Evidence suggests a critical role for dopamine in the reinforcing effects of cocaine in rats and primates. However, self-administration has been less often studied in the mouse species, and, to date, “knock-out” of individual dopamine-related genes in mice has not been reported to reduce the reinforcing effects of cocaine. We studied the dopamine D₁receptor and cocaine self-administration in mice using a combination of gene-targeted mutation and pharmacological tools. Two cohorts with varied breeding and experimental histories were tested, and, in both cohorts, there was a significant decrease in the number of D₁receptor knock-out mice that met criteria for acquisition of cocaine self-administration (2 of 23) relative to wild-type mice (27 of 32). After extinction of responding with saline self-administration, dose–response studies showed that cocaine reliably and dose dependently maintained responding greater than saline in all wild-type mice but in none of the D₁receptor knock-out mice. The D₁-like agonist SKF 82958 (2,3,4,5,-tetrahydro-6-chloro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrobromide) and the D₂-like agonist quinelorane both functioned as positive reinforcers in wild-type mice but not in D₁receptor mutant mice, whereas food and intravenous injections of the opioid agonist remifentanil functioned as positive reinforcers in both genotypes. Finally, pretreatment with the D₁-like antagonist SCH 23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-01] produced surmountable antagonism of the reinforcing effects of cocaine in the commonly used strain C57BL/6J. We conclude that D₁receptor knock-out mice do not reliably self-administer cocaine and that the D₁receptor is critical for the reinforcing effects of cocaine and other dopamine agonists, but not food or opioids, in mice.

Sex differences in spatial navigation indicate that women may focus on positional, landmark cues whereas men favor Euclidean, directional cues. Some studies have investigated sex differences in proximal and distal cue use; however, sex differences in gradient (i.e., graded features) and pinpoint (i.e., single, defined) cue perception remain unexamined. In the current experiments, paired photographs were presented in which the 2nd photograph showed the same scene with cues removed (Experiment 1) or isolated (Experiment 2) from the 1st photograph. In Experiment 1, women showed less disruption of task performance than men showed following cue removal but were slowest after proximal pinpoint cue removal. Male performance was slowed by distal gradient and proximal pinpoint cue removal. In Experiment 2, women were faster than men at identifying isolated proximal and distal pinpoint cues and were more accurate at identifying isolated distal gradient and distal pinpoint cues. Better pinpoint cue perception and memory in women indicates one possible mechanism underlying female preference for landmark-based navigation strategies. Findings also show that whereas men may preferentially rely on distal gradient cues they are not better at perceiving those cues than are women.