Effects of intraventricular 6-hydroxydopamine and replacement therapy with norepinephrine, dopamine, and serotonin on self-stimulation in diencephalic and mesencephalic regions in the rat.

Although 6-hydroxydopamine (6-OHDA) reduced the rate of hypothalamic self-stimulation, it is not known whether the same effect is produced at other reinforcing sites remote from the hypothalamus. This was investigated in rats implanted with rewarding probes in the hypothalamus, in the substantia nigra, in the midbrain, and in the pontine region. Two patterns of self-stimulation emerged in each subject. One, characterized by short, medium and long-stimulus-train durations, was seen in the hypothalamus, in the substantia nigra, and in selected sites in the pons. The other, which comprised only short stimulus-trains, was found in the medial midbrain and in the pontine region. 6-OHDA (250 mug intraventricular route) reduced the rate of responding in the regions where responding was for short, medium, and long stimulus trains. It has a minor effect on responding in regions where the brain rewards were exclusively of short duration. Thus, self-stimulation in the hypothalamus, in the substantia nigra and in the pons was suppressed after 6-OHDA, while self-stimulation in the medial midbrain and at sites in the pons, where selection was for short trains, was only slightly below control levels after 6-OHDA. L-Norepinephrine (L-NE) (10, 20 and 30 mug) injected into the lateral ventricle of the 6-OHDA-treated rats temporarily reinstated self-stimulation in the lateral hypothalamus but not in the substantia nigra and not in the pontine region where the pattern of selection had been for long brain rewards. Dopamine (DA) was not effective as an antagonist of the suppressant action of 6-OHDA. Serotonin (5-HT) reinstated self-stimulation behavior in the lateral hypothalamus but not in the other positive regions. Its action was less than that of NE and did not take place in all animals tested.     

Self-stimulation at the lateral hypothalamus and locus coeruleus after specific unilateral lesions of the dopamine system

A group of rats was trained to press levers for electrical stimulation from bipolar electrodes aimed at the lateral hypothalamus (LH), and another group was trained to self-stimulate from electrodes in the locus coeruleus (LC). All rats in both groups were subjected to unilateral injections of 6-hydroxydopamine into the substantia nigra and midbrain ventral tegmentum. The lesions produced profound depletions of dopamine from the ipsilateral frontal cortex, nucleus accumbens/olfactory tubercle, and corpus striatum. Pretreatment with desmethylimipramine prevented loss of noradrenaline in excess of that caused by electrode implantation. The destruction of the dopamine projections produced a persistent and pronounced deficit in intracranial self-stimulation from ipsilateral electrodes in both the LH and LC groups, but only transient effects on self-stimulation from contralateral electrodes at these sites. These results suggest that an intact dopamine system is required for the expression of self-stimulation behaviour.     

Region-specific reductions of intracranial self-stimulation after uncontrollable stress: Possible effects on reward processes

Rates of responding for intracranial self-stimulation from the medial forebrain bundle, nucleus accumbens and substantia nigra were evaluated in mice that had been exposed to either escapable shock, yoked inescapable shock or no shock treatment. Whereas performance was unaffected by escapable shock, marked reductions of responding from the medial forebrain bundle and nucleus accumbens were evident following the uncontrollable shock treatment. Responding from the substantia nigra was unaffected by the stress treatment. Uncontrollable shock is thought to reduce the rewarding value of responding for electrical brain stimulation from those brain regions in which stressors are known to influence dopamine activity.     

Effects of kainic acid lesions of the striatum on self-stimulation in the substantia nigra and ventral tegmental area

Unilateral kainic acid lesions of the dorsal striatum provided evidence for a dissociation of neural substrates of brain-stimulation reward at sites in the ventral tegmental area and substantia nigra. The lesions caused a significant increase in current intensity thresholds at substantia nigra placements, whereas similar lesions had no effect on self-stimulation thresholds at sites in the ventral tegmentum. In addition, the rate-increasing effects of d-amphetamine (0.1–1.0 mg/kg) on self-stimulation were determined before and after lesions to the dorsal striatum. No significant changes in dose-response curves were observed at either loci. Amphetamine-induced rotation was used to confirm damage to the dorsal striatum and lesioned animals were observed to rotate towards the side of the lesion. In contrast, sham-lesioned animals showed turning away from the side stimulated electrically in previous tests. The results of the self-stimulation and rotation experiments are discussed in the context of neural substrates of reward and motor activity.     

