Locus Coeruleus Activity Research Articles

Excitatory action of N-methyl- d-aspartate on the rat locus coeruleus is mediated by nitric oxide: an in vivo voltammetric study

Biochemical, electrophysiological and behavioural studies have provided evidence that activation of N-methyl- d-aspartate (NMDA) receptors contributes to the hyperactivity of noradrenergic neurons of the locus coeruleus (LC) in precipitated opioid withdrawal. Recently, it was demonstrated that central administration of nitric oxide (NO) synthase inhibitors suppresses this hyperactivity suggesting that NO mediates the NMDA receptor activation of LC in opioid withdrawal. Using a combination of microdialysis and in vivo voltammetry, this study examined whether local application of NMDA to the LC in opioid naive animals mimics the NO-dependent LC response seen in opioid withdrawal. In the urethane anaesthetized rat, perfusion of the LC (2 μl min −1) with a solution of NMDA (5 mmol) via a microdialysis probe for 9 min resulted in a rapid and robust increase (290.1±32.2% above baseline) in the catechol oxidation current (CA·OC) recorded from the LC using differential normal pulse voltammetry (DNPV). The NMDA microdialysis also produced a large increase in the blood pressure (150.4±6.9% above baseline). An injection of the non-competitive NMDA receptor antagonist (+)MK-801 (0.5 mg kg −1 i.v.), given 45 min after the start of NMDA application, rapidly returned both the CA·OC signal and the blood pressure response to baseline levels. Pretreatment of animals with intraventricular nitric oxide synthase (NOS) inhibitor, N ω -nitro- l-arginine methyl ester ( l-NAME) (100 μg) significantly inhibited NOS activity in the LC, PAG-PVG and cerebellum. This dose of l-NAME, administered prior to application of NMDA by microdialysis abolished the NMDA-induced rise in the CA⋅OC recorded in the LC and the increase in systolic blood pressure. The results show that in voltammetry experiments, NMDA produces hyperactivity of LC and hypertension, responses that are dependent upon the synthesis of NO. Thus, in opioid naive rats, regional NMDA application via microdialysis mimics characteristics of the LC response that occur during the antagonist-precipitated opioid withdrawal.

Phasic activation of the locus coeruleus enhances responses of primary sensory cortical neurons to peripheral receptive field stimulation

In the present study we examined the effects of phasic activation of the nucleus locus coeruleus (LC) on transmission of somatosensory information to the rat cerebral cortex. The rationale for this investigation was based on earlier findings that local microiontophoretic application of the putative LC transmitter, norepinephrine (NE), had facilitating actions on cortical neuronal responses to excitatory and inhibitory synaptic stimuli and more recent microdialysis experiments that have demonstrated increases in cortical levels of NE following phasic or tonic activation of LC. Glass micropipets were used to record the extracellular activity of single neurons in the somatosensory cortex of halothane-anesthetized rats. Somatosensory afferent pathways were activated by threshold level mechanical stimulation of the glabrous skin on the contralateral forepaw. Poststimulus time histograms were used to quantitate cortical neuronal responses before and at various time intervals after preconditioning burst activation of the ipsilateral LC. Excitatory and postexcitatory inhibitory responses to forepaw stimulation were enhanced when preceded by phasic activation of LC at conditioning intervals of 200–500 ms. These effects were anatomically specific in that they were only observed upon stimulation of brainstem sites close to (>150 μm) or within LC and were pharmacologically specific in that they were not consistently observed in animals where the LC-NE system had been disrupted by 6-OHDA pretreatment. Overall, these data suggest that following phasic activation of the LC efferent system, the efficacy of signal transmission through sensory networks in mammalian brain is enhanced.

