 and responding than was AM 251. *p < .05 difference between AM 251 and both SKF 83566 and raclopride. Regression equations: AM 251: Y = 766.2 + 9.27 X. SKF 83566: Y = 86.17 + 30.57 X. Raclopride: Y = 25.5 + 31.7 X.