Task-Dependent Effects of SKF83959 on Operant Behaviors Associated With Distinct Changes of CaMKII Signaling in Striatal Subareas

Abstract

Background: SKF83959, an atypical dopamine (DA) D1 receptor agonist, has been used to test the functions of DA-related receptor complexes in vitro, but little is known about its impact on conditioned behavior. The present study examined the effects of SKF83959 on operant behaviors and assayed the neurochemical mechanisms involved.

Methods: Male rats were trained and maintained on either a fixed-interval 30-second (FI30) schedule or a differential reinforcement of low-rate response 10-second (DRL10) schedule of reinforcement. After drug treatment tests, western blotting assayed the protein expressions of the calcium-/calmodulin-dependent protein kinase II (CaMKII) and the transcription factor cyclic AMP response element binding protein (CREB) in tissues collected from 4 selected DA-related areas.

Results: SKF83959 disrupted the performance of FI30 and DRL10 behaviors in a dose-dependent manner by reducing the total number of responses in varying magnitudes. Moreover, the distinct profiles of the behavior altered by the drug were manifested by analyzing qualitative and quantitative measures on both tasks. Western-blot results showed that phospho-CaMKII levels decreased in the nucleus accumbens and the dorsal striatum of the drug-treated FI30 and DRL10 subjects, respectively, compared with their vehicle controls. The phospho-CREB levels decreased in the nucleus accumbens and the hippocampus of drug-treated FI30 subjects but increased in the nucleus accumbens of drug-treated DRL10 subjects.

Conclusions: Our results provide important insight into the neuropsychopharmacology of SKF83959, indicating that the drug-altered operant behavior is task dependent and related to regional-dependent changes of CaMKII-CREB signaling in the mesocorticolimbic DA systems.

Keywords: Atypical dopamine receptor agonist; dorsal striatum; neurochemical mechanism; nucleus accumbens; schedule-controlled behavior.

Figure 1.

Dose effects of SKF83959 on fixed-interval 30-second schedule (FI30) behavior (Experiment 1) as measured by: inter-response time (IRT) distribution with the 30-second interval (A), total number of responses (B), the number of reinforced responses (C), and the duration of post-reinforcement pause (PRP). Asterisks denote significant differences between the indicated dose treatment and the vehicle control by post hoc tests: **P < .01, ***P < .001.

Figure 2.

Dose effects of SKF83959 on differential reinforcement of low-rate response 10-second schedule (DRL10) behavior (Experiment 1) as shown by inter-response time (IRT) distribution (A), total number of responses (B), the number of reinforced responses (C), the number of nonreinforced responses (D), the number of burst responses (E), peak rate (F), and peak time (G). Asterisks denote significant differences between the indicated dose treatment and the vehicle control by post hoc tests: *P < .05, **P < .01.

Figure 3.

Representative immunoblots and quantitative analyses of phospho-calcium-/calmodulin-dependent protein kinase II (pCaMKII) and calcium-/calmodulin-dependent protein kinase II (CaMKII) expression levels in the medial prefrontal cortex (PFC), dorsal striatum (DS), nucleus accumbens (NAc), and hippocampus (Hippo) in the vehicle- and SKF83959-treated rats after behavioral tests on fixed-interval 30-second schedule (FI30) (A–D) and differential reinforcement of low-rate response 10-second schedule (DRL10) (E–H). The number in each bar represents the sample size of the corresponding group being analyzed. Asterisks denote significant differences between drug treatment and vehicle control: *P < .05; **P < .01 (Experiment 2).

Figure 4.

Representative immunoblots and quantitative analyses of phospho-cyclic AMP response element binding protein (pCREB) and cyclic AMP response element binding protein (CREB) expression levels in the medial prefrontal cortex (PFC), dorsal striatum (DS), nucleus accumbens (NAc), and hippocampus (Hippo) in the vehicle- and SKF83959-treated rats after behavioral test on fixed-interval 30-second schedule (FI30) (A–D) and differential reinforcement of low-rate response 10-second schedule (DRL10) (E–H). The number in each bar represents the sample size of the corresponding group being analyzed. Asterisks denote significant differences between drug treatment and vehicle control: *P < .05; **P < .01 (Experiment 2).

Figure 5.

Dose effects of SKF83959 on spontaneous locomotor activity: (top) distance measured in 5-minute blocks and (bottom) total distance during the 30-minute test (Experiment 3).