Differential effects of morphine and D-amphetamine on self-stimulation from closely adjacent regions in rat midbrain

The effects of morphine were investigated on self-stimulation from numerous electrode placements in the area of the substantia nigra or in the ventral half of mesencephalic central gray matter. Before pharmacological testing, current intensity was reduced to yield stable, submaximal rates of self-stimulation. Rats were then injected daily with morphine for 10 days, and were tested three hours after injection. Between days 5 and 10 of treatment, many rats self-stimulated at more than 150% of baseline, but some others reduced self-stimulation to as little as 3% of baseline. Histological evaluation revealed that morphine facilitated self-stimulation when the electrode tip was located more than 0.3 mm from substantia nigra or more than 0.2 mm from the midline of central gray. In rats with electrode tips closer to substantia nigra or to the midline of central gray, morphine often reduced or failed to alter self-stimulation rates. The effects of a low dose of D-amphetamine (0.1 mg/kg) were investigated on electrode placements in the substantia nigra area. Placements close to the dorsal border of substantia nigra yielded less facilitation of self-stimulation by D-amphetamine than did placements located more dorsally or medially. Possible catecholaminergic substrates of these differential effects are discussed.     

Cortical lesions interfere with behavioral recovery from unilateral substantia nigra lesions induced by brain grafts

Effects of aspiration lesions of the cerebral cortex on the behavioral effects of intraventricular substantia nigra grafts were investigated. Apomorphine-induced rotational behavior consequent to unilateral lesions of the substantia nigra was used as a behavioral measure. Substantia nigra grafts reduced rotational behavior in animals with sham cortical lesions. Cortical lesions also decreased rotational behavior and, in these animals, no additional decrease in rotational behavior was induced by substantia nigra grafts. It is concluded that cortical lesions alter striatal circuitry so as to preclude a behavioral effect of substantia nigra grafts.     

Lesions of the Cerebral Cortex and Caudate-Putamen Enhance GABA Function in the Rat Superior Colliculus

Unilateral lesions of the rat frontal cortex were made either alone or in combination with the caudate-putamen in order to examine (a) their morphological influence on the substantia nigra and (b) their neurochemical influence on GABA function in the superior colliculus. One to two months following the combined lesion, neuronal somata in the ipsilateral pars reticulata of the substantia nigra were clearly hypertrophied (+ 30%). Morphological changes in the substantia nigra were not evident contralaterally or in animals bearing only cortical lesions. One to two months following cortex-only lesions, no significant alterations in tectal GABA concentration were observed. However, the combined lesion induced elevations of GABA within both the medial and lateral sectors of the intermediate and deep layers of the superior colliculus. This effect was restricted to the ipsilateral side and was most pronounced in lateral sectors. The vast majority of GABA released from superfused control tectal slices by a depolarizing stimulus (35 mM KCl) was calcium-dependent. Such evoked GABA release from ipsilateral tectal slices was significantly reduced (- 25%) by unilateral lesions of the substantia nigra, a structure that is known to provide GABA-containing inputs to the tectum. In contrast, cortical lesions alone significantly enhanced the evoked tectal GABA release (+ 66%), although their influence was again confined to the ipsilateral side. Combined lesions of the cerebral cortex and caudate-putamen significantly enhanced the evoked GABA release from tectal slices in both hemispheres but the changes were most marked ipsilaterally (+ 147%). It is suggested that the hypertrophy of GABA-containing nigrotectal somata seen after removal of corticostriatal, corticotectal and in particular GABA-containing striatonigral fibres may reflect concomitant increases in GABA synthesis within and/or sprouting of nigrotectal terminals.     

