Biomedical subjects

M E Olds

Publications and source records attributed to M E Olds.

At least 19 recordsLinked to original sources

PubMed2006

Relation between rotation in the 6-OHDA lesioned rat and dopamine loss in striatal and substantia nigra subregions.

The relation between the rotation response to drug-induced activation of the dopamine (DA) receptor in the rat unilaterally lesioned with 6-hydroxydopamine (6-OHDA) in the substantia nigra (SN) and the loss of DA in subregions of the SN and caudate-putamen (C/PUT) is not clear. Here this relation was examined in 23 rats classified as rotators to amphetamine (5 mg/kg). After their response was characterized in terms of ipsilateral rotation, contralateral rotation, and oral stereotypy in one place, they were divided into high, medium, low, and very low rotators. The loss of DA in each group was visualized on brain sections immunoreacted to tyrosine hydroxylase (TH). The density of the TH label on the side of the lesion was compared to that on the intact side. In the ventral midbrain, the density was determined in the SN subdivided into far lateral, lateral, central, and medial subregions and also in the ventral tegmental area (VTA). In the forebrain, it was determined in the C/PUT subdivided into lateral, central, and medial subregions and also in the nucleus accumbens (ACC). These measurements led to three principal findings. The first was a positive overall correlation between rotation and loss of TH label. The second was a correlation between rotation and penetration of the loss from the lateral subregions into more medial areas. The third was a larger loss in SN and VTA (midbrain) than in C/PUT and ACC (forebrain). These findings show that rotation depended not only on the overall loss of DA but also on its distribution across subregions. The loss in the lateral subregion, always the largest regardless of the rate of rotation, may have been the first step in inducing the motor abnormality, and the loss in the central and medial subregions may have served to enhance the abnormality due to the loss in the lateral subregion.

Amphetamine↗

PubMed2005

Behavioral and anatomical effects of quinolinic acid in the striatum of the hemiparkinsonian rat.

Parkinson's disease (PD), a hypokinetic disorder, and Huntington's disease (HD), a hyperkinetic disorder, share the fact that in the motor pathways the dysfunction starts in the striatum. In PD the projection neurons are overactive due to decreased inhibitory regulation by lost dopamine afferents, while in HD the output from the striatum is insufficient due to loss of projection neurons. This study aimed to determine whether the introduction of a mild HD condition in the PD striatum can counter the hypokinetic condition. The experiment was carried out in the 6-OHDA rat model for PD in which amphetamine, 5 mg/kg, evokes an asymmetric rotation response toward the side of the 6-OHDA lesion (ipsilateral rotation). The response to amphetamine in this study was fractionated into multiple components and measured automatically. After baseline measurements, the subjects were divided into four groups. Group I was unilaterally sham-lesioned in medial, central, and lateral striatum. Group II was injected quinolinic acid (QA) 20 nM in medial, central, and lateral striatum. Group III was injected QA 60 nM in central striatum. Group IV was injected QA 120 nM in central striatum. The effects of QA were measured weekly. The sham lesions in Group I had no effects. In Group II, ipsilateral rotation was reduced and replaced by oral stereotypy, a competitive behavior. In Group III, ipsilateral rotation decreased, but to a lesser degree than in Group II. In Group IV, QA had no effects. Histological findings show a unilateral loss of tyrosine immunoreactive (TH) neurons in substantia nigra and of fibers in striatum in all subjects. In addition, in Group II the striatum was atrophied. These findings suggest that the shift in Group II from ipsilateral rotation to oral stereotypy after QA was due to reduced striatal output caused by a loss of projection neurons, a loss insufficient to induce HD symptoms, but sufficient to counter the PD condition.

Adrenergic Agents↗

PubMed2003

Behavioral and subthalamic effects of combining a fetal ventral mesencephalic transplant in striatum with an electrolytic lesion of the entopeduncular nucleus in the rat with a unilateral 6-OHDA lesion of substantia nigra.