Fedotozine inhibits colorectal distention (CRD)-induced stimulation of locus coeruleus (LC) activity and abdominal contraction response (ACR) in rats

Fedotozine inhibits colorectal distention (CRD)-induced stimulation of locus coeruleus (LC) activity and abdominal contraction response (ACR) in rats

The biphasic effects of locus coeruleus noradrenergic activation on dendrodendritic inhibition in the rat olfactory bulb

Some forms of olfactory learning require intact noradrenergic terminals in the olfactory bulb that originate from the locus coeruleus. To clarify the action of noradrenergic inputs on the dendrodendritic interaction between mitral and granule cells in the rat olfactory bulb, we analyzed field potentials in the granule cell layer of the olfactory bulb evoked by paired-pulse stimulation of the lateral olfactory tract before and after the activation of the locus coeruleus. Locus coeruleus activation by glutamate injection in the vicinity of the nucleus changed only the test response without any effect on conditioning response. Paired-pulse inhibition measured from the ratio of test response amplitude to conditioning response amplitude was significantly depressed immediately after locus coeruleus activation. Conversely, 2 min later, paired-pulse inhibition was significantly potentiated. The significant potentiation of inhibition lasted for several minutes. The depression–potentiation sequence of paired-pulse inhibition was blocked by infusion of timolol, a β-antagonist, into the olfactory bulb, in a dose-dependent manner, but not by infusion of phentolamine, an α-antagonist. Infusion of isoproterenol, a β-agonist, into the bulb mimicked the depression of paired-pulse inhibition by locus coeruleus activation. These results suggest that glutamate activation of the locus coeruleus produces a depression–potentiation sequence in granule cell-mediated feedback inhibition onto mitral cells in the olfactory bulb through β-adrenergic receptors.

Light and electron microscopic evidence for topographic and monosynaptic projections from neurons in the ventral medulla to noradrenergic dendrites in the rat locus coeruleus

Physiological studies have shown that afferents from the nucleus paragigantocellularis (PGi) in the rostral ventral medulla underlie the modulation of locus coeruleus (LC) activity by a variety of stimuli. However, there have been no anatomical demonstrations of a monosynaptic projection from neurons in the PGi to the LC. Thus, biotinylated dextran amine (BDA) was iontophoretically injected into the ventral medulla and single-tissue sections were processed for peroxidase localization of BDA and gold–silver labeling of tyrosine hydroxylase (TH). Discrete microinjections of BDA were placed into either the medial or lateral aspects of the ventral medulla. For medially placed injections, a medio-dorsal pathway to the LC was observed. This trajectory resulted in a predominant innervation of the ventral LC. Lateral injection placements yielded a fiber pathway that coursed more laterally within the medullo-pontine reticular formation and primarily innervated the dorsolateral LC. These light microscopic data suggested that neurons in the PGi use distinct pathways to innervate the LC and are topographically organized within this structure. Electron microscopic analyses of the LC region indicated that axon terminals originating from either subregion were equally likely to contact noradrenergic neurons in the LC. Approximately 57% and 62% of BDA-labeled terminals originating from the medial ( n=150) or lateral ( n=150) aspects of the ventral medulla, respectively, formed heterogeneous synaptic contacts (i.e., inhibitory- and excitatory-type) with dendrites containing TH. It is well known that the PGi is a functionally diverse region that is involved in sensory integration, autonomic regulation and pain modulation. It is also known that LC efferents are spatially organized with respect to their postsynaptic targets. Taken together, our findings that subdivisions of the ventral medulla topographically and monosynaptically innervate the LC suggest that regionally specific PGi neurons target subsets of LC neurons with efferent targets that may possess analogous functional correlates.

