Effects of acute administration of the GABA(B) receptor agonist baclofen on behavioral flexibility in rats

Abstract

Rationale: The ability to adjust response strategies when faced with changes in the environment is critical for normal adaptive behavior. Such behavioral flexibility is compromised by experimental disruption of cortical GABAergic signaling, as well as in conditions such as schizophrenia and normal aging that are characterized by cortical hyperexcitability. The current studies were designed to determine whether stimulation of GABAergic signaling using the GABA(B) receptor agonist baclofen can facilitate behavioral flexibility.

Methods: Male Fischer 344 rats were trained in a set-shifting task in which they learned to discriminate between two response levers to obtain a food reward. Correct levers were signaled in accordance with two distinct response rules (rule 1: correct lever signaled by a cue light; rule 2: correct lever signaled by its left/right position). The order of rule presentation varied, but they were always presented sequentially, with the trials and errors to reach criterion performance on the second (set shift) rule providing the measure of behavioral flexibility. Experiments determined the effects of the GABA(B) receptor agonist baclofen (intraperitoneal, 0, 1.0, 2.5, and 4.0 mg/kg) administered acutely before the shift to the second rule.

Results: Baclofen enhanced set-shifting performance. Control experiments demonstrated that this enhancement was not simply due to improved discrimination learning, nor was it due to impaired recall of the initial discrimination rule.

Conclusions: The results demonstrate that baclofen can facilitate behavioral flexibility, suggesting that GABA(B) receptor agonists may have utility for treating behavioral dysfunction in neuropsychiatric disorders.

Keywords: Baclofen; Behavioral flexibility; GABA(B) receptor; Prefrontal cortex; Set shifting.

Figure 1. Schematic of the set-shifting task and experimental designs

The set-shifting task employed two types of discrimination: visual cue discrimination and left/right discrimination. (A) During the visual cue discrimination, rats were required to respond on the lever illuminated by a cue light, irrespective of its left/right location. (B) During the left/right discrimination, rats were required to respond on the lever in a particular location (e.g., as in the illustration, always press the left lever), irrespective of whether that lever was illuminated by the cue light. (C) Outline of each of the four experiments.

Figure 2. Experiment 1: Baclofen facilitated set-shifting from visual cue to left/right discrimination learning

(A) Trials to criterion on the visual cue (initial) discrimination. (B) Trials to criterion on the left/right (set shift) discrimination following vehicle or baclofen (1, 2.5, or 4.0 mg/kg) administration. (C) Errors to criterion on the left/right (set shift) discrimination shown for all error types total and broken out by previously- and never-reinforced error types. Data are expressed as mean + SEM. * p < 0.05 compared to vehicle.

Figure 3. Experiment 2: Baclofen facilitated set-shifting from left/right to visual cue discrimination learning

(A) Trials to criterion on the left/right (initial) discrimination. (B) Trials to criterion on the visual cue (set shift) discrimination following vehicle or baclofen (1.0, 2.5, or 4.0 mg/kg) administration. (C) Errors to criterion on the visual cue (set shift) discrimination shown for all error types total and broken out by previously- and never-reinforced error types. Data are expressed as mean + SEM. * p < 0.05 compared to vehicle.

Figure 4. Experiment 3: Baclofen had no effect on acquisition of left/right or visual cue discriminations

(A) Trials to criterion on acquisition of the left/right discrimination following vehicle or baclofen (1.0 or 2.5 mg/kg) administration. (B) Trials to criterion on acquisition of the visual cue discrimination following vehicle or baclofen (1.0 or 2.5 mg/kg) administration Data are expressed as mean + SEM.

Figure 5. Experiment 4: Baclofen had no effect on recall of visual cue discrimination learning

(A) Trials to criterion on acquisition of the visual cue discrimination. (B) Trials required to re-establish criterion performance on re-test of the visual cue discrimination following vehicle or baclofen (1.0 or 2.5 mg/kg) administration. Data are expressed as mean + SEM.