Behavioral and electrophysiological methods were used to determine whether a transplant of dopamine-rich fetal tissue in striatum combined with an electrolytic lesion of the entopeduncular nucleus have additive effects in the unilaterally lesioned rat model for Parkinson's disease. The subjects were rats with the left substantia nigra lesioned with 6-hydroxydopamine (6-OHDA) and responding to systemic amphetamine with rotation toward the side of the lesion (ipsilateral rotation). The motor response to amphetamine was fractionated into six aspects, half reflecting the unilateral deafferentation in striatum and half representing those aspects of the response evoked in normal rats. After collection of baseline values, 25 rotators received a transplant of fetal ventral mesencephalic tissue in the left striatum and 20 received a transplant and, at the same time, an electrolytic lesion of the left entopeduncular nucleus. Testing for the motor response to amphetamine resumed after 4 weeks of recovery and continued at weekly intervals for 5 weeks. Upon completion of these tests, each rotator was implanted with multiple electrodes in the subthalamic nucleus. After recovery, multiunit responses to amphetamine and apomorphine were recorded from several electrodes in parallel during the motor response to the drugs. In rotators with transplant only, treatment with amphetamine evoked oral stereotypy and an attenuated ipsilateral rotation response. In rotators with combined transplant and entopeduncular lesion, ipsilateral rotation did not change or increased. Subthalamic responses to amphetamine and apomorphine were larger in rotators with combined transplant and entopeduncular lesion than in rotators with transplant alone. These findings indicate that the combination of transplant and pallidotomy in the 6-OHDA rat model for parkinsonism does not lead to additive benefits, an effect that may have been due to the nonselectivity of the electrolytic damage and/or of the lesion extending beyond the entopeduncular nucleus into the lateral hypothalamus.

Amphetamine↗

PubMed2003

Behavioral/neurophysiological investigation of effects of combining a quinolinic acid entopeduncular lesion with a fetal mesencephalic tissue transplant in striatum of the 6-OHDA hemilesioned rat.

Behavioral and electrophysiological methods were used to investigate the effects of combining a unilateral quinolinic acid lesion of the entopeduncular nucleus (QA/EP) with a striatal transplant of fetal ventral mesencephalic tissue in the 6-hydroxydopamine (6-OHDA) hemilesioned rat model for Parkinson's disease. The subjects were 6-OHDA-lesioned rats selected because their response to amphetamine treatment was a strongly biased rotation toward the side of the 6-OHDA lesion in the substantia nigra, at the expense of other evoked behaviors associated with amphetamine. Two experiments were performed. In the first, the motor effects of the QA/EP lesion alone and of the combination of QA/EP lesion with striatal transplant were determined by measuring six aspects of the motor response. In the second the electrophysiological effects of the two interventions on the responses of neurons in the subthalamic nucleus to amphetamine and apomorphine were determined in the 6-OHDA-lesioned rats. The results of the first experiment show that the QA/EP lesion by itself produced an attenuation of the rotation response and, simultaneously, an increase of oral stereotypy. They also show that the combination of QA/EP lesion with striatal transplant was more effective than the single intervention, inducing more attenuation of rotation and more oral stereotypy. The results of the second experiment show that the responses of subthalamic neurons to amphetamine in the behaving hemiparkinsonian rat with combined QA/EP lesion and transplant were larger than the responses in the hemiparkinsonian rat with the QA/EP lesion alone. However, even these larger responses in the rats with combined intervention were not as large as those recorded at the same time in the subthalamus in the opposite, intact, hemisphere. The results of the two experiments, both of which show enhanced motor and neuronal sensitivity to amphetamine after the combined intervention, suggest that such a multiple approach might prove more beneficial than a one-site intervention targeting either the EP or the striatum.

Amphetamine↗

PubMed2001

Entopeduncular lesions facilitate and thalamic lesions depress spontaneous and drug-evoked motor behavior in the hemiparkinsonian rat.

Pallidotomy is a neurosurgical procedure designed to ameliorate the akinesia and bradykinesia associated with Parkinson's disease. In the present study, the effects of pallidal-like lesions on motor behavior in the hemiparkinsonian rat were compared to the effects of lesions in the ventrolateral thalamus, a target of entopeduncular projections feeding motor-related information to motor cortex. Six aspects of spontaneous and evoked behavior induced by amphetamine and apomorphine in the hemiparkinsonian rat with either bilateral electrolytic entopeduncular lesions or bilateral electrolytic ventrolateral thalamic lesions were measured for 60 min. Saline or amphetamine, 5 mg/kg, or apomorphine, 0.3 mg/kg, were administered IP 5 min before the tests. The results show that on all measures except time spent resting the hemiparkinsonian rats with the entopeduncular lesions were more active than the hemiparkinsonian rats with the thalamic lesions. The asymmetrical rotation responses to dopamine receptor stimulation evoked by amphetamine and apomorphine were influenced by the general effect on gross motor behavior, as shown by the response being very large in the entopeduncular group and very small in the thalamic group. These results are consistent with current thinking about the functional organization of the basal ganglia according to which damage of the entopeduncular nucleus reduces its inhibitory control of the thalamic motor regions, thereby promoting thalamic facilitation of motor cortex, and damage to the thalamic motor regions has the opposite effect. These effects of the lesions translate, respectively, into hyperactivity and hypoactivity without blocking the asymmetrical rotation response of the hemiparkinsonian rat.