Potent excitatory influence of prefrontal cortex activity on noradrenergic locus coeruleus neurons

An influence of the prefrontal cortex on noradrenergic locus coeruleus neurons would have profound implications for the function of the locus coeruleus system. Although the medial prefrontal cortex does not substantially innervate the core of the nucleus locus coeruleus, evidence indicates that the medial prefrontal cortex projects to regions containing locus coeruleus dendrites; indirect medial prefrontal cortex-locus coeruleus projections are also possible. Here, we examined influences of prefrontal cortex activity on locus coeruleus firing rates by activating or inactivating the medial prefrontal cortex while recording impulse activity of locus coeruleus neurons extracellularly in anaesthetized rats. Most of our electrical stimulation experiments were conducted in rats which underwent lesions of the ascending dorsal bundle of noradrenergic fibres from the locus coeruleus to eliminate locus coeruleus projections to the prefrontal cortex, because antidromic activation of locus coeruleus from the prefrontal cortex affects even non-driven locus coeruleus neurons through collaterals. Single pulse stimulation (1 mA, 0.3-0.5 ms) of the dorsomedial (frontal region 2) or prelimbic region of the medial prefrontal cortex synaptically activated 13/16 (81%) or 16/56 (29%) locus coeruleus neurons, respectively. Train stimulation (20 Hz for 0.5 s) synaptically activated greater percentages of locus coeruleus cells, 11/12 cells (92%) for the dorsomedial prefrontal cortex, and 41150 cells (82%) for the prelimbic cortex. No inhibitory responses in the locus coeruleus were obtained with dorsomedial prefrontal stimulation, and weak inhibition was found in 16% of locus coeruleus cells with prelimbic stimulation. Electrical stimulation of more lateral frontal cortex (Frl area) had no effects on locus coeruleus activity. Chemical stimulation of the dorsomedial prefrontal cortex with l-glutamate (10 or 100 mM) or d, l-homocysteic acid (10 mM) phasically activated 15/26 (55%) locus coeruleus cells, and 15/68 cells (22%) with prelimbic stimulation; such activation was sometimes followed by long-lasting oscillatory activity. No locus coeruleus cells exhibited purely inhibitory responses with chemical stimulation of any prefrontal cortex site. Inactivation of the dorsomedial or prelimbic region of the prefrontal cortex with lidocaine microinjection (2%, 180 or 300 nl) reduced locus coeruleus firing rates in 6/10 (60%) or 7/19 (37%) locus coeruleus cells, respectively. In no case did lidocaine in any prefrontal cortex site activate a locus coeruleus neuron. These results indicate that the medial prefrontal cortex provides a potent excitatory influence on locus coeruleus neurons. The fact that inactivation of the medial prefrontal cortex suppressed locus coeruleus firing indicates that the medial prefrontal cortex also provides a resting tonic excitatory influence on locus coeruleus activity.

Slow oscillations as a probe of the dynamics of the locus coeruleus-frontal cortex interaction in anesthetized rats

Multiunit or single unit activity recorded simultaneously from frontal cortex (FC) and locus coeruleus (LC) under ketamine anesthesia revealed that both regions show slow oscillatory activity, together or separately. If, however, both regions are engaged in this oscillatory activity, there is a systematic relationship between their phases with peak LC firing always following FC firing by 200–400 ms. This was confirmed by cross-correlational analyses, which indicated that the two structures temporarily form a resonant system. The FC-LC resonant state is, however, loose enough to remain open to other intrinsic or extrinsic influences, keeping the measured frequencies of oscillations at each site slightly different, as demonstrated by a delailed analysis of the autocorrelograms. An injection of lidocaine at the frontal cortex site, while sharply reducing the prefrontal activity to essentially zero, leads to an increase of the LC activity and to a modification of the shape of the LC autocorrelogram, but does not change appreciably the phase relationship between the activity in the two structures during the diminishing activity in FC.

