Local infusion of calcium-free solutions in vivo activates locus coeruleus neurons

doi:10.1016/0361-9230(91)90273-M

Brain Research Bulletin

Volume 27, Issue 1, July 1991, Pages 5-12

https://doi.org/10.1016/0361-9230(91)90273-M Get rights and content

Abstract

Microinfusion of calcium (Ca⁺⁺)-free artificial cerebrospinal fluid onto locus coeruleus (LC) neurons in vivo potently increased their discharge rate, while response of these cells to a sensory stimulus was significantly reduced. These effects resulted in part from interference with the calcium-dependent potassium conductance in these neurons, as microinfusions of solutions having barium substituted for calcium partially mimicked the effects of Ca⁺⁺-free infusions. In addition, microinfusion of control medium containing the Ca⁺⁺ channel blocker, cadmium (2–20 mM), also mimicked the effect of the Ca⁺⁺-free solution. This study presents an effective means by which extracellular concentrations of neuromodulatory ions can be manipulated in vivo. In addition, these results indicate that extracellular Ca⁺⁺ potently modulates the spontaneous as well as evoked activity of central noradrenergic neurons in vivo.

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Cited by (18)

3-Monoiodothyronamine: The rationale for its action as an endogenous adrenergic-blocking neuromodulator
2010, Brain Research
Citation Excerpt :
Injection pipettes (tip diameter 12–20 μm) were fashioned from micro-dispensing capillary tubes as described previously (Akaoka and Aston-Jones, 1991). Opiate withdrawal-induced hyperactivity of locus coeruleus neurons is substantially mediated by augmented excitatory amino acid input (Akaoka and Aston-Jones, 1991; Shiekhattar et al., 1991). The thin lumen of these pipettes allowed accurate measurement of microinjection volume (accuracy within 15 nl).
The investigations reported here were designed to gain insights into the role of 3-monoiodothyronamine (T1AM) in the brain, where the amine was originally identified and characterized. Extensive deiodinase studies indicated that T1AM was derived from the T4 metabolite, reverse triiodothyronine (revT3), while functional studies provided well-confirmed evidence that T1AM has strong adrenergic-blocking effects. Because a state of adrenergic overactivity prevails when triiodothyronine (T3) concentrations become excessive, the possibility that T3's metabolic partner, revT3, might give rise to an antagonist of those T3 actions was thought to be reasonable. All T1AM studies thus far have required use of pharmacological doses. Therefore we considered that choosing a physiological site of action was a priority and focused on the locus coeruleus (LC), the major noradrenergic control center in the brain. Site-directed injections of T1AM into the LC elicited a significant, dose-dependent neuronal firing rate change in a subset of adrenergic neurons with an EC₅₀ = 2.7 μM, a dose well within the physiological range. Further evidence for its physiological actions came from autoradiographic images obtained following intravenous carrier-free ¹²⁵I-labeled T1AM injection. These showed that the amine bound with high affinity to the LC and to other selected brain nuclei, each of which is both an LC target and a known T3 binding site. This new evidence points to a physiological role for T1AM as an endogenous adrenergic-blocking neuromodulator in the central noradrenergic system.
Role of orexin input in the diurnal rhythm of locus coeruleus impulse activity
2008, Brain Research
Citation Excerpt :
Response magnitudes to FS were calculated as the total number of spikes recorded from 20 to 100 ms following stimulation minus the expected number of spikes (average number of spikes/s recorded 1 min prior to FS). Injection pipettes (tip diameter 12–20 μm) were fashioned from microdispensing capillary tubes as described previously (Akaoka and Aston-Jones, 1991; Shiekhattar et al., 1991). The thin lumen of these pipettes allowed accurate measurement of microinjections volume (accuracy within 15 nl).