Amphetamine↗

PubMed1999

Subthalamic responses to amphetamine and apomorphine in the behaving rat with a unilateral 6-OHDA lesion in the substantia nigra.

The activity of neurons in the subthalamic nucleus (STN) of the behaving rat, before and after a unilateral 6-OHDA lesion of the substantia nigra, was recorded with the extracellular technique to determine whether it was altered following systemic amphetamine, 5 mg/kg, apomorphine, 3 mg/kg, and apomorphine, 0.3 mg/kg, and whether in cases of altered activity, it was related to the drug-induced motor response expressed concurrently. Activity in the STN of intact rats increased dramatically after amphetamine, 5 mg/kg. This excitatory response had the same latency, similar magnitude, and the same duration as the motor response expressed in terms of locomotion and oral stereotypy. Motor and unit responses were also induced by amphetamine after the lesion with 6-hydroxydopamine (6-OHDA), but now the excitatory response was attenuated while the motor response was not. The effects of the 6-OHDA lesion were the same in all animals with loss of the nigra dopamine neurons, regardless of whether they were rotators or non-rotators. Activity in the STN of intact rats also increased after apomorphine, 3 mg/kg, and again, this increase was correlated with the increase in motor behavior, but both responses were of shorter duration than the responses to amphetamine. The increases in unit activity and motor behavior induced by apomorphine in the 6-OHDA-lesioned rats had the same magnitude but lasted longer than in the intact rats. Treatment with apomorphine, 0.3 mg/kg, of the intact rats produced small and very brief increases in the activity of the STN and in motor behavior. The same treatment given the 6-OHDA-lesioned rats produced responses of larger magnitude but no change in duration. These findings demonstrate a role for STN neurons in the mediation of the motor behaviors induced by stimulation of the dopamine receptor. The results also show that a unilateral lesion of the substantia nigra with 6-OHDA did not block these responses but altered them in a manner consistent with a dopaminergic deafferentation of the basal ganglia. The increased activity in the STN during the expression of dopamine-dependent motor behavior conflicts with the current model of basal ganglia function that assumes prejudicial effects of excessive STN activity on the expression of motor behavior. An explanation for this conflict suggests that it is more apparent than real.

Action Potentials↗

PubMed1998

Globus pallidus lesions depress the excitatory responses to apomorphine but not amphetamine in the subthalamic nucleus of the behaving rat with a 6-OHDA nigra lesion.

The role of the dopaminergic innervation of the basal ganglia on the activity in the subthalamic nucleus (STN) evoked by amphetamine and apomorphine in the behaving rat was examined. The aim was to determine the relationship between that neural activity and the movements evoked by the drugs. Bilateral electrolytic lesions of the globus pallidus (GP), superimposed on the earlier unilateral lesion in substantia nigra (SN) with 6-hydroxydopamine (6-OHDA) affected differently the excitatory responses in the STN evoked by amphetamine and apomorphine and the motor responses to the drugs recorded concurrently. Before the GP lesions, the administration of amphetamine, 5 mg/kg, to the unilaterally deafferented rat induced increased activity in the STN and simultaneously increased movement in the animal. After the GP lesions, the excitatory response to amphetamine in the STN was not different from that seen before the GP lesions. The motor response was also unchanged. In contrast, the GP lesions altered the excitatory response to apomorphine, 3 mg/kg. Before these lesions, the administration of apomorphine to the 6-OHDA lesioned animal evoked a robust and long-lasting excitatory response in the STN and, concurrently, a long-lasting motor response. After the GP lesions, both responses to apomorphine were attenuated. These differential effects of the GP lesions on the unit and motor responses to the two drugs are viewed as representing the effects of the damage in the GP on the dopaminergic innervation contributing to the regulation of activity in the STN. In the 6-OHDA animal, the dopamine afferents innervating the basal ganglia had already been dramatically reduced by 6-OHDA. The GP lesions did not significantly add to the number of these afferents previously eliminated; therefore, the excitatory and motor responses to amphetamine were not changed by the GP lesions. But the GP damage served to eliminate the dopamine receptor in the GP and thus reduced the density of the dopamine receptor in the basal ganglia available for binding to apomorphine. Therefore, the excitatory and motor responses to apomorphine were attenuated after the GP lesions compared to the responses before these lesions.