Locus coeruleus electrophysiological activity and responsivity to corticotropin-releasing factor in inbred hypertensive and normotensive rats

The spontaneously hypertensive rat (SHR) and its normotensive progenitor, the Wistar–Kyoto rat (WKY), have been shown to be differentially responsive to the behavioral and endocrine effects of both stress and corticotropin-releasing factor (CRF), both of which increase locus coeruleus (LC) electrophysiological activity. However, the effect of central administration of CRF in these rat strains has yet to be examined. In the present studies, LC electrophysiological responsivity to intracerebroventricular infusions of CRF was assessed in SHR, an inbred strain of WKY rats (the WKY LJ rat), and an outbred normotensive rat strain, Sprague-Dawley (SD) rats. Spontaneous LC discharge rate, mean arterial blood pressure and heart rate were also examined. LC activity was increased to the same extent in the three rat strains in response to a 3 μg dose of CRF. However, WKY LJ rats showed an exaggerated LC in response to a 1 μg dose of CRF in comparison to the other rat strains tested at this dose. Spontaneous discharge rates of individual LC neurons were lower in both SHR and WKY LJ rats than in SD rats. Further, the variability of the discharge rates of LC neurons was greater in WKY LJ rats than in the other two strains. These results indicate that the WKY LJ rat may provide a useful model for assessing the role of sensitivity to CRF in stress responsiveness.

Activation of locus coeruleus by prefrontal cortex is mediated by excitatory amino acid inputs

We examined the role of excitatory amino acids (EAAs) in activation of noradrenergic locus coeruleus (LC) neurons evoked by electrical stimulation of the medial prefrontal cortex (mPFC) in halothane-anesthetized rats. Microinfusion of the specific N-methyl- d-aspartate antagonist 2-amino-5-phosphonopentanoic acid (AP5, 50 or 100 μM) into the LC significantly suppressed LC responses evoked by mPFC stimulation. Microinfusion of the selective non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 25 or 50 μM) also significantly reduced evoked LC responses. Simultaneous microinfusion of both AP5 and CNQX considerably increased the proportion of LC neurons which exhibited complete suppression of evoked responses (81%), compared to either AP5 or CNQX alone (∼50% each). These results indicate that LC activation by mPFC stimulation is mediated by both NMDA- and non-NMDA-type EAA channels.

24-7 - An analysis of the effects of acute and chronic fluoxetine on extracellular norepinephrine in the rat hippocampus during stress

The locus coeruleus (LC) noradrenergic system is activated by a range of arousing and stressful stimuli. The serotonergic inputs to this structure have been shown to attenuate LC activation under some conditions. The present study examined the effect of fluoxetine, a selective serotonin reuptake inhibitor (SSRI) known to be a clinically effective antidepressant, on basal and stress-induced norepinephrine (NE) release. Basal and stress-induced NE efflux in the rat hippocampus were assessed using in vivo microdialysis techniques. The effect of a 30 minute tailpinch stressor on extracellular concentration of NE was compared in rats treated with fluoxetine either once prior to tailpinch or twice daily for 14 days and, respectively, in unhandled controls and vehicle-treated control animals. A single fluoxetine injection prior to tailpinch did not significantly alter the tailpinch-induced increase of extracellular NE as compared to naive controls. However, there was an enhanced NE response to tailpinch in chronic fluoxetine versus chronic vehicle-treated control rats. Thus, acute blockade of 5-HT uptake by fluoxetine does not affect NE release in response to tailpinch stress. Chronic fluoxetine administration, however, results in a potentiated evoked response of the LC-NE system. One action of chronic fluoxetine, which may relate to therapeutic efficacy, is an increase in responsivity of LC neurons.

Noradrenergic suppression of synaptic transmission may influence cortical signal-to-noise ratio.

