Jorge H. Pazo

Substantia nigra pars reticulata single unit activity in normal and 60HDA-lesioned rats: Effects of intrastriatal apomorphine and subthalamic lesions

The spontaneous activity and the response to intrastriatal application of apomorphine of substantia nigra pars reticulata (SNpr) single units was studied in four experimental groups of rats: (1) normal rats; (2) subthalamic nucleus (STN) lesioned rats; (3) rats bearing a 6‐hydroxydopamine (6OHDA) lesion; and (4) 6OHDA‐lesioned animals with an additional STN lesion. Thirty‐eight percent of units from 6OHDA‐lesioned rats showed a bursting pattern of spontaneous activity, which was never found in normal rats. STN lesions had no effect on the spontaneous activity of SNpr units from normal rats, but reduced the percentage of burst units in 6OHDA‐lesioned animals. Intrastriatal apomorphine produced responses in 62% of SNpr units from normal rats and 85% of units from 6OHDA‐lesioned animals (P < 0.05). In addition, the modifications in the firing rate and in the coefficient of variation of the interspike intervals induced by intrastriatal apomorphine were significantly greater for the units isolated from 6OHDA‐lesioned rats. In particular, it was noted that all the burst units responded to apomorphine, showing the highest changes in firing rate and coefficient of variation. However, intrastriatal apomorphine did not always turn the activity of burst units into a more physiological pattern. STN lesions reduced the percentage of units responding to intrastriatal apomorphine in normal rats. In 6OHDA‐lesioned rats, STN lesions reduced the number of responsive units, and their change in mean firing rate and coefficient of variation. Our results show that the STN participates in the genesis of the bursting pattern of activity of SNpr units in 6OHDA‐lesioned rats, and that STN lesions can partially revert the abnormal spontaneous and apomorphine‐induced responses of SNpr units in these animals. Synapse 27:278–293, 1997.

Quantitative Study of Salivary Secretion in Parkinson's Disease

We examined basal and reflex salivary flow rate and composition in 46 patients with Parkinsons disease (PD), both in off and on conditions, compared to 13 age‐matched controls without underlying disease or treatment affecting autonomic function. Whole saliva was collected 12 hours after withdrawal of dopaminergic drugs and at the peak of levodopa‐induced motor improvement. Twenty‐three of the 46 PD patients had received domperidone a week before the study. Basal salivary flow rate was significantly lower in PD patients in the off state compared to controls (P < 0.005). Levodopa increased salivary flow rate (P < 0.05) both in the domperidone‐pretreated and untreated groups. Citric acid stimulated salivary flow rate in both the off and on states in PD patients. This effect was higher in the domperidone‐pretreated patients. Salivary concentration of sodium, chloride, and amylase was higher in PD patients than in controls and was not affected by levodopa or domperidone treatment. Levodopa stimulates both basal and reflex salivary flow rate in PD. The mechanism appears to be central, as the effect is not blocked by domperidone. Domperidone may have a peripheral effect that potentiates reflex salivary secretion. Salivary composition is abnormal in PD and is not affected by levodopa treatment.

Effects of melatonin on spontaneous and evoked neuronal activity in the mesencephalic reticular formation

The acute effects of melatonin on the spontaneous activity of single cells in the mesencephalic reticular formation were studied in 40 male rats unanesthetized and immobilized with Flaxedil. One hundred and ten neurons were explored. Only 64 modified their spontaneous activity after the intravenous administration of melatonin. This response consisted of an increase in neural firing (6 neurons), decrease (55 neurons) and biphasic response of decrease and increase (3 neurons). When the effect of melatonin on the evoked activity in the mesencephalic neurons by peripheral stimulation (sciatic and photic) was checked an increase of the number of neurons that showed inhibitory responses to photic stimulation was found. No changes in blood pressure and EEG were observed at the doses of melatonin used (200, 400 and 600 micrograms/100 g of body weight). However, with doses of 600 micrograms a tendency toward synchronization was seen in the EEG. The present observations indicate an inhibitory effect of melatonin on the spontaneous neuronal activity of the mesencephalic reticular formation. This effect may contribute to the changes in the sleep-wakefulness cycle and anticonvulsant action attributed to this hormone.