Amphetamine↗

PubMed1996

Dopaminergic basis for the facilitation of brain stimulation reward by the NMDA receptor antagonist, MK-801.

MK-801 (dizocilpine maleate), an antagonist of the NMDA receptor, was given alone or in combination with dopamine D1 and D2 receptor antagonists to rats self-stimulating in lateral hypothalamus to determine whether the dopamine neurons play a role in mediating the effects of MK-801. MK-801 given at a dose of 0.1 mg/kg i.p. to self-stimulators induced a prolonged facilitation of lever-pressing, but given to non-self-stimulators, the drug had no effects. Pretreatment of self-stimulators with the dopamine D1 receptor antagonist Schering 23390 (SCH 23390), 0.2 mg/kg given i.p. 15 min before MK-801, prevented the facilitation seen with MK-801, but did not suppress self-stimulation. SCH 23390 given alone suppressed self-stimulation. Pretreatment of self-stimulators with the dopamine D1/D2 receptor antagonist, haloperidol, 0.2 mg/kg given i.p. 15 min before MK-801, also prevented the facilitation of self-stimulation induced by MK-801 yet did not suppress self-stimulation. Haloperidol given alone suppressed self-stimulation. Pretreatment of self-stimulators with both SCH 23390 and haloperidol 15 min before MK-801 prevented the facilitation seen with MK-801 and suppressed self-stimulation. The combined treatment with SCH 23390 and haloperidol (without MK-801) suppressed self-stimulation, and the suppression lasted longer than the suppression seen when the two dopamine receptor antagonists were given as pretreatment, before MK-801. Pretreating self-stimulators with the combination of SCH 23390 and haloperidol 15 min before amphetamine (2 mg/kg) prevented the facilitatory response and suppressed responding for the brain reward. The suppression was of shorter duration than the suppression seen after the injection of SCH 23390 plus haloperidol. The treatment of self-stimulators with both MK-801 and amphetamine resulted in a greater and longer-lasting facilitation than the increase in responding produced by either drug alone. The similarity between the effects of MK-801 and those of amphetamine and between the effects of pretreatment with the dopamine receptor antagonists before MK-801 and before amphetamine suggests that dopaminergic activity played a significant role in the action underlying the effects of MK-801 on brain stimulation reward.

Amphetamine↗

PubMed1995

Dopamine agonists prevent or counteract the suppression of brain stimulation reward by fenfluramine.

The interaction between the serotonin (5-HT) and the dopamine (DA) systems in the modulation of intracranial self-stimulation (ICSS), a DA-dependent behavior, was investigated. Chronically implanted rats for ICSS in the medial forebrain bundle were tested for the effects of fenfluramine at a dose of 20 mg/kg, and then for the effects of 10 mg/kg piribedil plus 2 mg/kg amphetamine, injected 30 min before fenfluramine or 60 min after fenfluramine. Our aim was to determine whether the action of fenfluramine at the DA binding site could be blocked by prior occupation, or whether if it were occupied by fenfluramine it could be reversed. Fenfluramine, 20 mg/kg, injected alone, suppressed ICSS for 5-7 h. The suppression was followed by a prolonged recovery during which ICSS was profounded depressed. Repeating the treatment 7 days later produced the same response, except that the suppression was of shorter duration. In another group of animals, pretreatment with piribedil plus amphetamine 30 min before fenfluramine prevented the suppression of ICSS. Instead, ICSS was briefly attenuated, then restored to baseline levels, and then facilitated. Repeating the treatment 7 days after the first treatment potentiated this response. The attenuation was now even briefer, the recovery more rapid, and the facilitation more robust. In still another group of animals, fenfluramine was given just before the ICSS session began. Predictably, the effect was a total cessation of ICSS. At 60 min into the session, piribedil plus amphetamine was injected. The response showed a rapid recovery of ICSS followed by facilitation.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗

PubMed1994

Opposite effects of PCA and chlorimipramine on ICSS and on its facilitation by amphetamine.