The dorsal and medial raphe projections to the substantia nigra in the rat: Electrophysiological, biochemical and behavioural observations

Electrophysiological experiments have been performed in urethane anaesthetized rats to investigate the projections from the dorsal (DRN) and medial raphe nuclei (MRN) to the substantia nigra. The biochemical and behavioural effects following discrete electrolytic lesions in the dorsal and medial raphe have also been investigated.Stimulation of the DRN produced predominantly inhibition of spontaneous activity of single neurones in the substantia nigra though some neurones were also excited. Bilateral stimulation of the substantia nigra produced antidromic spikes in DRN and MRN neurones.Lesions of the DRN and MRN produced a significant reduction in substantia nigra 5-HT concentration. Additionally, DRN lesions reduced striatal 5-HT, while MRN lesions reduced hippocampal 5-HT. Both lesions increased substantia nigra HVA concentration but did not affect DA concentration. Neither DRN nor MRN lesions affected striatal HVA, although DA levels were significantly elevated after 14 days.Animals with DRN lesions explored more than controls or MRN-lesioned animals. However, this behaviour was transient and was not observed after 14 days. On the other hand, MRN-lesioned animals were significantly hyperactive.These observations suggest that the substantia nigra receives a direct monosynaptic inhibitory input from the DRN and MRN and that these pathways use 5-HT as a neurotransmitter serving to tonically inhibit dopaminergic neurones. While 5-HT and dopamine appear to be involved in the control of motor behaviour, the precise relationship between these serotoninergic and dopaminergic systems in this respect is unclear.     

Self-stimulation and circling reveal functional differences between medial and lateral substantia nigra

Functional differences between medial and lateral substantia nigra (SN) sites mediating intracranial self-stimulation (ICSS) and circling behaviours were explored. It was found that, for medial SN stimulation sites, d- and l-amphetamine (1 mg/kg) had equipotent, slightly facilitatory effects on ICSS rates while for lateral SN stimulation sites, d-amphetamine increased and l-amphetamine decreased ICSS rates. It is suggested that these effects may be due to medial and lateral dopamine cells having different sensitivities to amphetamine isomers.Imposed continuous stimulation of the ICSS sites induced contralateral circling from the medial SN placements and ipsilateral circling from the lateral SN placements. In rats receiving lesions through the ICSS electrode, d-amphetamine (2 mg/kg) induced ipsilateral circling following medial SN damage and contralateral circling after lateral SN damage. These results suggest that lateral and medial SN mechanisms of ICSS and circling differ, and that the lateral SN may be antagonistic to medial SN mechanisms involved in circling behaviour.     

Behavioral characterization of intracranial self-stimulation from mesolimbic, mesocortical, nigrostriatal, hypothalamic and extra-hypothalamic sites in the non-inbred CD-1 mouse strain

A behavioral analysis of intracranial self-stimulation (ICSS) was provided for mesolimbic/mesocortical, nigrostriatal, hypothalamic and extrahypothalamic sites in the CD-1 mouse. Robust responding and rapid acquisition of mesocortical ICSS appeared dorsally along notably fluorescent sites in rostral and caudal planes. ICSS was diminished demonstrably in medial and ventral positions in posterior planes. Mesolimbic ICSS from the medial and ventral nucleus accumbens (Nas), was accompanied by significant elevations in locomotor activity, corresponding to regions of dopamine (DA) and cholecystokinin co-localization. Stimulation-induced seizures appeared from both the Nas as well as the mesocortex. ICSS from the ventral tegmental field (VTA) was evident along its medial, lateral and dorsal borders with longer pulse durations more likely to elicit responding. Seizure activity was absent from the VTA. Striatal ICSS was conspicuously poor in dorsal and medial locations; regions presumably devoid of tegmental innervation. ICSS emerged from both the ventrocaudal and anteromedial striatum; regions linked to innervation by the dorsolateral and ventromedial VTA. The red nucleus, a previously neglected self-stimulation site supported marked responding for ICSS. Regions supporting rubral ICSS were correlated with thalamic innervation sites; notably the ventrolateral thalamic nucleus and the parafascicular nucleus, regions found to support ICSS. The substantia nigra supported high rates of responding for ICSS when electrode placement was restricted to the dorsomedial portion of the pars compacta. Electrode deviations lateral and dorsal to the substantia nigra pars medialis induced a progressive decline in responding. Hypothalamic sites were found to support significant responding for ICSS, although such performance was frequently associated with seizure induction. Taken together these data (1) provide the first behavioral analysis of ICSS in mice responding from previously unexamined DA sites in the mesolimbic (e.g. VTA, Nas) and nigrostriatal systems (e.g. caudate, red nucleus) (2) suggest an anatomical reconsideration of the assumptions underlying the elicitation of ICSS from the frontal cortex (3) suggest that the neural circuitry underlying thalamic, caudate, rubral and frontal cortical ICSS are interrelated and (4) suggest that the Nas and the frontal cortex, like the hypothalamus, in the mouse appear to be particularly sensitive to stimulation-induced seizures.     