Subthalamic nucleus lesions reduce low frequency oscillatory firing of substantia nigra pars reticulata neurons in a rat model of Parkinson's disease

Single unit recordings performed in animal models of Parkinsons disease revealed that output nuclei neurons display modifications in firing pattern and firing rate, which are supposed to give rise to the clinical manifestations of the illness. We examined the activity pattern of single units from the substantia nigra pars reticulata, the main output nuclei of the rodent basal ganglia, in urethane-anesthetized control and 6-hydroxydopamine-lesioned rats (a widespread model of Parkinsons disease). We further studied the effect of a subthalamic nucleus lesion in both experimental groups. Subthalamic nucleus lesion produces behavioral improvement in animal models of Parkinsons disease, and was expected to reverse the changes induced by 6-hydroxydopamine lesions. A meticulous statistical investigation, which included a non-biased classification of the recorded units by means of cluster analysis, allowed us to identify a low frequency oscillation of firing rate ( approximately 0.9 Hz) occurring in approximately 35% of the units recorded from 6-hydroxydopamine-lesioned rats, as the main feature differentiating 6-hydroxydopamine-lesioned and control rats. Subthalamic nucleus lesions significantly reduced the proportion of oscillatory units in 6-hydroxydopamine-lesioned rats. However, the population of nigral units recorded from rats bearing both lesions still differed significantly from control units. These results suggest that oscillatory activity in the basal ganglia output nuclei may be related to some clinical features of parkinsonism, and suggest a putative mechanism through which therapeutic interventions aimed at modifying subthalamic nucleus function produce clinical benefit in Parkinsons disease.

Substantia nigra pars reticulata units in 6-hydroxydopamine-lesioned rats: Responses to striatal D2 dopamine receptor stimulation and subthalamic lesions

In order to increase our understanding of Parkinsons disease pathophysiology, we studied the effects of intrastriatally administered selective dopamine receptor agonists on single units from the substantia nigra pars reticulata of 6‐hydroxydopamine (6‐OHDA)‐lesioned rats with or without an additional subthalamic nucleus lesion. Nigral pars reticulata units of 6‐OHDA‐lesioned rats were classified into two types, showing regular and bursting discharge patterns, respectively (‘non‐burst’ and ‘burst’ units). Non‐burst and burst units showed distinct responses to intrastriatal quinpirole (the former were excited and burst units inhibited). Furthermore, subthalamic nucleus lesions significantly decreased the number of nigral units showing a spontaneous bursting pattern, and reduced the proportion of units that responded to quinpirole. In contrast, subthalamic lesions did not alter the proportion of nigral units that responded to SKF38393, although the lesions changed some response features, e.g. response type and magnitude. Burst analysis showed that quinpirole did not modify the discharge pattern of burst units, whereas SKF38393 produced a shift to regular firing in 62% of the burst units tested. In conjunction, our results support that: (i) the subthalamic nucleus has an important influence on output nuclei firing pattern; (ii) striatal D2 receptors have a strong influence on nigral firing rate, and a less relevant role in controlling firing pattern; (iii) burst and non‐burst units differ in their response to selective stimulation of striatal dopamine receptors; (iv) the effects of striatal D2 receptors on nigral units are mainly, though not exclusively, mediated by the subthalamic nucleus; and (v) nigral responses to SKF38393 involve the subthalamic nucleus.

Basal ganglia and functions of the autonomic nervous system

Abstract1. The aim of this mini-review was to describe an underrecognized but important aspect of the basal ganglia diseases, the dysfunction of the autonomic nervous system that patients suffer owing to the degenerative process affecting these structures, mainly Parkinsons disease.2. We analyze the most prevalent autonomic abnormalities in these patients from an experimental and clinical point of view.

Hyposialorrhea as an early manifestation of Parkinson disease

We sought to determine whether hyposialorrhea is an early manifestation of Parkinson disease (PD). We measured basal and citric acid stimulated secretion of whole saliva in 20 patients with early stage (Hoehn-Yahr I-II) PD who had motor symptoms for less than 1 year and were on no medication and 11 age matched controls. Compared to controls, PD patients had significant reduction of both basal (0.0964+/-0.08 vs 0.293+/-0.112 ml/min, p<0.001) and reflex (0.263+/-0.213 vs 0.537+/-0.313 ml/min, p<0.001) salivary secretion. Our findings confirm that hyposialorrhea is an early autonomic manifestation of PD.