The long-term effects of chloramphetamine (PCA) and chlorimipramine (CHLOR) on intracranial self-stimulation (ICSS) were investigated in sessions lasting 13 h. PCA, 5 mg/kg given IP, led first to an attenuation of ICSS lasting 3 h, then to a slow recovery to baseline rates, and then to a facilitation of ICSS lasting 6 h. Repeating the treatment 7 days later resulted in less attenuation of ICSS, more rapid recovery, and longer-lasting facilitation. Again, repeating the treatment with PCA 7 days later but injecting simultaneously amphetamine (AMPH) 2 mg/kg IP, altered the response seen with PCA alone. The attenuation phase was missing but the facilitatory phase remained except that it occurred early and was of shorter duration than after PCA given alone. Pretreatment with haloperidol (HALO) 0.5 or 1.0 mg/kg IP before PCA blocked the facilitatory phase of the response. CHLOR injected at a dose of 15 mg/kg IP attenuated ICSS. The combined administration of CHLOR and AMPH led to the CHLOR-attenuation of ICSS being replaced by a modest facilitation. These results are discussed in terms of the biochemical actions of PCA and CHLOR on the serotonin and dopamine systems.

Animals↗

PubMed1992

Effects of acute and chronic fenfluramine on self-stimulation and its facilitation by amphetamine.

DL-Fenfluramine (20 mg/kg) releasing serotonin and amphetamine (2 mg/kg) releasing dopamine were given to adult rats trained to bar press for electrical stimulation to the medial forebrain bundle. Amphetamine treatment enhanced lever-pressing for 1-2 h. A single fenfluramine treatment rapidly suppressed self-stimulation with slow recovery in 5-7 days to a rate below the initial basal rate. A second treatment a week later again suppressed response rate and rates returned to a still lower baseline. Combined fenfluramine-amphetamine treatment at this time transiently abolished lever pressing for 1-3 h followed by 9-11 h of enhanced responding. The serotonin antagonist, ketanserine (0.1 mg/kg), but not cyproheptadine (0.1 mg/kg i.p.), partially protected against the effects of fenfluramine. The serotonin agonist, quipazine (0.5 mg/kg), but not dimethoxyiodophenylisopropylamine (DOI) (2.2 mg/kg), partially substituted for fenfluramine in the combined treatment. Fenfluramine markedly depleted serotonin and 5-hydroxyindoleacetic acid in frontal cortex, hippocampus, and caudate putamen. Ventral and midline midbrain regions were less affected. Combined fenfluramine and amphetamine treatment elevated dopamine levels in frontal cortex, hippocampus and caudate-putamen, but not in midbrain. These findings support a serotonin-dopamine interaction in self-stimulation behavior and suggest that repeated fenfluramine treatment results in chronic low level serotonergic stimulation and diminished serotonin storage capacity.

Amphetamine↗

PubMed1992

Enhanced dopamine metabolism in accumbens leads to motor activity and concurrently to increased output from nondopamine neurons in ventral tegmental area and substantia nigra.

We previously have reported that nondopamine (non-DA) neurons in substantia nigra (SN) and ventral tegmental area (VTA) of the rat show increased discharge rates during amphetamine (AMPH) and apomorphine (APO)-induced motor activity. The present study represents an attempt to determine the contribution of nucleus accumbens (ACC) dopaminergic activity to these effects, and to ascertain whether the effects in VTA differ from those seen in SN when dopaminergic activity is enhanced locally in ACC. The experiments were carried out in male albino rats (300-400 g) chronically implanted with multiple fine wire electrodes (62 microns) aimed at the pars reticulata of SN (SNR) and VTA. Unit activity was recorded extracellularly in the behaving rat, from neurons identified on the basis of the properties of their action potentials as representing the output of the non-DA neurons in these two structures. In each drug session, unit activity was recorded in parallel from several probes, while motor activity was measured with the open-ended wire technique. But with the recording technique used, a unit represented in most instances the output of a small family of neurons (3-10). Each animal underwent a series of tests given on consecutive days. During these tests, motor and unit activity were measured for 90 min before the drug was administered, and for 135 min after. The first test was of the effects of AMPH, 5 mg/kg, given by the systemic route. The second was of the effects of saline containing 0.1% ascorbic acid (the vehicle) injected bilaterally in ACC, in a volume of 2 microliters per side. The third and all subsequent tests were of the effects of a mixture containing 40 micrograms AMPH, 20 micrograms DA, and 20 micrograms pargyline (P) dissolved in 2 microliters of the vehicle, injected bilaterally in ACC. The results showed that systemic AMPH made the animal hyperactive and at the same time, increased the discharge rate of the non-DA neurons. The bilateral injections of the vehicle in ACC, increased motor activity for about 7 min, an effect interpreted as a rebound from the restraint of the animal during the intracerebral injections, and then depressed motor throughout the 135 min of the postinjection recording period. The effect of the vehicle was to depress unit activity. The effects of injecting the mixture in ACC was to increase motor activity, but with the magnitude and duration of the increase depending on the number of treatments received.(ABSTRACT TRUNCATED AT 400 WORDS)

