Behavioral economics of food reinforcement and the effects of prefeeding, extinction, and eticlopride in dopamine D2 receptor mutant mice

Abstract

Rationale: Several studies have investigated the reinforcing effects of food in genetically engineered mice lacking dopamine D(2) receptors (DA D(2)Rs); however, behavioral economic analyses quantifying reinforcement have not been conducted.

Objective: The role of DA D(2)Rs in food reinforcement was examined by comparing responding under various fixed-ratio (FR) schedules of reinforcement, and effects of extinction, satiation, and the DA D(2)R antagonist eticlopride, in mice with and without genetic deletions of the receptor.

Results: Response rates of DA D(2)R knockout (KO) mice were generally lower than those of littermate wild-type (WT) and heterozygous (HET) mice. The demand curve (consumption vs. FR value) for KO mice decreased more steeply than that of HET or WT mice, suggesting that reinforcing effectiveness is decreased with DA D(2)R deletion. Prefeeding decreased, whereas extinction increased overall response rates as a proportion of baseline, with no significant genotype differences. Both (+)- and (-)-eticlopride dose-dependently decreased responding in all genotypes with (-)-eticlopride more potent than (+)-eticlopride in all but KO mice. The enantiomers were equipotent in KO mice, and similar in potency to (+)-eticlopride in WT and HET mice.

Conclusions: That prefeeding and extinction did not vary across genotypes indicates a lack of involvement of DA D(2)Rs in these processes. Differences between (-)-eticlopride effects and extinction indicate that DA D(2)R blockade does not mimic extinction. The maintenance of responding in KO mice indicates that the DA D(2)R is not necessary for reinforcement. However, the economic analysis indicates that the DA D(2)R contributes substantially to the effectiveness of food reinforcement.

Fig. 1

Changes in overall response rate (top panels), run rate (middle panels), and post-reinforcement pause (bottom panels) as a function of FR value for lever pressing (left column of graphs) or nose poking (right column of graphs). Each data point represents the average across individual mice within a genotype. Error bars represent ±standard error of the mean. Note that no PRP values are plotted for the KO mice for lever pressing under FR 160 because no reinforcers were obtained at that FR value

Fig. 2

Representative nose poking cumulative records of performances from a DA D₂R WT, HET, and KO mouse. Ordinates, cumulative responses. Abscissae, time (with calibrations in 5 minute increments). Diagonal marks indicate reinforcer deliveries except during extinction where they indicate operation of the feeder and associated stimulus changes. The recording runs continuously throughout experimental sessions, including the 10-sec timeout periods following pellet delivery. The top panel shows baseline records of performances. Note that records for HET and KO mice are displaced to the right. The encircled sections are magnified 200 fold. The second row shows records from the same WT mouse as in the first row during prefeeding of either twice (2×) or four times (4×) its daily amount, on the day prior to the selected session. The third row shows the effects of extinction and a low dose of (-)-eticlopride, with higher doses displayed in the fourth and fifth rows, again for the same WT mouse as in the first row

Fig. 3

Changes in consumption as a function of price (FR value). Consumption decreased as a function of increases in price for all three genotypes and for both lever pressing (left panel) and nose poking (right panel). Consumption decreased more rapidly for KO than HET or WT mice for both lever pressing and nose poking (i.e., consumption of KO mice was more elastic). Each data point is the average across individual mice. Changes in consumption as a function of price were well-described by the exponential model of demand (solid line, dotted line, and dashed lines are best fitting curves for WT, HET, and KO mice, respectively) and obtained estimates of α were consistent with the suggestion that reinforcer effectiveness was lowest for KO mice, intermediate for HET mice, and highest for WT mice (see Table 1)

Fig. 4

Changes in overall response rate (top row), run rate (middle row), and PRP value (bottom row), expressed as a proportion of baseline responding for lever pressing (left column) and nose poking (right column), during sessions following days when mice were fed either double (2X) or quadruple (4×) their daily feed amounts or in which responding no longer resulted in pellet delivery (EXT). Each bar represents the average across individual mice. Error bars represent ±standard error of the mean.

Fig. 5

Changes in overall response rate (top row: WT; middle row: HET; bottom row: KO), expressed relative to baseline response rates for lever pressing (left column) and nose poking (right column), during sessions preceded by injection (i.p.) of either (+)- or (-)-eticlopride. Each symbol represents the average across individual mice. Error bars represent ±standard error of the mean.

Fig. 6

Response rate plotted as a function of each ratio in the session for WT mice for sessions during which extinction was in effect (top row) or sessions following administration of (-)-eticlopride (bottom row) for lever pressing (left column) and nose poking (right column). Each symbol represents the average across individual mice. Error bars represent ±standard error of the mean.