Co-release of noradrenaline and dopamine in the cerebral cortex elicited by single train and repeated train stimulation of the locus coeruleus

Abstract

Background: Previous studies by our group suggest that extracellular dopamine (DA) and noradrenaline (NA) may be co-released from noradrenergic nerve terminals in the cerebral cortex. We recently demonstrated that the concomitant release of DA and NA could be elicited in the cerebral cortex by electrical stimulation of the locus coeruleus (LC). This study analyses the effect of both single train and repeated electrical stimulation of LC on NA and DA release in the medial prefrontal cortex (mPFC), occipital cortex (Occ), and caudate nucleus. To rule out possible stressful effects of electrical stimulation, experiments were performed on chloral hydrate anaesthetised rats.

Results: Twenty min electrical stimulation of the LC, with burst type pattern of pulses, increased NA and DA both in the mPFC and in the Occ. NA in both cortices and DA in the mPFC returned to baseline within 20 min after the end of the stimulation period, while DA in the Occ reached a maximum increase during 20 min post-stimulation and remained higher than baseline values at 220 min post-stimulation. Local perfusion with tetrodotoxin (TTX, 10 microM) markedly reduced baseline NA and DA in the mPFC and Occ and totally suppressed the effect of electrical stimulation in both areas. A sequence of five 20 min stimulations at 20 min intervals were delivered to the LC. Each stimulus increased NA to the same extent and duration as the first stimulus, whereas DA remained elevated at the time next stimulus was delivered, so that baseline DA progressively increased in the mPFC and Occ to reach about 130 and 200% the initial level, respectively. In the presence of the NA transport (NAT) blocker desipramine (DMI, 100 microM), multiple LC stimulation still increased extracellular NA and DA levels. Electrical stimulation of the LC increased NA levels in the homolateral caudate nucleus, but failed to modify DA level.

Conclusion: The results confirm and extend that LC stimulation induces a concomitant release of DA and NA in the mPFC and Occ. The different time-course of LC-induced elevation of DA and NA suggests that their co-release may be differentially controlled.

Figure 1

Schematic representations (redrawn from Paxinos and Watson's Atlas, 1997) of the cerebral areas implanted with dialysis probes.

Figure 2

A: microphotograph showing the electrode localization into the locus coeruleus. B: schematic representation of locus coeruleus stimulation parameters; each vertical line represent a stimulus (700 μA, 250 μs), burst were delivered in 250 ms.

Figure 3

Effect of locus coeruleus stimulation on extracellular NA and DA levels in the medial prefrontal and occipital cortex. Stimuli were delivered in bursts, as described in Methods, for a duration of 20 min (horizontal solid lines). Data are means ± SE, expressed as percent of mean basal value. Filled symbols indicate p < 0.05 with respect to basal values (Dunnett test)

Figure 4

Effect of locus coeruleus stimulation on extracellular NA and DA levels in the medial prefrontal and occipital cortex locally perfused with TTX. TTX perfusion started after collection of basal samples, as indicated by the dashed line. Burst stimuli were delivered 40 min (two samples) after the beginning of TTX perfusion, for a duration 20 min (horizontal solid line). Data are means ± SE, expressed as percent of mean basal value. Filled symbols indicate p < 0.05 with respect to basal values (Dunnett test).

Figure 5

Effect of repeated locus coeruleus stimulation on extracellular NA and DA levels in the medial prefrontal and occipital cortex. Stimuli were delivered in bursts, as described in Methods (horizontal solid lines). Data are means ± SE, expressed as percent of mean basal value. Filled symbols indicate p < 0.05 with respect to basal values (Dunnett test).

Figure 6

Effect of TTX perfusion during repeated locus coeruleus stimulation on extracellular NA and DA levels in the occipital cortex. Stimuli were delivered in bursts, as described in Methods (horizontal solid lines). TTX perfusion started with the third stimulation administration, as indicated by the dashed line. Data are means ± SE, expressed as percent of mean basal value. Filled symbols indicate p < 0.05 with respect to basal values (Dunnett test).

Figure 7

Effect of repeated locus coeruleus stimulation on extracellular NA and DA levels in the medial prefrontal cortex and caudate nucleus. Stimuli were delivered in bursts, as described in Methods (horizontal solid lines). Data are means ± SE, expressed as percent of mean basal value. Filled symbols indicate p < 0.05 with respect to basal values (Dunnett test).

Figure 8

Effect of repeated locus coeruleus stimulation on extracellular NA and DA levels in the medial prefrontal and occipital cortex locally perfused with DMI. 100 μM DMI was administered through reverse dialysis for at least 2 h before stimulation, as represented by the dotted line. Stimuli were delivered in bursts, as described in Methods, for a duration 20 min (horizontal solid lines). Data are means ± SE, expressed as percent of mean basal value. Filled symbols indicate p < 0.05 with respect to basal values (Dunnett test).

Figure 9

Effect of stimulation outside the locus coeruleus on extracellular NA and DA levels in the medial prefrontal cortex and caudate nucleus. Stimuli were delivered in bursts, as described in Methods (horizontal solid lines). Data are means ± SE, expressed as percent of mean basal value.