Amphetamine↗

PubMed1990

Enhanced dopamine receptor activation in accumbens and frontal cortex has opposite effects on medial forebrain bundle self-stimulation.

This study was undertaken to investigate the effects of activating dopamine receptors in accumbens and prefrontal cortex on self-stimulation behavior in the medial forebrain bundle. The experiments were carried out in rats chronically implanted with one stimulating electrode in medial forebrain bundle and two bilaterally-placed cannulas for giving injections into accumbens or prefrontal cortex. After completion of training, animals classified as responders and non-responders were given drug tests. The non-responders were tested to determine the effects of the treatment on motor activity. The self-stimulation task involved the depression of a lever to obtain a stimulus of 0.25 s duration, 60 Hz sine waves applied to the medial forebrain bundle. Dopamine receptor activation in accumbens or prefrontal cortex was induced with bilateral injections in these structures of a mixture containing 5 mg dopamine, 10 mg d-amphetamine sulfate and 5 mg pargyline mixed in 0.5 ml saline containing 0.1% ascorbic acid (dopamine + d-amphetamine sulfate + pargyline, the cocktail). Each injection was of 2 microliters/side, yielding a concentration of 20 micrograms of dopamine, 40 micrograms of d-amphetamine sulfate and 20 micrograms of pargyline/injection. The bilateral injections were given immediately before the self-stimulation session which lasted 12 h, starting in late afternoon. The effects of saline containing the ascorbate were determined in control sessions. Saline injected bilaterally in accumbens or prefrontal cortex of self-stimulators or non-self-stimulators had no effects on the response-rate of self-stimulators or on the gross motor activity of non-responders. In contrast, the cocktail of dopamine + d-amphetamine sulfate + pargyline injected in accumbens of self-stimulators induced a complex response which included first a facilitation, then a prolonged suppression and then again one or two episodes of facilitation interspersed with periods of suppression of self-stimulation and then a return to baseline rats. The same cocktail of dopamine + d-amphetamine sulfate + pargyline injected bilaterally in accumbens of non-self-stimulators resulted also in a complex response including as a first component a facilitation of responding, but the complex effect was of shorter duration and lower magnitude, never raising the rate of lever-pressing to levels meeting self-stimulation criteria. The same cocktail of dopamine + d-amphetamine sulfate + pargyline injected in prefrontal cortex of self-stimulators simply attenuated or suppressed responding, and the effect lasted for most of the session. The same effect was seen in non-self-stimulators indicating a decrease in gross motor activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1988

The response of non-dopamine neurons in substantia nigra and ventral tegmental area to amphetamine and apomorphine during hypermotility: the striatal influence.

The effects of haloperidol pretreatment in striatum on the motor response, and on concurrently recorded unit responses of nondopamine (DA) neurons in substantia nigra (SN) and ventral tegmental area (VTA) to systemic amphetamine and apomorphine, were investigated with the objective of determining the role of the striatum in the output of putative DA output neurons. Unit and motor activity were recorded in the male rat, chronically implanted with 9 electrodes in SN and VTA and with two cannulae for bilateral injections into striatum. The recording electrodes were 3 bundles of 3 wires, each wire in the bundle of a different length, but all 3 aimed at SN, pars reticulata, or VTA. In each recording session, unit activity was derived from 7 wires while gross motor activity was recorded with the open-ended wire technique. The subjects were tested under two conditions. In the first, the vehicle was injected bilaterally into striatum 90 min before one of the DA agonists was injected by the intraperitoneal route. In the second, the DA antagonist haloperidol was injected bilaterally into striatum before the systemic treatment with the DA agonist. In subjects which received injections of the vehicle into striatum, amphetamine induced a large motor response, and concurrently, a large increase in the rate of discharge of a portion of the identified non-DA neurons in SN and VTA. In subjects which received injections of haloperidol into striatum, amphetamine induced a smaller behavioral response, a smaller increase in the rate of discharge of these neurons in SN but not in VTA where the increase was of the same magnitude as controls. In control subjects, apomorphine induced an increase in motor activity and concurrently, an increase in the rate of firing of the identified non-DA neurons in SN and VTA. But the increases were of somewhate smaller magnitude and much shorter duration than the increases induced by amphetamine. In subjects which had been pretreated with haloperidol in striatum, apomorphine induced an increase in motor activity that was of the same magnitude as the insion that the striatum has the capacity to influence the output of non-DA neurons only in SN but also in VTA, indicating that, if there is a specialization of function, it is only relative.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1988

