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. Recent studies have established that the observed effects are also found in completely closed economies. In addition, the receptor specificity is being examined in other DAR mutant mice. In DA D3R and DA D4 mutants the demand curve was not different in KO and WT mice, indicating that these receptor mechanisms are not involved in reinforcing efficacy of food. These effects were obtained both in open and closed economies. Dopaminergic mechanisms appear to be largely involved in attention deficit hyperactivity disorder (ADHD). In order to study these mechanisms and how they regulate attention a widely used laboratory analog of the continuous performance test (5-choice serial reaction time task or 5CSRTT) was implemented. Unfortunately, the effects of drugs that are useful in treating ADHD are not reliably active under this procedure. Reports from clinicians indicate that attention problems are more pronounced in individuals experiencing intermittent rather than continuous reinforcement. We modified the 5CSRTT so that correct responses were only intermittently reinforced. Rats were trained to respond on the 5CSRTT on a fixed ratio (FR) 1, FR 3, or FR 10 schedule of reinforcement. Drugs that were and were not expected to enhance performance were then administered before experimental sessions. Significant increases in accuracy of signal detection were not typically obtained under the FR 1 schedule with any drug. However, d-amphetamine, methylphenidate, and nicotine typically increased accuracy under the FR 3 and FR 10 schedules. With improved predictive validity we can now use the 5CSRTT to study dopaminergic mechanisms in attention processes. Actions that are thought to be involved in the reinforcing effects of opioid drugs are widely thought to exert their effects by initial agonist actions at opioid receptors that then are mediated downstream by the dopamine system. Collaborative studies have indicated that the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4) also contributes to opioid reinforcement. The unnatural isomer of suppressed opioid-induced conditioned place preference and the self-administration of the opioid agonist, remifentanil. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. A combination of in silico and biophysical data supported the ability of (+)-naloxone and remifentanil to bind to TLR4. Collectively, these data indicate that other actions mediated by TLR4 may contribute to the known dopaminergic mechanisms that are involved in reinforcing effects of opioid drugs.

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Soto, Paul L; Hiranita, Takato; Xu, Ming et al. (2016) Dopamine D?-Like Receptors and Behavioral Economics of Food Reinforcement. Neuropsychopharmacology 41:971-8
Soto, Paul L; Grandy, David K; Hursh, Steven R et al. (2015) Erratum to: behavioral economics of food reinforcement and the effects of prefeeding, extinction, and eticlopride in dopamine D? receptor mutant mice. Psychopharmacology (Berl) 232:1669
Soto, Paul L; Hiranita, Takato; Grandy, David K et al. (2014) Choice for response alternatives differing in reinforcement frequency in dopamine D2 receptor mutant and Swiss-Webster mice. Psychopharmacology (Berl) 231:3169-77
Soto, Paul L; Katz, Jonathan L (2013) Interactions of cocaine with dopamine D?-like antagonists in squirrel monkeys. Psychopharmacology (Berl) 226:393-400
Hutchinson, M R; Northcutt, A L; Hiranita, T et al. (2012) Opioid activation of toll-like receptor 4 contributes to drug reinforcement. J Neurosci 32:11187-200
Katz, Jonathan L; Su, Tsung-Ping; Hiranita, Takato et al. (2011) A Role for Sigma Receptors in Stimulant Self Administration and Addiction. Pharmaceuticals (Basel) 4:880-914
Soto, Paul L; Grandy, David K; Hursh, Steven R et al. (2011) Behavioral economics of food reinforcement and the effects of prefeeding, extinction, and eticlopride in dopamine D2 receptor mutant mice. Psychopharmacology (Berl) 215:775-84
Koffarnus, Mikhail N; Katz, Jonathan L (2011) Response requirement and increases in accuracy produced by stimulant drugs in a 5-choice serial reaction-time task in rats. Psychopharmacology (Berl) 213:723-33
Li, Su-Min; Collins, Gregory T; Paul, Noel M et al. (2010) Yawning and locomotor behavior induced by dopamine receptor agonists in mice and rats. Behav Pharmacol 21:171-81
Soto, Paul L; Katz, Jonathan L (2009) Fluoxetine does not alter the ability of dopamine D(1)- and D(2)-like agonists to substitute for cocaine in squirrel monkeys. Pharmacol Biochem Behav 92:219-23

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