The roles of specific dopamine (DA) receptors in the expression of various behavioral effects, including those induced by cocaine, are the subject of these investigations. Particular attention is focused on psychomotor stimulant and subjective interoceptive, and reinforcing effects. Several studies have indicated a role of DA in reinforcing effects of drugs and natural reinforcers such as food. A link between DA D2 receptors and obesity through a modification of brain reinforcement mechanisms has also been suggested. One hypothesis suggests that decreased expression of DA D2 receptors decreases the effectiveness of all reinforcers. Using behavioral economic measures we assessed the reinforcing effects of food in DA D2 receptor mutant mice. Behavioral economic theory shows that consumption of a commodity, or demand, is a function of price. Thus, rate of reinforcement (consumption of the commodity) was assessed as a function of the number of required responses (fixed-ratio value, or behavioral price of the commodity). The data were fitted with the equation: logQ=logQ0+k(e-Q0C-1), where C = the price of each reinforcer, k = the range of the data, is a free parameter representing the inverse of reinforcer efficacy, and Q0 is a free parameter representing consumption under no-price conditions. The demand curve decreased more steeply in KO than HET or WT mice, indicating lower reinforcing efficacy with DA D2 receptor deletion. Additionally, and consistent with economic theory, these effects were obtained regardless of the type of response (lever press or nose poking response, with effort greater for lever presses). The genetic differences in demand function were reflected in values that were inversely related to DA D2 receptor population (i.e., KO>HET>WT). The data indicate that DA D2 receptors are involved in reinforcement, though the fact that the behavior was initially developed and maintained in KO mice indicates that D2 receptors are not necessary for reinforcement. Clearly the D2 receptor role in reinforcing effects is subtle and requires tools with appropriate power for its evaluation. Although reinforcement was related to DA D2 receptor populations, partial satiation (a decrease in the motivation for the reinforcer) did not have effects that were related to DA D2 receptor density. The effects of giving the subjects a meal before sessions with food reinforcement were not significantly different across DA D2R KO, HET, and WT mice. Thus the motivational effects of food deprivation, in contrast to the reinforcing effects of food itself, appear largely independent of DA D2 receptor populations. Several authors have suggested that blockade of DA receptors is functionally equivalent to eliminating reinforcement (extinction). We tested this notion by comparing extinction in DA D2R KO mice to that in DA D2R WT and HET mice. Contrary to this hypothesis extinction was similar across these genotypes. In addition, the DA D2 receptor antagonist, (−)-eticlopride dose-dependently decreased responding in all genotypes, with (−)-eticlopride more potent than its (+)-enantiomer in all but KO mice, where the enantiomers were equipotent. This pharmacology substantiates that effects of (−)-eticlopride were specifically due to DA D2 receptor antagonism, and not due to an off-target action. Additionally, the effects of (−)-eticlopride were different from those of DA D2 receptor deletion indicating that the effects of the drug are not specifically due to antagonism of the reinforcing effects of food presentation. These studies are currently being extended to closed economies and to other DAR mutant mice, including DA D3R and DA D4R mutants. The role of DA D3 receptors in the subjective effects of cocaine was examined by training mice to discriminate cocaine from saline injections under a fixed-ratio 10 schedule of food reinforcement. The cocaine dose-effect curves were not different in mice with and without DA D3 receptors. The putative D3 partial agonist, BP897, and antagonists (NGB2904, nafadotride) were tested alone and with cocaine. None of the drugs produced cocaine-like responding in either line of mice. BP897 significantly shifted the cocaine curve 3.5 and 1.5-fold to the right in WT and KO mice, respectively. The shift in KO mice indicates that the effects of BP897 are not exclusively dependent on activity at DA D3Rs. The greater shift in the cocaine dose-effect curve in WT mice suggests a small role for DA D3 receptors in the subjective effects of cocaine. Together with the similarity of the cocaine effects in the two lines of mice, these results indicate a minimal role of DA D3 receptors in the subjective effects of cocaine. Dopaminergic (DA) agonist-induced yawning in rats seems to be mediated by DA D3 receptors, and low doses of several DA agonists decrease locomotor activity, an effect attributed to presynaptic D2 receptors. Effects of several DA agonists on yawning and locomotor activity were examined in rats and mice. Yawning was reliably produced in rats, and by the cholinergic agonist, physostigmine, in both the species. However, DA agonists were ineffective in producing yawning in SwissWebster or DA D2R and DA D3R knockout or wild-type mice. The drugs significantly decreased locomotor activity in rats at one or two low doses, with activity returning to control levels at higher doses. In mice, the drugs decreased locomotion across a 100010 000-fold range of doses, with activity at control levels (U-91356A) or above control levels ( )-7-hydroxy- 2-dipropylaminotetralin HBr, quinpirole at the highest doses. Low doses of agonists decreased locomotion in all mice except the DA D2R knockout mice, but were not antagonized by DA D2R or D3R antagonists (L-741 626, BP 897, or PG01037). Yawning does not provide a selective in-vivo indicator of DA D3R agonist activity in mice. Decreases in mouse locomotor activity by the DA agonists seem to be mediated by D2 DA receptors.
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