Correlation between the discharge rate of non-dopamine neurons in substantia nigra and ventral tegmental area and the motor activity induced by apomorphine.

The effects of systemic apomorphine on the discharge rates of non-dopamine neurons of the ventral tegmental area and the substantia nigra were investigated in the behaving rat to determine the relationship between the neural responses and the motor activity induced by the dopamine agonist. Apomorphine, 3.0 mg/kg, induced large increases in motor activity and in the rate of firing of non-dopamine neurons in both ventral tegmental area and substantia nigra. The effects were similar in both structures, but only a portion of the non-dopamine neurons sampled were sensitive to the dopamine agonist. The motor and unit responses were correlated for latencies, magnitude and duration. These effects were dose-responsive, 0.75 mg/kg and 1.5 mg/kg inducing smaller behavioral and neural responses than 3.0 mg/kg. Apomorphine, 3.0 mg/kg, given to rats pretreated with haloperidol, 1.5 mg/kg, 60 min before the recording session, induced smaller behavioral and neural responses than in controls. The dopamine agonist given to rats in which gross motor activity was prevented through light anesthesia with urethan, 600 mg/kg, led to a decrease in the magnitude of the unit response in ventral tegmental area, and to a potentiation of the response in substantia nigra. In rats with bilateral electrolytic lesions of nucleus accumbens given one week earlier, apomorphine induced a smaller behavioral response than in controls, and differential effects on the neural responses. In ventral tegmental area the response was the same as in controls, but in substantia nigra it was blocked. These results indicate the presence in substantia nigra and ventral tegmental area of subpopulations of non-dopamine neurons responding with excitation to experimental manipulations that activate dopamine receptors. The dissociation between the motor effects of apomorphine and the neural effects in the subjects prevented from expressing gross motor activity, and in the lesioned animals, indicates that the neural responses were not the result of behavioral feedback. And the differential effects of apomorphine in ventral tegmental area and substantia nigra in these two groups of subjects suggest that the dopamine motor influence, at this brain level, may be fractionated, different groups of non-dopamine neurons conveying different aspects of the dopamine influence on motor activity to premotor neurons. The results, taken together, support the notion that non-dopamine efferent neurons in ventral tegmental area and substantia nigra function as dopamine output neurons, their output being critical for the behavioral effects of dopamine agonists.

Action Potentials↗

PubMed1988

Amphetamine-induced increase in motor activity is correlated with higher firing rates of non-dopamine neurons in substantia nigra and ventral tegmental area.

The responses of non-dopamine neurons in substantia nigra and ventral tegmental area to systemic amphetamine were investigated in the behaving rat chronically implanted with multiple fine-wire electrodes. The neurons were identified with electrophysiological criteria requiring that the signals be of biphasic shape, short duration (less than 2.0 ms), and show high and regular rates of discharge (greater than 20 spikes/s). In recording sessions lasting 240 min, single and multiple unit activity was recorded from seven electrodes, and motor activity was measured automatically with the open-ended wire technique. The movement counts provided an index of gross motor activity, not of the specific movements occurring during DA behaviors. D-Amphetamine, 5.0 mg/kg, given by the intraperitoneal route at 90 min into the session, induced an increase in motor activity and in the firing rate of some non-dopamine neurons. The behavioral and neural responses were correlated for magnitude, latencies and duration. But not all non-dopamine neurons in ventral tegmental area, and substantia nigra showed responses to amphetamine. When unit responses were obtained, they were obtained in subjects which showed large motor responses. In substantia nigra, responsive and non-responsive units were interdigitated and found mainly in the pars reticulata subdivision. In the ventral tegmental area, responsive and non-responsive neurons were interdigitated throughout this structure. The effects of amphetamine were dose-responsive, doses of 1.0, 2.0 and 3.0 mg/kg inducing smaller behavioral and unit responses than 5.0 mg/kg. D-Amphetamine, 5.0 mg/kg, was more effective than L-amphetamine, given at the same dose, in inducing these changes. In rats pretreated with systemic haloperidol, 1.5 mg/kg, the behavioral and neural responses to D-amphetamine, 5.0 mg/kg, were greatly attenuated. In rats pretreated with a subanesthetic dose of urethan, 600 mg/kg, to prevent changes in gross motor activity, the response to D-amphetamine in ventral tegmental area was attenuated, but it was of normal magnitude in substantia nigra. In rats with bilateral electrolytic lesions of nucleus accumbens, D-amphetamine induced a smaller motor response than in controls, but the neural responses in ventral tegmental area and substantia nigra were the same as in controls. These findings support the notion that non-dopamine neurons in ventral tegmental area and substantia nigra, pars reticulata, play a role in the motor function of the A9 and A10 dopamine neurons, and in the behavioral effects of amphetamine.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1986

