RESUMO
KEY POINTS: Cholinergic projections from the pedunculopontine tegmental nucleus (PPTg) to the retrotrapezoid nucleus (RTN) are considered to be important for sleep-wake state-dependent control of breathing. The RTN also receives cholinergic input from the postinspiratory complex. Stimulation of the PPTg increases respiratory output under control conditions but not when muscarinic receptors in the RTN are blocked. The data obtained in the present study support the possibility that arousal-dependent modulation of breathing involves recruitment of cholinergic projections from the PPTg to the RTN. ABSTRACT: The pedunculopontine tegmental nucleus (PPTg) in the mesopontine region has important physiological functions, including breathing control. The PPTg contains a variety of cell types, including cholinergic neurons that project to the rostral aspect of the ventrolateral medulla. In addition, cholinergic signalling in the retrotrapezoid nucleus (RTN), a region that contains neurons that regulate breathing in response to changes in CO2 /H+ , has been shown to activate chemosensitive neurons and increase inspiratory activity. The present study aimed to identify the source of cholinergic input to the RTN and determine whether cholinergic signalling in this region influences baseline breathing or the ventilatory response to CO2 in conscious male Wistar rats. Retrograde tracer Fluoro-Gold injected into the RTN labelled a subset of cholinergic PPTg neurons that presumably project directly to the chemosensitive region of the RTN. In unrestrained awake rats, unilateral injection of the glutamate (10 mm/100 nL) in the PPTg decreased tidal volume (VT ) but otherwise increased respiratory rate (fR ) and net respiratory output as indicated by an increase in ventilation (VE ). All respiratory responses elicited by PPTg stimulation were blunted by prior injection of methyl-atropine (5 mm/50-75 nL) into the RTN. These results show that stimulation of the PPTg can increase respiratory activity in part by cholinergic activation of chemosensitive elements of the RTN. Based on previous evidence that cholinergic PPTg projections may simultaneously activate expiratory output from the pFRG, we speculate that cholinergic signalling at the level of RTN region could also be involved in breathing regulation.
Assuntos
Neurônios Colinérgicos/fisiologia , Núcleo Tegmental Pedunculopontino/fisiologia , Animais , Derivados da Atropina/farmacologia , Pressão Sanguínea , Fenômenos Eletrofisiológicos , Ácido Glutâmico/farmacologia , Ácido Cinurênico/farmacologia , Masculino , Ratos , Ratos Wistar , Receptor Muscarínico M1/metabolismo , Fenômenos Fisiológicos RespiratóriosRESUMO
Generalised tonic-clonic seizures, generated by abnormal neuronal hyper-activity, cause a significant and long-lasting increase in the nociceptive threshold. The pedunculopontine tegmental nucleus (PPTN) plays a crucial role in the regulation of seizures as well as the modulation of pain, but its role in postictal antinociceptive processes remains unclear. In the present study, we aimed to investigate the involvement of PPTN neurons in the postictal antinociception. Wistar rats had their tail-flick baseline recorded and were injected with ibotenic acid (1.0⯵g/0.2⯵L) into the PPTN, aiming to promote a local neurotoxic lesion. Five days after the neuronal damage, pentylenetetrazole (PTZ; 64â¯mg/kg) was intraperitoneally administered to induce tonic-clonic seizures. The tail-withdrawal latency was measured immediately after the seizures (0â¯min) and subsequently at 10-min intervals until 130â¯min after the seizures were induced pharmacologically. Ibotenic acid microinjected into the PPTN did not reduce the PTZ-induced seizure duration and severity, but it diminished the postictal antinociception from 0 to 130â¯min after the end of the PTZ-induced tonic-clonic seizures. These results suggest that the postictal antinociception depends on the PPTN neuronal cells integrity.