Norepinephrine has been proposed to influence signal-to-noise ratio within cortical structures, but the exact cellular mechanisms underlying this influence have not been described in detail. Here we present data on a cellular effect of norepinephrine that could contribute to the influence on signal-to-noise ratio. In brain slice preparations of the rat piriform (olfactory) cortex, perfusion of norepinephrine causes a dose-dependent suppression of excitatory synaptic potentials in the layer containing synapses among pyramidal cells in the cortex (layer Ib), while having a weaker effect on synaptic potentials in the afferent fiber layer (layer Ia). Effects of norepinephrine were similar in dose-response characteristics and laminar selectivity to the effects of the cholinergic agonist carbachol, and combined perfusion of both agonists caused effects similar to an equivalent concentration of a single agonist. In a computational model of the piriform cortex, we have analyzed the effect of noradrenergic suppression of synaptic transmission on signal-to-noise ratio. The selective suppression of excitatory intrinsic connectivity decreases the background activity of modeled neurons relative to the activity of neurons receiving direct afferent input. This can be interpreted as an increase in signal-to-noise ratio, but the term noise does not accurately characterize activity dependent on the intrinsic spread of excitation, which would more accurately be described as interpretation or retrieval. Increases in levels of norepinephrine mediated by locus coeruleus activity appear to enhance the influence of extrinsic input on cortical representations, allowing a pulse of norepinephrine in an arousing context to mediate formation of memories with a strong influence of environmental variables.

An analysis of the effects of acute and chronic fluoxetine on extracellular norepinephrine in the rat hippocampus during stress

The locus coeruleus (LC) noradrenergic system is activated by a range of arousing and stressful stimuli. The serotonergic inputs to this structure have been shown to attenuate LC activation under some conditions. The present study examined the effect of fluoxetine, a selective serotonin reuptake inhibitor (SSRI) known to be a clinically effective antidepressant, on basal and stress-induced norepinephrine (NE) release. Basal and stress-induced NE efflux in the rat hippocampus were assessed using in vivo microdialysis techniques. The effect of a 30 minute tailpinch stressor on extracellular concentration of NE was compared in rats treated with fluoxetine either once prior to tailpinch or twice daily for 14 days and, respectively, in unhandled controls and vehicle-treated control animals. A single fluoxetine injection prior to tailpinch did not significantly alter the tailpinch-induced increase of extracellular NE as compared to naive controls. However, there was an enhanced NE response to tailpinch in chronic fluoxetine versus chronic vehicle-treated control rats. Thus, acute blockade of 5-HT uptake by fluoxetine does not affect NE release in response to tailpinch stress. Chronic fluoxetine administration, however, results in a potentiated evoked response of the LC-NE system. One action of chronic fluoxetine, which may relate to therapeutic efficacy, is an increase in responsivity of LC neurons.

Locus coeruleus activation by colon distention: role of corticotropin-releasing factor and excitatory amino acids

The present study was designed to elucidate the neurotransmitters involved in activation of the noradrenergic nucleus, locus coeruleus, by distention of the distal colon. Locus coeruleus spontaneous discharge rate was recorded from halothane-anesthetized rats before, during and after distention of the colon produced by inflation of a balloon catheter with varying volumes of water. Locus coeruleus activation by colon distention was volume-dependent and reversible. Activation of cortical electroencephalographic activity was temporally correlated with locus coeruleus activation during colon distention and prolonged distention (greater than 2 min) resulted in tachyphalaxis to both locus coeruleus and cortical electroencephalographic activation. The corticotropin-releasing factor antagonist, DPheCRF 12–41, administered intracerebroventricularly (3 μg) or microinfused into the locus coeruleus (10 ng) significantly attenuated locus coeruleus activation produced by lower, but not higher magnitudes of colon distention, implicating corticotropin-releasing factor afferents to the locus coeruleus in this response. Consistent with this, prior exposure to 30 min of footshock stress, which desensitizes locus coeruleus neurons to corticotropin-releasing factor, produced a similar attenuation of locus coeruleus activation by low, but not high magnitudes of distention. Kynurenic acid, administered intracerebroventricularly (5 μmol), significantly antagonized locus coeruleus activation by all magnitudes of colon distention. However, this excitatory amino acid antagonist was ineffective when administered directly into the locus coeruleus (0.3 nmol). Together, these findings suggest that low magnitudes of colon distention activate the locus coeruleus-noradrenergic system via corticotropin-releasing factor release within the locus coeruleus and that excitatory amino acid neurotransmission at a site distal to the locus coeruleus is necessary for this response. Activation of the locus coeruleus-noradrenergic system during colon distention may serve as a cognitive limb of the peripheral parasympathetic response. This activation may also play a role in disorders characterized by comorbidity of colonic and psychiatric symptoms, such as irritable bowel syndrome.