The role of the lateral cortico-cortical prefrontal pathway in self-stimulation of the medial prefrontal cortex in the rat

Effects of electrolytic and kainic acid lesions at several stereotaxic planes of the lateral cortico-cortical prefrontal efferent pathway on self-stimulation of the medial prefrontal cortex were investigated. Electrolytic bilateral lesion of the sulcal prefrontal cortex, the first terminal area of this pathway, produced no effects on self-stimulation of the medial prefrontal cortex. However, bilateral electrolytic lesion of this pathway at the rostral part of the external capsule produced a permanent abolition of self-stimulation of the medial prefrontal cortex. These effects seemed selective since operant behaviour to obtain water, similar to that performed for self-stimulation and used as a control, was not affected by the lesion except on the 1st, 3rd (P less than 0.01) and 5th (P less than 0.05) days postlesion. Interestingly, bilateral microinjections of kainic acid (10 nmol in 0.8 microliters) at the same stereotaxic planes of the external capsule where electrolytic lesion was produced, had no effects on self-stimulation. These results suggest that fibres-of-passage through the external capsule are responsible for the abolition of self-stimulation. Bilateral electrolytic lesion of the entorhinal cortex, one of the caudal terminal areas of this descending set of fibres, produced a short transient decrease of self-stimulation of the medial prefrontal cortex. These results are discussed on the basis that complex, rather than single circuits are involved in maintaining self-stimulation in this neocortical area.     

The relationship between lesion site, dopamine neurons, and turning behavior in the rat

The phenomenon of turning after administration of amphetamine to rats with unilateral lesions in the midbrain has been studied to determine the anatomical locus of the lesion site in relation to turning behavior. Lesions which encroached upon the substantia nigra to a significant extent were always effective; lesions in a large number of structures dorsal to the substantia nigra were not. These data are consistent with the hypothesis that destruction of part of the nigrostriatal tract is essential for the behavior. On the other hand, six rats with lesions medial to and not encroaching upon the substantia nigra also showed clear-cut turning behavior. This finding is consistent with other observations which suggest that the nigrostriatal pathway courses medially to the substantia nigra before turning rostrally towards the striatum.     

Intracranial self-stimulation: mapping against the lateral boundaries of the dopaminergic cells of the substantia nigra

The lateral boundaries of the substantia nigra, zona compacta, were mapped for intracranial self-stimulation in rats. The boundaries of the positive region for self-stimulation were found to correspond to the boundaries of the dopaminergic cell layer. These data strengthen the view that rewarding stimulation in this system activates the tegmental dopaminergic celss or, more likely, their immediate afferents.     

Relations between the basal ganglia and the thalamus of the primate. New morphologic data. New physiopathologic interpretations

Considerable progress has been made over the last few years in our knowledge of the thalamus and basal ganglia and their relationships to the cerebral cortex. More detailed topographic studies in the macaque have demonstrated the separation, in the lateral region of the thalamus, between afferent cerebellar and basal ganglia territories. These territories fail to correlate with the subdivision between ventral and dorsal elements or the limits of a single cytoarchitectonic nucleus. The cerebellar territory corresponds to VIL (or VPLo) which projects towards the primary cortex, and to VIM (or area X) and DI (or VLc) which project towards premotor cortex. The nigral (and tectal) territory corresponds to VOM (or VAmc) and to some parts of the medial nucleus and projects mainly towards the oculomotor area, supplementary motor area and prefrontal cortex. In return, the oculomotor area and substantia nigra project towards the colliculus superior. Several thalamic nuclei constitute the pallidal territory: VOL (or VLo) projects mainly towards supplementary motor area, LPo (or VApc) and Do towards the prefrontal cortex. The median center, which receives afferents from pallidum and motor cortex, projects towards the striatum but also the motor cortex. The parafascicular nucleus projects towards the striatum and premotor cortex. It is still not possible to transpose data acquired in the macaque to man, but functional reinterpretations are possible. A system which involves the median pallidum, VOL and supplementary motor area could control motor initiative and flow of movement. A second system, involving the substantia nigra, colliculus superior, thalamic relay and oculomotor area could control posture. The pallidum and substantia nigra, anterior part of lateral mass, medial nucleus and prefrontal cortex could elaborate motor programmes.     