Assuntos
Analgesia , Ácido Ibotênico/toxicidade , Núcleo Tegmental Pedunculopontino/fisiologia , Convulsões/fisiopatologia , Animais , Ácido Ibotênico/administração & dosagem , Masculino , Microinjeções , Medição da Dor , Pentilenotetrazol/farmacologia , Ratos , Convulsões/induzido quimicamente , Fatores de TempoRESUMO
Several efforts have been made to understand the involvement of rapid eye movement (REM) sleep for cognitive processes. Consolidation or retention of recognition memories is severely disrupted by REM sleep deprivation (REMSD). In this regard, pedunculopontine tegmental nucleus (PPT) and other brainstem nuclei, such as pontine nucleus (Pn) and oculomotor nucleus (OCM), appear to be candidates to take part in this REM sleep circuitry with potential involvement in cognition. Therefore, the objective of this study was to investigate a possible association between the performance of Wistar rats in a declarative memory and PPT, Pn, and OCM activities after different periods of REMSD. We examined c-Fos and choline acetyltransferase (ChaT) expressions as indicators of neuronal activity as well as a familiarity-based memory test. The animals were distributed in groups: control, REMSD, and sleep rebound (REB). At the end of the different REMSD (24, 48, 72, and 96 h) and REB (24 h) time points, the rats were immediately tested in the object recognition test and then the brains were collected. Results indicated that OCM neurons presented an increased activity, due to ChaT-labeling associated with REMSD that negatively correlated (r = -0.32) with the cognitive performance. This suggests the existence of a cholinergic compensatory mechanism within the OCM during REMSD. We also showed that 24 h of REMSD impacted similarly in memory, compared to longer periods of REMSD. These data extend the notion that REM sleep is influenced by areas other than PPT, i.e., Pn and OCM, which could be key players in both sleep processes and cognition.
Assuntos
Cognição/fisiologia , Memória/fisiologia , Complexo Nuclear Oculomotor/metabolismo , Privação do Sono/metabolismo , Animais , Colinérgicos/farmacologia , Cognição/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Neurônios/metabolismo , Complexo Nuclear Oculomotor/efeitos dos fármacos , Núcleo Tegmental Pedunculopontino/efeitos dos fármacos , Núcleo Tegmental Pedunculopontino/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Sono REMRESUMO
Anatomical and functional studies have shown that the NADPH-diaphorase-positive cholinergic neurons of the pedunculopontine nucleus (PPN) send projections to several areas in the brain. The purpose of this work was to investigate whether bilateral lesions with quinolinic acid, a neurotoxin with greater selectivity for NADPH-diaphorase-positive neurons, aimed at the compact portion of the PPN would affect the performance of adaptive behaviors, such as sleep, locomotion, and spontaneous alternation. Lesioned animals were divided in a low lesion group (LL, <50% neuron loss) and a high lesion group (HL, ≥50% neuron loss). The LL animals did not show any significant changes in sleep patterns, as compared to controls. In contrast, the HL group showed a significant increase in the number of REM sleep periods, and a reduction of REM sleep average duration, but did not differ in the total time spent in REM sleep. HL animals also showed an increase in the number of SWS periods, though wakefulness parameters did not show significant alterations. The duration and number of both REM and SWS sleep episodes were significantly correlated with the number of NADPH-diaphorase-positive neurons in the PPN. The short-term habituation pattern of locomotion, the vertical exploratory activity, as well as the thigmotaxis (an index of emotionality), displayed by LL and HL rats in a novel environment were similar to those of control animals. Likewise, there were no significant differences in spontaneous alternation among the groups. Our results indicate that quinolinic acid lesions of NADPH-diaphorase-positive cholinergic neurons localized in the posterior region of the PPN disrupt normal sleep structure, while motor activity and spontaneous alternation remain unaffected.
Assuntos
Emoções/fisiologia , Comportamento Exploratório/fisiologia , Locomoção/fisiologia , Memória de Curto Prazo/fisiologia , Núcleo Tegmental Pedunculopontino/fisiologia , Ácido Quinolínico/toxicidade , Fases do Sono/fisiologia , Animais , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/fisiologia , Emoções/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , NADPH Desidrogenase/metabolismo , Núcleo Tegmental Pedunculopontino/efeitos dos fármacos , Ratos , Ratos Wistar , Fases do Sono/efeitos dos fármacosRESUMO
The effects of intraperitoneal (i.p.) or intrathecal (i.t.) injection of antagonists of acetylcholine, noradrenaline, serotonin, dopamine, opioids and GABA on stimulation-produced antinociception (SPA) from the pedunculopontine tegmental nucleus (PPTg) of rats were studied using the tail-flick test. The electrical stimulation of the PPTg produced a strong and long-lasting increase in tail-flick latency. The intensity and duration of the effect were significantly reduced in rats pretreated with i.p. or i.t. atropine (a non-selective muscarinic cholinergic antagonist), or i.t. phenoxybenzamine or WB 4101 (non-selective and selective alpha(1)-adrenergic antagonists, respectively). Intraperitoneal phenoxybenzamine, i.p. or i.t. methysergide or naloxone (non-selective serotonin and opioid antagonists, respectively), or i.t. idazoxan (a selective alpha(2)-adrenergic antagonist) only reduced the duration of the effect. The duration of SPA from the PPTg was increased by i.t. phaclofen (a GABA(B) antagonist). The effect from the nucleus was not altered following i.t. bicuculline (a GABA(A) antagonist), or i.p. or i.t. mecamylamine, propranolol or haloperidol (non-selective nicotinic cholinergic, beta-adrenergic and dopaminergic antagonists, respectively). Thus, SPA from the PPTg involves the spinal activation of muscarinic and alpha(1)-adrenergic but not nicotinic cholinergic, beta-adrenergic and dopaminergic mechanisms. Serotonergic, endogenous opioid and alpha(2)-adrenergic mechanisms are involved in the duration but not in the intensity of the effect.
Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Analgésicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Núcleo Tegmental Pedunculopontino/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/fisiologia , Receptores Muscarínicos/fisiologia , Medula Espinal/efeitos dos fármacos , Animais , Estimulação Elétrica , Injeções Espinhais , Masculino , Núcleo Tegmental Pedunculopontino/fisiologia , Ratos , Ratos Wistar , Medula Espinal/fisiologiaRESUMO
The effects of flesinoxan, a selective 5-HT1A receptor agonist, and of WAY 100635, a selective high affinity 5-HT1A receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. Systemic administration of flesinoxan (0.03 and/or 0.06 micromol/kg, s.c.) increased waking (W) and sleep latencies and reduced REM sleep (REMS) and the number of REM periods during the first and/or second 2-h period after treatment. Systemic injection of WAY 100635 (0.46 and/or 0.92 micromol/kg, s.c.) augmented W and REMS latency and reduced REMS and the number of REM periods during the 6-h recording period. Microinjection of flesinoxan (0.03, 0.06 and/or 0.12 nmol) into the laterodorsal tegmental nucleus (LDT) reduced REMS and the number of REM periods, and augmented REMS latency during the first, second, and/or third 2-h recording period. Direct infusion of WAY 100635 (0.06 and/or 0.12 nmol) into the LDT increased REMS and the number of REM periods during the first and/or second 2 h of recording. It is proposed that the activation by flesinoxan of postsynaptic 5-HT1A receptors located in the LDT could be responsible for the REMS suppression. The increase in REMS after the blockade of postsynaptic 5-HT1A receptors in the LDT by WAY 100635 further supports our proposal. The effects of systemic flesinoxan on sleep variables may depend mainly on the activation of postsynaptic 5-HT1A receptors, whereas the effects corresponding to systemic WAY 100635 may be predominantly related to the blockade of presynaptic somatodendritic 5-HT1A autoreceptors.
Assuntos
Núcleo Tegmental Pedunculopontino/efeitos dos fármacos , Piperazinas/farmacologia , Piridinas/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Sono REM/efeitos dos fármacos , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Masculino , Microinjeções , Núcleo Tegmental Pedunculopontino/fisiologia , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Sono REM/fisiologia , Fatores de Tempo , Vigília/efeitos dos fármacosRESUMO
INTRODUCTION: There is currently a growing interest for conducting studies into the electrical and neurochemical activity of the pedunculopontine nucleus (PPN) due to the privileged position occupied by this structure in the flow of information to and from the cortex. This nucleus acts as a relay, not only for the motor information that is processed in the basal ganglia but also for information of an emotional type, whose main centre is the nucleus accumbens. It is also strongly linked with the aspects that determine the mechanisms governing addiction to certain drugs. DEVELOPMENT: We conduct a detailed analysis of the main findings from studies of the role played by the PPN in the physiopathology of Parkinsonism, namely the study of metabolic activity, immunohistochemical studies with different tracers, electrophysiological studies that have confirmed the immunohistochemical observations, as well as deep electrical stimulation carried out in non human primates. Furthermore, we also examine the part played by this structure in the processing of emotional information associated with different learning tasks. CONCLUSIONS: Overall, the authors grant the PPN a privileged position in the physiopathology of the axial disorders related to Parkinson s disease; its most important afference, stemming from the subthalamic nucleus, appears to play a key role in the understanding of the part played by the PPN in Parkinsonism.