Roles of catecholamine terminals and intrinsic neurons of the ventral tegmentum in self-stimulation investigated in neonatally dopamine-depleted rats.

Three series of experiments were undertaken to determine whether the residual catecholamine (CA) terminals or intrinsic neurons of ventral tegmentum (VT) in rats given 6-hydroxydopamine (6-OHDA) after desmethylimipramine (DMI) in the lateral ventricles at birth, mediated VT self-stimulation (SS). In Experiment I, male pups were injected bilaterally on days 3 and 5 with 6-OHDA (total dose 200 micrograms) or with the vehicle after pretreatment with DMI (50 mg/kg, IP) 30 min earlier. Each subject, 150 days old, was implanted bilaterally in the VT with electrode-cannula units. Both the dopamine (DA)-depleted and control groups yielded similar percentages of self-stimulators. The rate of responding was, however, slightly but significantly lower in the DA-depleted group than in the controls. In Experiment II, 8 DA-depleted and 7 control rats were pretreated with pargyline (50 mg/kg, IP) and then given unilateral injections of 6-OHDA in the VT, in the tissue below the SS electrode. These intracerebral injections of 6-OHDA had no effect on VT SS in both groups. Seventeen controls and 12 DA-depleted rats, in Experiment III, were given injections of kainic acid (KA; 5 nM) either ipsilaterally or contralaterally. The ipsilateral injection abolished SS (14 days of testing), whereas the contralateral injection had no effects on ipsilateral SS in both groups. Histochemical fluorescence study in Experiment I and II showed that the neonatal treatment with DMI + 6-OHDA had reduced the number of DA-containing perikarya in the VT and that reinjection of 6-OHDA into the VT caused the disappearance of the residual CA terminals in tissue surrounding the electrode tip.

Animals↗

PubMed1985

Comparison of hyperactivity in adult rats induced by neonatal intraventricular 6-hydroxydopamine following pargyline or desmethylimipramine treatment.

The relative roles of norepinephrine (NE) and dopamine (DA) in sustaining neonatal hyperactivity were assessed in rats given 6-hydroxydopamine (6-OHDA) neonatally into the lateral ventricles after pargyline (P) or desmethylimipramine (DMI) pretreatment. On day 5 after birth, male and female rat pups were pretreated with P (50 mg/kg IP) or DMI (25 mg/kg IP) 30 min before receiving bilateral injections of 6-OHDA (200 micrograms/5 microliters saline containing ascorbic acid 1.0 mg/ml) into the lateral ventricles. Controls were pretreated with P or DMI and then received injections of saline containing the ascorbate. Spontaneous activity was measured in a stabilimeter at ages 30-31, 42-45, 60-63, 75-77, and 120-122 days. Activity in controls and P + 6-OHDA animals was also measured at 254 days of age. The sessions lasted 45 min, except those testing activity in the 254-day-old rats which lasted 12 h. Regional assays of catecholamines carried out when the animals were 150 days old revealed that in the P + 6-OHDA group the levels of NE were reduced in frontal cortex (7% of control levels), caudate (21%), and hippocampus (14%). The NE levels were unchanged or slightly elevated in hypothalamus, ventral midbrain, and pons. The DA levels in the P + 6-OHDA group were depleted in caudate (8%) and ventral midbrain (32%), and unchanged in hypothalamus and pons. In the DMI + 6-OHDA group the NE levels were reduced in caudate (25%) and elevated in hippocampus (188%). The DA levels were depleted in caudate (3%) and ventral midbrain (22%).(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