Kainic acid-induced substantia nigra seizure in rats: behavior, EEG and metabolism

RATIONALE: In order to clarify the role of substantia nigra pars reticulata (SNr) upon the development of epileptic seizure, kainic acid (KA) was injected into a unilateral SNr. MATERIALS AND METHODS: Wistar rats weighing 250-350 g were used. A stainless-steel cannula and depth electrode were inserted stereotaxically into the left substantia nigra pars reticulata (SNr). At 7 days after surgery, 1.0 microg of KA was injected into the left SNr. Experiment 1: In eight rats, behavior and electroencephalograms (EEG) were continuously recorded for about 30 h, and intermittently monitored following 1 month. Experiment 2: Two hours after KA injection into SNr, rats demonstrated status epilepticus. Then, 100 microCi/kg of [(14)C]2-deoxyglucose (2-DG) was intravenously injected in seven rats, and the rats were processed for autoradiographic study. RESULTS: Changes in behavior and EEG: On EEG, a secondary generalized seizure status was observed at about 70 min after KA injection. In video, limbic seizure manifestations such as salivation were observed as a initial symptom and followed by rolling and generalized tonic seizures. [(14)C]deoxyglucose autoradiographic study demonstrated increased local cerebral glucose metabolism in the medial and lateral septal nucleus, substantia nigra, hippocampus, parietal cortex, piriform cortex, medial and lateral geniculate nucleus, anterodorsal, lateral and ventral nucleus of the thalamus, amygdala and midbrain reticular formation. SUMMARY: The result suggested that the substantia nigra played an important role in the secondary generalization in the substantia nigra seizure model due to the decreased function of the GABAergic projection system induced by an excessive epileptic excitation of SNr.     

Evaluation of stressor effects on intracranial self-stimulation from the nucleus accumbens and the substantia nigra in a current intensity paradigm

The effect of uncontrollable footshock was evaluated in animals responding for intracranial self-stimulation from the nucleus accumbens and the substantia nigra (pars compacta) in a descending current intensity paradigm. Responding for brain stimulation from the nucleus accumbens was found to be affected by the stressor at the upper end of the rate-intensity curve. In contrast, responding for brain stimulation from the substantia nigra was unaffected by the stressor at any of the current intensities employed. The variations of responding for self-stimulation from the nucleus accumbens were unrelated to alterations of locomotor activity or rearing. It is suggested that stressor-provoked reductions of responding for intracranial self-stimulation are not a result of the brain stimulation taking on aversive properties, but rather reflect a reduction in the reinforcing or motivational value associated with the stimulation.     

Trigeminal-basal ganglia interaction: control of sensory-motor gating and positive reinforcement

Functional interactions between the basal ganglia and the perioral area were analyzed by means of electrical brain stimulation in the rat. The first experiment showed that unilateral stimulation of the substantia nigra sensitized the contralateral perioral area for a biting reflex upon its tactile stimulation. This biting reflex consists of lip withdrawal, orienting towards and biting into the stimulus source. The same sites in the substantia nigra also produced electrical self-stimulation using bar-pressing as the operant. A positive correlation was found between threshold currents for biting and for self-stimulation. However, the current levels necessary for reinforcement were considerably higher than those to facilitate the biting reflex. In the second experiment, it was found that manipulation of the perioral area by unilateral vibrissae removal reduced the rate of electrical self-stimulation in the substantia nigra. This effect was lateralized, depended on time after vibrissae removal, and could be reversed by systemic injections of the dopamine receptor agonist apomorphine. These results, which provide evidence for a reciprocal interaction between the basal ganglia and the perioral area, are discussed with respect to mechanisms of sensory-motor gating, motivation and reinforcement.     

