Behavioral characteristics of dopamine D5 receptor knockout mice

Abstract

Major psychiatric disorders such as attention-deficit/hyperactivity disorder and schizophrenia are often accompanied by elevated impulsivity. However, anti-impulsive drug treatments are still limited. To explore a novel molecular target, we examined the role of dopamine D₅ receptors in impulse control using mice that completely lack D₅ receptors (D5KO mice). We also measured spontaneous activity and learning/memory ability because these deficits could confound the assessment of impulsivity. We found small but significant effects of D₅ receptor knockout on home cage activity only at specific times of the day. In addition, an analysis using the q-learning model revealed that D5KO mice displayed lower behavioral adjustment after impulsive actions. However, our results also showed that baseline impulsive actions and the effects of an anti-impulsive drug in D5KO mice were comparable to those in wild-type littermates. Moreover, unlike previous studies that used other D₅ receptor-deficient mouse lines, we did not observe reductions in locomotor activity, working memory deficits, or severe learning deficits in our line of D5KO mice. These findings demonstrate that D₅ receptors are dispensable for impulse control. Our results also indicate that time series analysis and detailed analysis of the learning process are necessary to clarify the behavioral functions of D₅ receptors.

Figure 1

Effects of genotype on Drd5 and Drd1 gene expression. (a) Drd5 gene relative expression levels in D5KO (KO, dark bars) mice and wildtype (WT, white bars) littermates. (b) Drd1 gene relative expression levels in D5KO (KO, dark bars) mice and WT (white bars) littermates. Mix means a mixture of KO and wildtype samples. Hip: hippocampus, mPFC: medial prefrontal cortex, Str: striatum. The data are presented as the means ± SEM.

Figure 2

Effects of genotype on 24 h locomotor activity in home cages and on parameters in the open field test. (a) Home cage locomotor activity of D5KO mice and wildtype littermates every 2 h. *p < 0.05. (b) The total distance traveled in the open field test was divided into seven time phases (10 min bins). (c) The number of total crossings (crossings of the lines made by the division of the field [45 × 45 cm] into 7.5 cm × 7.5 cm squares) in the open field test was divided into seven time phases (10 min bins). (d) The percentage of time spent in the central area, a measure of decreased anxiety-like behavior in the open field test, was divided into seven time phases (10 min bins). The filled circles indicate D5KO mice and white squares indicate WT littermates. The data are presented as the means ± SEM.

Figure 3

The effects of dopamine D₅ receptor KO on the parameters in the Y maze test. (a) The percentage of spontaneous alternation, a measure of working memory, in D5KO mice and their WT littermates. (b) The total number of arm entries, a measure of locomotor activity, of D5KO mice and their WT littermates. The data are presented as the means ± SEM.

Figure 4

Averaged function values for the q-learning model at the end of the simulation with estimated parameters. Each simulation was run for 900 steps and 100 simulations were performed. Figure contains averaged values for these simulations at each elapsed time (s). The black line represents the flash timing of the trial. Each line represents the following: Probability density function (p.d.f.) of experience (blue); the p.d.f. of experience distribution. P.d.f. of non-reward (orange); the p.d.f. of non-reward distribution. Prob. of confidence (green); the probability of confidence at each elapsed time. P.d.f. of choice (red); the p.d.f. of choice distribution. Survival of choice (purple): the survival function of the choice distribution.

Figure 5

Effects of acute duloxetine administration on impulsive action. (a) The percentage of premature responses, a measure of impulsive action, of male D5KO mice and their WT littermates. (b) The percentage of premature responses, a measure of impulsive action, of female D5KO mice and their WT littermates. (c) Accuracy, the percentage of correct responses of male D5KO mice and their WT littermates. (d) Accuracy, the percentage of correct responses of female D5KO mice and their WT littermates. (e) The percentage of omissions of male D5KO mice and their WT littermates. (f) The percentage of omissions of female D5KO mice and their WT littermates. (g) The mean correct response latency (s) of male D5KO mice and their WT littermates. (h) The mean correct response latency (s) of female D5KO mice and their WT littermates. (i) The mean reward response latency (s) of male D5KO mice and their WT littermates. (j) The mean reward response latency (s) of female D5KO mice and their WT littermates. The black bars indicate D5KO mice and white bars indicate WT littermates. The data are presented as the means ± SEM. *p < 0.05.

Figure 6

Sessions used for q-learning analysis and duloxetine administrations and illustration of the functions used in the q-learning model in the 3-choice serial reaction time task. (a) Training sessions after a pre-training period were used for q-learning analysis to assess the learning process. A gray or red box indicates one session. Duloxetine was administered after five SD1-ITI9 were completed. SD1-ITI5 stands for stimulus duration of one second and inter trial interval (ITI) of 5 s. SD1-ITI9 stands for stimulus duration of one second and inter trial interval (ITI) of 9 s. (b) X-axis represents elapsed time (sec) from the starting time of trials. The vertical black line at 5 s indicates the timing of the light stimulus. Each line represents the following: Probability density function (p.d.f.) of experience (blue); the p.d.f. of experience distribution. P.d.f. of non-reward (orange); the p.d.f. of non-reward distribution. Prob. of confidence (green); the probability of confidence at each elapsed time. P.d.f. of choice (red); the p.d.f. of choice distribution. Survival of choice (purple): the survival function of the choice distribution.