Striatal modulation of the jaw opening reflex

The effect of striatal electrical and chemical conditioning stimulation (L-glutamate 80-160 nmoles/0.5 microl) on the jaw opening reflex (JOR) was studied in Sprague-Dawley male rats anesthetized with urethane. The JOR was evoked by stimulation of the tooth pulp of lower incisors. This response was suppressed by transection of the dental root, which indicates according with the bibliography, a specific activation of the pulp nerves. Three type of responses were obtained on the evoked JOR by conditioning stimulation of the striatum; being the main one the suppression of the reflex elicited by tooth pulp activation. A second type of response was an increase of the tooth-JOR amplitude. This effect was observed more frequently with glutamate stimulation rather than with electrical activation of the striatum. A third response was observed with chemical stimulation but not by electrical stimulation of the striatum. This was a triphasic response which consisted in an increase followed by an inhibition and a late increase of the tooth-JOR amplitude. A biphasic effect, an increase prior to a decrease of the JOR amplitude, was also recorded with a minor frequency. The distribution of effective sites for electrical and chemical stimulation within the striatum are mainly similar located in the rostral aspect of the nucleus, with the inhibitory sites in the middle of the nucleus and intermingled with the excitatory ones. The complex responses (tri/biphasic) were observed ventrally and caudally in the nucleus. On the basis of the results mentioned above, one could assume that the striatum is related to the modulation of the JOR evoked probably by nociceptive stimulation. However, activation of other type of fibers could not be ruled out.

Turning behaviour induced by stimulation of the 5‐HT receptors in the subthalamic nucleus

The basal ganglia, which receive a rich serotonergic innervation, have been implicated in hyperkinetic and hypokinetic disorders. Moreover, a decrease in subthalamic nucleus (STN) activity has been associated with motor hyperactivity. To address the role of subthalamic serotonergic innervation in its motor function, turning behaviour was studied in rats with stimulation of the subthalamic serotonin (5‐HT) receptors by intracerebral microinjections. The intrasubthalamic administration of 5‐HT induced dose‐dependent contralateral turning behaviour, with a maximal effect at a dose of 2.5 µg in 0.2 µL. Similar results were observed with microinjections of other 5‐HT receptor agonists: quipazine (a 5‐HT2B/C/3 agonist), MK‐212 (a 5‐HT2B/C agonist) and m‐chlorophenylbiguanidine (a 5‐HT3 agonist), while microinjections of 5‐HT into the zona incerta or in the previously lesioned STN were ineffective. The effect of 5‐HT was blocked by coadministration of the antagonist mianserin. Stimulation of subthalamic 5‐HT receptors in animals bearing a lesion of the nigrostriatal pathway did not modify the motor response, which indicates that the dopamine innervation of the nucleus is not involved in this effect. Kainic acid lesion of the substantia nigra pars reticulata (SNr) suppressed the contralateral rotations elicited by stimulation of 5‐HT2B/C/3 subthalamic receptors. This suggests a role of the subthalamic–nigral pathway in the turning activity. Furthermore, the partial blockade of glutamatergic receptors in the SNr by the antagonist DNQX increased the contralateral circling elicited by stimulation of 5‐HT receptors in the STN. We concluded that the activation of the 5‐HT2B/C and 5‐HT3 subthalamic receptors elicited contralateral turning behaviour, probably via the subthalamic–nigral pathway.

Cholinergic mechanisms within the caudate nucleus mediate changes in blood pressure

Microinjections of 10 micrograms of carbachol into the caudate nucleus induced changes in the blood pressure of cats anesthetized locally, paralyzed and artificially respired. These responses were dependent on the site of injection. Carbachol, microinjected at rostral levels of the caudate nucleus, elicited pressor responses while a decrease in blood pressure was observed following injections at caudal levels. Both of these effects were blocked by prior microinjection of atropine. Microinjections of carbachol outside the caudate did not affect the resting blood pressure. However, injections of carbachol into the lateral ventricle always produced pressor responses independent of the site of injection along the antero-posterior extension of the ventricle. On the other hand, microinjections of dopamine (20 micrograms) into the caudate nucleus failed to modify blood pressure. From this study, it is concluded that within the caudate nucleus there are two different muscarinic mechanisms, which when activated, mediate changes in blood pressure, possibly through the sympathetic nervous system.