Noradrenaline and dopamine elevations in the rat prefrontal cortex in spatial working memory

Abstract

The role of prefrontal cortical dopamine (DA) in the modulation of working memory functions is well documented, but substantial evidence indicates that the locus ceruleus noradrenergic system also modulates working memory via actions within the prefrontal cortex (PFC). This study shows that PFC noradrenaline (NA) and DA dialysate levels phasically increase when rats perform correctly in a delayed alternation task in a T-maze, a test of spatial working memory. However, NA levels were markedly enhanced in animals trained to alternate compared with rats that acquired the spatial information about the location of food in the maze but were untrained to make a choice to obtain the reward. In contrast, PFC DA elevations occurred independently of whether the animal had acquired the trial-specific information for correct task execution. The contribution of anticipatory responses to catecholamine efflux was also evaluated by exposing rats to an environment signaling the presence of the reward in the successive alternation task. No conditioned NA efflux was observed in either group. In contrast, in both groups, DA efflux increased in the anticipatory phase of the test to the same levels of those reached during the task. These data provide the first direct evidence for a selective activation of PFC NA transmission during a spatial working memory task. We propose that, in the working memory task, DA is primarily associated with reward expectancy, whereas NA is involved in the active maintenance of the information about a goal and the rules to achieve it.

Figure 1.

Schematic diagram of the delayed alternation task used in the present study. A group of rats was trained to search and locate the food reward in the T-maze with both arms always baited (Alternation-untrained), whereas a second group of animals was trained to alternate to locate the reward (Alternation-trained). During both training and testing sessions, all of the animals were first placed for 10 min in a cage adjacent to the T-maze (waiting cage) before visiting the maze. Testing in the maze was performed for 32 consecutive trials (10 min). An interval of 10 s was introduced between the trials by placing the rats in the “intertrial delay compartment.” For details, see Materials and Methods.

Figure 2.

Location of the microdialysis probes in the PFC. a, Drawing of coronal sections of the rat brain showing the location of the 4 mm microdialysis probes (vertical lines). Numbers indicate millimeters from bregma, according to the atlas of Paxinos and Watson (1986). b, Superimposed bright-field/fluorescence image of a 40 μm section of PFC showing the diffusion pattern of Fluorogold (brighter area) in the region surrounding the probe. The section is taken from a rat killed 3 d after the perfusion of the probe for 10 min with 0.1% Fluorogold (neutral red staining). c, Fluorescence-positive cells in the LC in a section from the same rat in b after perfusion of the fluorescent dye in the PFC. Some Fluorogold-positive neurons are also visible in the caudal portion of the Raphe nucleus. 4V, Fourth ventricle.

Figure 3.

Performance in a delayed alternation task is associated with an increase in NA release in the rat PFC. a, Profile of NA release in untrained rats during baseline (white circles), in the waiting cage (w; gray circles), during the task (t; black circles), and again in the home cage (white circles). b, Changes in PFC NA levels in rats trained to alternate in the T-maze. Circles are as in a. The abscissa represents the number of 10 min dialysate samples. Points represent means ± SEM of nine animals per group. ^*p < 0.05 versus the average of the four baseline values (Dunnett's multiple-comparison test).

Figure 5.

Performance in the alternation task is associated with selective NA efflux in the PFC of trained rats. a, Total efflux of NA relative to baseline during the 10 min exposure to the maze and in the successive 10 min sample. b, Total efflux of DA during the 10 min exposure to the maze and in the successive 10 min sample. Values are means ± SEM of the area under the curve of the monoamine efflux in 20 min and are normalized with respect to the averaged catecholamine efflux in the home cage in 20 min (100%). “Home” bars represent the normalized area of the last two baseline samples (20 min efflux) taken before placing the different groups of rats in the waiting cage. ^*p < 0.5 (Student's t test). ns, Not significant. Error bars represent SEM.

Figure 6.

PFC DA, but not NA, efflux increases in the anticipatory phase of the test in conditioned rats. a, PFC NA and DA levels during the anticipatory phase of the test (waiting cage) and during the test in the T-maze in rats untrained to alternate. b, PFC NA and DA levels during the anticipatory phase of the test (waiting cage) and during the test in the T-maze in rats trained to alternate. Bars represent monoamine levels in 10 min samples, are expressed as the percentage of respective baseline values in each group (average of 4 baseline samples in the home cage), and are means ± SEM of five [pseudoconditioned groups (pseudo)] or nine [conditioned groups (cond)] animals. ^*p < 0.05 (Student's t test). ns, Not significant. Error bars represent SEM.

Figure 4.

Profile of DA efflux in the rat PFC during the different phases of the behavioral test. a, Changes in PFC DA levels in untrained rats during baseline (white circles), in the waiting cage (w; gray circles), during the task (t; black circles), and again in the home cage (white circles). b, Changes in PFC DA levels in rats trained to alternate in the T-maze. Circles are as in a. The abscissa represents the number of 10 min dialysate samples. Points are means ± SEM of nine animals per group. ^*p < 0.05 versus the average of the four baseline values (Dunnett's multiple-comparison test).