Ventral tegmental self-stimulation selectively induces opioid peptide release in rat CNS

Intracranial self-stimulation (ICS) is thought to activate neuronal systems involved in processing natural reinforcing agents. Metabolic mapping studies have previously demonstrated a subset of CNS structures specifically engaged by ICS in animals receiving stimulation actively vs. passively. Since opiates are known to enhance JCS behavior and presumably its reinforcing properties, the current study addressed the question of the role of opioid peptides as mediators of ICS. Rats were trained on a fixed ration (FR) 20 schedule of responding maintained by ICS. Following response stabilization, rats were assigned either to an active or a corresponding yoked stimulation group at 1 of 2 schedules of reinforcement (i. e., FR1-YFR1, FR20-YFR20, or sedentary control), and opioid peptide release was inferred from in vivo receptor occupancy. Autoradiographic analyses identified 3 groups of structures. Treatment-induced alterations in occupancy were seen in the medial dorsal nucleus of the thalamus, basolateral amygdala, ventral pallidum, medial habenula, dorsal raphe, posterior hypothalamus, substantia nigra pars compacta, agranular preinsular cortex, and zona incerta. Depending upon the structure, peptide release was dependent upon stimulus contingency (active vs. yoked) and/or schedule (FR1 vs. FR20). Evidence for ICS-induced inhibition of peptide release was found in the habenula and preinsular cortex. Nine additional structures, all components of, or receiving projections from, the limbic system, revealed complex interactions between ICS treatment and the electrode side. Finally, a widespread ipsilateral increase in receptor binding was seen rostrally from the cingulate, olfactory tubercle, and nucleus accumbens, along the lateral hypothalamus and hippocampus, and extending caudally to the substantia nigra and ventral tegmentum. These later effects appear to be related to stimulation-induced changes in blood flow and subsequent ligant presentation increases. Collectively, these data point towards the ability of rewarding brain stimulation to activate discrete neuronal opioid systems contingent upon specific behavioral as well as stimulus conditions. © 1993 Wiley-Liss, Inc.     

Unilateral 6-hydroxydopamine lesions of dopamine neurons produce bilateral self-stimulation deficits

Sixteen rats, which had electrode implants in each hemisphere which generated comparable self-stimulation rate-intensity functions, were used in this study. Eight of the rats received unilateral 6-hydroxydopamine injections into the substantia nigra pars compacta, which produced severe unilateral losses of dopamine and were effective in generating apomorphine-induced turning away from the injected hemisphere. Of the remaining 8 rats, 5 received unilateral 6-hydroxydopamine lesions aimed at the ventral tegmental area and 3 were give vehicle injections. The vehicle injections were without effect on self-stimulation and the ventral tegmental injections had an overall transient facilitative effect on self-stimulation. The 6-hydroxydopamine lesions of the pars compacta, however, had variable effects. In some rats there was a marked bilateral reduction in self-stimulation over 8 weeks; whereas, there was little, if any, effect in other rats. The rats which sustained the bilateral deficits also sustained the greatest unilateral loss of dopamine. The unilateral 6-hydroxydopamine lesions of the pars compacta consistently blocked the facilitative influence of 0.5 mg/kg of D-amphetamine on self-stimulation bilaterally, and this effect persisted over 8 weeks of postoperative testing. These results were considered supportive of a response rather than reinforcement role for dopamine in the mediation of self-stimulation behavior.     

The cortico-nigral projection in the cat. An experimental study with silver impregnation methods

Following lesions of various parts of the cerebral cortex in cats the terminal distribution of cortico-nigral fibers has been studied by means of silver impregnation methods. A modest number of cortico-nigral fibers have been traced from the gyrus proreus, the “supplementary motor” area, the “primary sensory-motor” area and the “secondary sensory” area. Lesions of the remaining regions of the cerebral cortex did not give rise to terminal degeneration in the substantia nigra. The number of cortico-nigral fibers was considerably less than expected from the data available in the literature. The cortico-nigral projection system is chiefly homolateral. A few crossed cortico-nigral fibers were found following lesions of the gyrus proreus or the “supplementary motor” area. The majority of the corticofugal fibers from these two cortical region and the “secondary sensory” area terminate on the somata or the proximal dendrites of the cells in the nigra complex. Following lesions of the “primary sensory-motor” area of the cerebral cortex, terminal degenerating fibers were only seen in the neuropil of the substantia nigra. The findings are discussed briefly.