Release of serotonin in the rat locus coeruleus: effects of cardiovascular, stressful and noxious stimuli.

To investigate the function of serotonergic neurons within the locus coeruleus, this brain nucleus of conscious, freely moving rats was superfused with artificial cerebrospinal fluid through a push-pull cannula and the extracellular concentration of serotonin was determined in the superfusate. Serotonin release was increased by depolarization with veratridine (5 microM) or 80 mM K+, while superfusion with tetrodotoxin (1 microM) or systemic administration of 8-hydroxy-2-(di-n-propylamino)tetralin substantially diminished the release rate of serotonin in the locus coeruleus. The pressor response to intravenous infusion of noradrenaline (4 micrograms/kg/min) was associated with a pronounced increase in the release rate of serotonin. Superfusion of the locus coeruleus with tetrodotoxin (1 microM) abolished the increase in serotonin release evoked by the pressor response. A fall of blood pressure produced by intravenous administration of nitroprusside (150 micrograms/kg/min) or chlorisondamine (3 mg/kg) diminished the release rate of serotonin. Immobilization, noise (95 dB) or tail pinch increased the release of serotonin in the locus coeruleus and slightly elevated blood pressure. Chlorisondamine abolished the rise in blood pressure elicited by tail pinch without influencing the increased serotonin release. Tail pinch-induced serotonin release was abolished by superfusion with tetrodotoxin. The findings demonstrate that neuronal serotonin release in the locus coeruleus responds to cardiovascular and sensory stimuli, suggesting a function of serotonergic neurons in central blood pressure regulation, as well as in the modulation of locus coeruleus activity by stress and noxious stimuli.

Fos-like immunoreactivity in locus coeruleus after classical conditioning of the rabbit's nictitating membrane response

We investigated the changes in Fos-like immunoreactivity in the locus coeruleus (LC) after classical conditioning of the rabbit's nictitating membrane. Specifically, we compared unpaired versus paired presentations of a tone conditioned stimulus (CS) and a tactile unconditioned stimulus (US; near the eye). After two training sessions, only paired presentations resulted in acquisition of a conditioned response. This was associated with comparatively less LC Fos expression than with unpaired presentations. Similar observations have been reported for the ventrolateral medulla which is a major source of afferents to LC. The present results are consistent with a role of LC in attention and learning: activity increases as the animal attends to the CS and US. When the relationship between CS and US has been established, LC activity decreases.

Activation of locus coeruleus by stimulation of prefrontal cortex mediated by excitatory amino acid inputs

Activation of locus coeruleus by stimulation of prefrontal cortex mediated by excitatory amino acid inputs

Rapid Acquisition of Discriminative Responding in Monkey Locus Coeruleus Neurons

Publisher Summary This chapter summarizes several studies that investigate the hypothesis that locus coeruleus (LC) activity can influence the acquisition of a new task contingency. Three adult Cynomolgus monkeys have been overtrained for several months on one stimulus contingency in the task. Subsequently, reversal has been instituted unexpectedly by abruptly reversing the meaning of the target and nontarget stimuli. In this task, LC neurons have been selectively and phasically activated by CS+ stimuli. The studies indicate that phasic responses to CS+ stimuli are specifically related to their meaning and not driven by their sensory characteristics. After reversal of the stimulus-response contingency, all LC neurons tested reversed their stimulus-response profile and became selectively responsive to the new target (old nontarget) stimuli and have been unresponsive to the old target stimuli (new nontarget). To analyze the temporal relationship between LC and behavioral responses during acquisition of a new stimulus contingency, the rate of reversal of LC phasic responses has been compared with the rate of behavioral reversal for the same task epochs. In particular, by this point after reversal, LC neurons exhibited very little response to old target (new nontarget) stimuli. The early changes that occur in LC tonic and stimulus-evoked activity after task reversal indicate that the LC may play an active role in acquisition of stimulus significance. The widespread efferent anatomy of the norepinephrine (NE)-LC system indicates that it may be involved in a very general aspect of learning rather than for learning one type of task only. Specifically, LC could play a role in acquisition of a new contingency by altering the relative salience of target and nontarget stimuli.

