Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors

Abstract

People with depression and other neuropsychiatric disorders can experience motivational dysfunctions such as fatigue and anergia, which involve reduced exertion of effort in goal-directed activity. To model effort-related motivational dysfunction, effort-based choice tasks can be used, in which rats can select between obtaining a preferred reinforcer by high exertion of effort vs. a low effort/less preferred option. Preclinical data indicate that dopamine transport (DAT) inhibitors can reverse pharmacologically-induced low-effort biases and increase selection of high-effort options in effort-based choice tasks. Although classical DAT blockers like cocaine can produce undesirable effects such as liability for misuse and psychotic reactions, not all DAT inhibitors have the same neurochemical profile. The current study characterized the effort-related effects of novel DAT inhibitors that are modafinil analogs and have a range of binding profiles and neurochemical actions (JJC8-088, JJC8-089, RDS3-094, and JJC8-091) by using two different effort-related choice behavior tasks in male Sprague-Dawley rats. JJC8-088, JJC8-089, and RDS3-094 significantly reversed the low-effort bias induced by the VMAT-2 inhibitor tetrabenazine, increasing selection of high-effort fixed ratio 5 lever pressing vs. chow intake. In addition, JJC8-089 reversed the effects of tetrabenazine in female rats. JJC8-088 and JJC8-089 also increased selection of high-effort progressive ratio responding in a choice task. However, JJC8-091 failed to produce these outcomes, potentially due to its unique pharmacological profile (i.e., binding to an occluded conformation of DAT). Assessment of a broad range of DAT inhibitors with different neurochemical characteristics may lead to the identification of compounds that are useful for treating motivational dysfunction in humans.

Fig. 1. The effects of JJC8-088 on TBZ-induced changes on the FR/chow feeding choice procedure during the 30 min session (A-B).

A Lever presses (mean±SEM), #p < 0.01, TBZ/VEH significantly different from VEH/VEH; *p < 0.05, TBZ/7.5 mg/kg JJC8-088 significantly different from TBZ/VEH; **p < 0.01, TBZ/30.0 mg/kg JJC8-088 significantly different from TBZ/VEH. B Chow intake in grams (mean±SEM), #p < 0.01, TBZ/VEH significantly different from VEH/VEH; **p < 0.01, TBZ/15.0 and TBZ/30.0 mg/kg JJC8-088 significantly different from TBZ/VEH. The effects of JJC8-088 on PROG/chow feeding choice procedure during the 30 min session (C, D). C Lever presses (mean±SEM), **p < 0.01, 30.0 mg/kg JJC8-088 significantly different from VEH. D Chow intake in grams (mean ± SEM), **p < 0.01, 15.0 mg/kg, and 30.0 mg/kg JJC8-088 was significantly different from VEH.

Fig. 2. The effects of JJ8-089 on TBZ-induced changes on the FR/chow feeding choice procedure during the 30 min session (A-B).

A Lever presses (mean±SEM), #p < 0.01, TBZ/VEH significantly different from VEH/VEH; **p < 0.01, TBZ/7.5 and TBZ/15.0 mg/kg JJ8-089 significantly different from TBZ/VEH. B Chow intake in grams (mean±SEM), #p < 0.01, TBZ/VEH significantly different from VEH/VEH; **p < 0.01, TBZ/7.5 and TBZ/15.0 mg/kg JJ8-089 significantly different from TBZ/VEH. The effects of JJ8-089 on PROG/chow feeding choice procedure during the 30 min session (C, D). C Lever presses (mean ± SEM), *p < 0.05, 15.0 mg/kg JJ8-089 significantly different from VEH. D Chow intake in grams (mean ± SEM), **p <0.01, 7.5, and 15.0 mg/kg JJ8-089 significantly different from VEH.

Fig. 3. The effects of RDS3-094 on TBZ-induced changes on the FR/chow feeding choice procedure during the 30 min session (A-B).

A Lever presses (mean±SEM), #p < 0.01, TBZ/VEH significantly different from VEH/VEH; *p < 0.05, TBZ/15.0 mg/kg RDS3-094 significantly different from TBZ/VEH. B Chow intake in grams (mean ± SEM), #p < 0.01, TBZ/VEH significantly different from VEH/VEH; **p < 0.01, TBZ/15.0 mg/kg RDS3-094 significantly different from TBZ/VEH. The effects of RDS3-094 on PROG/chow feeding choice procedure during the 30 min session (C, D). C Lever presses (±SEM), ns. D Chow intake in grams (mean±SEM), *p < 0.05, RDS3-094 is significantly different than VEH; *p < 0.05, 3.75 mg/kg RDS3-094 is significantly different than VEH; **p < 0.01, 7.5 and 15.0 mg/kg RDS3-094 was significantly different from VEH.

Fig. 4. The effects of JJC8-091 on TBZ-induced changes on the FR/chow feeding choice procedure during the 30 min session (A-B).

A Lever presses (mean ± SEM), #p < 0.01, TBZ/VEH significantly different from VEH/VEH. B Chow intake in grams (mean ± SEM), #p < 0.01, TBZ/VEH significantly different from VEH/VEH; **p < 0.01, TBZ/60.0 mg/kg JJC8-091 significantly different from TBZ/VEH. The effects of JJC8-091 on PROG/chow feeding choice procedure during the 30 min session (C, D). C Lever presses (mean±SEM), *p < 0.05, 60.0 mg/kg JJC8-091 significantly different from VEH. D Chow intake in grams (±SEM), ns.

Fig. 5. The effects of JJ8-089 on TBZ-induced changes on the FR/chow feeding choice procedure in female rats (A, B).

A Lever presses (mean ± SEM), #p < 0.01, 2.0 mg/kg TBZ/VEH significantly different from VEH/VEH; *p < 0.05, TBZ/7.5 mg/kg JJ8-089 significantly different from TBZ/VEH. B Chow intake in grams (mean ± SEM), #p < 0.01, TBZ/VEH significantly different from VEH/VEH; **p < 0.01, TBZ/7.5, 3.75 and 15.0 mg/kg JJ8-089 significantly different from TBZ/VEH.