Activation of noradrenergic locus coeruleus (LC) neurons promotes wakefulness and behavioral arousal. In rats, LC neurons receive circadian inputs via a circuit that originates in the suprachiasmatic nucleus (SCN) and relays through the dorsomedial hypothalamus (DMH) to LC; this circuit input increases LC activity during the active period. DMH neurons expressing the peptide neurotransmitter orexin/hypocretin are ideally situated to act as a relay between SCN and LC due to their synaptic inputs from SCN and innervation of LC. Here, we examined the hypothesis that orexin is involved in transmitting circadian signals to LC using single-unit recordings of LC neurons in anesthetized rats maintained in 12:12 light–dark housing. We replicated earlier findings from this lab that LC neurons fire significantly faster on average during the active compared to rest periods. Local microinjection of an orexin antagonist, SB-334867-A attenuated the impulse activities of the fastest firing population of LC neurons during the active period. We also found that DMH orexin neurons project preferentially to LC and express a diurnal rhythm of activation that correlates with LC neuronal firing frequency. Therefore, we propose that DMH orexin neurons play a role in modulating the day–night differences of LC impulse activity.
The release of noradrenaline in the locus coeruleus and prefrontal cortex studied with dual-probe microdialysis
2001, Brain Research
Citation Excerpt :
This somewhat paradoxical finding suggest that calcium depletion stimulated LC neurons. This result is in agreement with the observation that calcium depletion potently increases the discharge rate of LC neurons [27]. Another explanation for the present observations in the PFC might be found in the strong behavioral activation that was observed during the calcium-free perfusion.
The present study was undertaken to investigate and compare the properties of noradrenaline release in the locus coeruleus (LC) and prefrontal cortex (PFC). For that aim the dual-probe microdialysis technique was applied for simultaneous detection of noradrenaline levels in the LC and PFC in conscious rats. Calcium omission in the LC decreased noradrenaline levels in the LC, but increased its levels in the PFC. Novelty increased noradrenaline levels in both structures. Infusion of the α₂-adrenoceptor agonist clonidine decreased extracellular noradrenaline in the LC as well as in the PFC. Infusion of the α_2A-adrenoceptor antagonist BRL44408, or the α₁-adrenoceptor agonist cirazoline into the LC or PFC caused a similar dose-dependent increase in both structures. When BRL44408 or cirazoline were infused into the LC, few effects were seen in the PFC. Infusion of the 5-HT_1A-receptor agonist flesinoxan into the LC or the PFC decreased the release of noradrenaline in both structures. When flesinoxan was infused into the LC, no effects were seen in the PFC. When the GABA_A antagonist bicuculline was applied to the LC, noradrenaline increased in the LC as well as in the PFC. It is concluded that the release of noradrenaline from somatodendritic sites and nerve terminals responded in a similar manner to presynaptic receptor modulation. The possible existence of dendritic noradrenaline release is discussed.
Potent excitatory influence of prefrontal cortex activity on noradrenergic locus coeruleus neurons
1998, Neuroscience
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.
Activation of locus coeruleus by prefrontal cortex is mediated by excitatory amino acid inputs
1997, Brain Research
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.
Local opiate withdrawal in locus coeruleus in vivo
1997, Brain Research
Hyperactivity of noradrenergic locus coeruleus (LC) neurons following withdrawal from chronic opiates has been implicated in the opiate withdrawal syndrome. Here, we report that local withdrawal induced in vivo by microinfusion of an opiate antagonist into the LC of morphine-dependent rats marginally, but significantly, activated LC neurons above the level obtained with local naloxone microinfusion in naive rats. This local withdrawal response contributes a significant fraction (∼19%) of the total LC hyperactivity induced by systemic naloxone.

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ArticleLocal infusion of calcium-free solutions in vivo activates locus coeruleus neurons

Abstract

Brain Res.

Brain Res.

J. Biol. Chem.

Neuroscience

Electrophysiological effects of local administration of apomorphine in the rat substantia nigra zona compacta

Neuroscience

Locus coeruleus activity in vitro: intrinsic regulation by a calcium-dependent potassium conductance but not alpha 2-adrenoceptors

J. Neurosci.

Activation of locus coeruleus from nucleus paragigantocellularis: a new excitatory amino acid pathway in brain

J. Neurosci.

GABA-Mediated inhibition of locus coeruleus from the dorsomedial nostral medulla

J. Neurosci.

The action of calcium on the electrical properties of squid axons

J. Physiol.

Calcium channel

Annu. Rev. Neurosci.

Extracellular free calcium and potassium during paroxymal activity in the cerebral cortex of the cat

Exp. Brain Res.

Article
Local infusion of calcium-free solutions in vivo activates locus coeruleus neurons