The locus coeruleus Is Directly Implicated in L-DOPA-Induced Dyskinesia in Parkinsonian Rats: An Electrophysiological and Behavioural Study

Despite being the most effective treatment for Parkinson's disease, L-DOPA causes a development of dyskinetic movements in the majority of treated patients. L-DOPA-induced dyskinesia is attributed to a dysregulated dopamine transmission within the basal ganglia, but serotonergic and noradrenergic systems are believed to play an important modulatory role. In this study, we have addressed the role of the locus coeruleus nucleus (LC) in a rat model of L-DOPA-induced dyskinesia. Single-unit extracellular recordings in vivo and behavioural and immunohistochemical approaches were applied in rats rendered dyskinetic by the destruction of the nigrostriatal dopamine neurons followed by chronic treatment with L-DOPA. The results showed that L-DOPA treatment reversed the change induced by 6-hydroxydopamine lesions on LC neuronal activity. The severity of the abnormal involuntary movements induced by L-DOPA correlated with the basal firing parameters of LC neuronal activity. Systemic administration of the LC-selective noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine did not modify axial, limb, and orolingual dyskinesia, whereas chemical destruction of the LC with ibotenic acid significantly increased the abnormal involuntary movement scores. These results are the first to demonstrate altered LC neuronal activity in 6-OHDA lesioned rats treated with L-DOPA, and indicate that an intact noradrenergic system may limit the severity of this movement disorder.

Ovarian-Steroid Modulation of Locus Coeruleus Activity in Female Rats: Involvement in Luteinising Hormone Regulation

The noradrenergic nucleus locus coeruleus (LC) has been reported to regulate luteinising hormone (LH) secretion in female rats. Both oestrogen and progestin receptors have been demonstrated in LC neurones, suggesting that these cells are possibly responsive to variations in circulating levels of ovarian steroids. We therefore evaluated changes in the activity of LC neurones during the oestrous cycle and after ovarian-steroid treatment in ovariectomised (OVX) rats, as determined by immunoreactivity to Fos-related antigens (FRA), which comprises all of the known members of the Fos family. Effects of ovarian steroids on the firing rate of LC neurones were also determined in a slice preparation. The number of FRA/tyrosine hydroxylase (TH)-immunoreactive (ir) neurones in the LC increased from 14.00-16.00 h on pro-oestrus, coinciding with the onset of the LH surge and rise in plasma progesterone. FRA immunoreactivity was unaltered during dioestrus. Oestradiol-treated OVX rats (OVX+E) displayed marked reduction in FRA/TH-ir neurones in LC compared to oil-treated OVX rats. Accordingly, oestradiol superfusion significantly reduced the spontaneous firing rate of LC neurones in slices from OVX rats. Compared to OVX+E, oestradiol-treated rats injected with progesterone at 08.00 h (OVX+EP) exhibited higher number of FRA/TH-ir neurones in the LC at 10.00 h and 16.00 h, and great amplification of the LH surge. Bath application of progesterone significantly increased the spontaneous firing rate of OVX+E LC neurones. Our data suggest that ovarian steroids may physiologically modulate the activity of LC neurones in females, with possible implications for LH secretion. Moreover, oestradiol and progesterone appear to exert opposite and complementary effects (i.e. whereas oestradiol inhibits, progesterone, after oestradiol priming, stimulates LC activity).

Locus coeruleus is a central chemoreceptive site in toads

The locus coeruleus (LC) has been suggested as a CO2 chemoreceptor site in mammals. This nucleus is a mesencephalic structure of the amphibian brain and is probably homologous to the LC in mammals. There are no data available for the role of LC in the central chemoreception of amphibians. Thus the present study was designed to investigate whether LC of toads (Bufo schneideri) is a CO2/H+ chemoreceptor site. Fos immunoreactivity was used to verify whether the nucleus is activated by hypercarbia (5% CO2 in air). In addition, we assessed the role of noradrenergic LC neurons on respiratory and cardiovascular responses to hypercarbia by using 6-hydroxydopamine lesion. To further explore the role of LC in central chemosensitivity, we examined the effects of microinjection of solutions with different pH values (7.2, 7.4, 7.6, 7.8, and 8.0) into the nucleus. Our main findings were that 1) a marked increase in c-fos-positive cells in the LC was induced after 3 h of breathing a hypercarbic gas mixture; 2) chemical lesions in the LC attenuated the increase of the ventilatory response to hypercarbia but did not affect ventilation under resting conditions; and 3) microinjection with acid solutions (pH = 7.2, 7.4, and 7.6) into the LC elicited an increased ventilation, indicating that the LC of toads participates in the central chemoreception.

Role of Locus coeruleus noradrenergic neurons in cardiorespiratory and thermal control during hypoxia

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The locus coeruleus and central chemosensitivity

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Role of neurokinin-1 expressing neurons in the locus coeruleus on ventilatory and cardiovascular responses to hypercapnia

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Locus coeruleus noradrenergic neurons and CO2 drive to breathing

The Locus coeruleus (LC) has been suggested as a CO2 chemoreceptor site in mammals. In the present study, we assessed the role of LC noradrenergic neurons in the cardiorespiratory and thermal responses to hypercapnia. To selectively destroy LC noradrenergic neurons, we administered 6-hydroxydopamine (6-OHDA) bilaterally into the LC of male Wistar rats. Control animals had vehicle (ascorbic acid) injected (sham group) into the LC. Pulmonary ventilation (plethysmograph), mean arterial pressure (MAP), heart rate (HR), and body core temperature (T-c, data loggers) were measured followed by 60 min of hypercapnic exposure (7% CO2 in air). To verify the correct placement and effectiveness of the chemical lesions, tyrosine hydroxylase immunoreactivity was performed. Hypercapnia caused an increase in pulmonary ventilation in all groups, which resulted from increases in respiratory frequency and tidal volume (V-T) in sham-operated and 6-OHDA-lesioned groups. The hypercapnic ventilatory response was significantly decreased in 6-OHDA-lesioned rats compared with sham group. This difference was due to a decreased V-T in 6-OHDA rats. LC chemical lesion or hypercapnia did not affect MAP, HR, and T-c. Thus, we conclude that LC noradrenergic neurons modulate hypercapnic ventilatory response but play no role in cardiovascular and thermal regulation under resting conditions.

5-HT2A serotoninergic receptor in the locus coeruleus participates in the first phase of lipopolysaccharide-induced fever

This study was aimed at testing the hypothesis that serotoninergic receptors in the locus coeruleus (LC) play a role in bacterial lipopolysaccharide-induced fever. To this end, 5-HT1A (WAY-100635; 3 mu g/100 nL) and 5-HT2A (ketanserin; 2 mu g/100 nL) antagonists were microinjected into the LC and body temperature was monitored by biotelemetry. Intra-LC microinjections of ketanserin or WAY-100635 caused no change in body temperature of euthermic animals. 5-HT2A antagonism abolished the first phase of the lipopolysaccharide-induced fever. Taken together, these results indicate that serotonin acting on 5-HT2A receptors in the LC mediates the first phase of the febrile response, whereas 5-HT1A receptors are not involved in the lipopolysaccharide-induced fever.

Serotonergic mechanisms on breathing modulation in the rat locus coeruleus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)