Regulation of a Putative Neurotransmitter Effect of Corticotropin-Releasing Factor: Effects of Adrenalectomy

This study tested the hypothesis that endogenous glucocorticoids regulate a putative neurotransmitter function of corticotropin-releasing factor (CRF) in the locus coeruleus (LC). LC spontaneous discharge and activation by intracerebroventricularly administered CRF, hypotensive challenge, sciatic nerve stimulation, and carbachol were compared in adrenalectomized and sham-operated halothane-anesthetized rats. LC spontaneous discharge was higher in adrenalectomized versus sham-operated rats. Intracoerulear microinfusion of a CRF antagonist decreased LC discharge rates of adrenalectomized rats to rates comparable with those observed in sham-operated rats but had no effect in sham-operated rats. The CRF dose-response curve was shifted in a complex manner in adrenalectomized rats, suggesting that a proportion of CRF receptors were occupied before CRF administration, and low doses of CRF were additive. Higher doses of CRF produced effects that were greater than predicted by simple additivity. Hypotensive challenge increased LC discharge rates of adrenalectomized rats by a magnitude greater than that predicted on the basis of additivity. In contrast, LC responses to carbachol and sciatic nerve stimulation were similar in both groups. The results suggest that adrenalectomy enhances tonic and stress-induced CRF release within the LC and also alters postsynaptic sensitivity of LC neurons to CRF. Because adrenalectomy also alters release of neurohormone CRF, the present study suggests that CRF actions as a neurohormone and as a neurotransmitter in the LC may be co-regulated. Such parallel regulation may underlie the coexistence of neuroendocrine and noradrenergic dysfunctions in stress-related psychiatric disorders.

403 Activation of locus coeruleus by stimulation of prefrontal cortex mediated by excitatory amino acid inputs

403 Activation of locus coeruleus by stimulation of prefrontal cortex mediated by excitatory amino acid inputs

Enhanced norepinephrine release in prefrontal cortex with burst stimulation of the locus coeruleus

The present study was designed to determine the relationship between the discharge of noradrenergic locus coeruleus (LC) neurons and norepinephrine release in the medial prefrontal cortex, a target of LC projections. The LC was electrically stimulated at varying frequencies and patterns for 20 min and extracellular norepinephrine levels were measured in the medial prefrontal cortex of halothane-anesthetized rats using in vivo microdialysis. Electrical stimulation of the LC at 3–10 Hz with an evenly spaced pattern of pulses (tonic stimulation) increased cortical norepinephrine levels in a frequency-dependent manner, with 5- and 10-Hz stimulation increasing norepinephrine levels by 49 ± 3% and 66 ± 20%, respectively. The LC was also stimulated with bursts of pulses designed to deliver physiologically relevant phasic stimulation using the same number of stimuli in a 20-min period as delivered by tonic stimulation at 3 Hz. Results revealed that norepinephrine levels were significantly higher with phasic stimulation compared to tonic stimulation. The present findings indicate that both frequency and pattern of LC discharge are determinants of norepinephrine terminal release. Additionally, bursts of LC activity, similar to those that occur in behaving animals, may be more effective in increasing terminal norepinephrine release on a per spike basis than tonic increases in activity.