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PubMed1989

Increased dopamine and serotonin metabolism in rat nucleus accumbens produced by intracranial self-stimulation of medial forebrain bundle as measured by in vivo microdialysis.

In the present study, we have used a newly developed microdialysis system to perfuse the nucleus accumbens (NAC) of conscious rats during spontaneous intracranial self-stimulation of the medial forebrain bundle (MFB). Chromatographic (HPLC-ECD) analysis of the perfusates showed that dopamine (DA) release increased, but with an unstable pattern during the actual period of self-stimulation. On the other hand, the main DA metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and a serotonin metabolite 5-hydroxyindoleacetic acid, were all markedly enhanced by self-stimulation, but with different time courses. These findings indicate that self-stimulation of the MFB in rats induces increases in both DA and serotonin activities in the NAC. Such changes may be involved in mediating self-stimulation of the MFB.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1976

[Effect of damage to the zone of the medial forebrain bundle and preoptic area on the activiy of a penicillin-induced epileptiform focus (phenomenon of the hyperactive determinant dispatch station)].

It was shown in experiments on cats under nembutal anesthesia that a lesion of the medial forebrain bundle (MFB) and partly of the preoptic region at the side of local penicillin application on the cerebral cortex (g. suprasylvius medius) results in depression of the epileptiform activity in the penicillin-induced focus, as well as in the secondary "mirror" focus, which appeared in the symmetrical cortex area of the other hemisphere. The MFB lesion at the "mirror" focus side led to depression of the seizure spike potentials in this focus only and did not change the activity in the primary epileptiform one. The described effects are considered from the aspect of the conception on the role of the determinant dispatch station (DDS) in the central nervous system: the primary epileptiform focus plays the role of the hyperactive DDS which induces the secondary focus and determines the character of its activity. The results of the study substantiate a suggestion that the MFB can take part in the modulation of the cortical epileptiform activity.

Animals↗
PubMed1998

Sequential changes of dopaminergic receptors in the rat brain after 6-hydroxydopamine lesions of the medial forebrain bundle.

We investigated the sequential patterns of changes in dopamine uptake sites, D1 and D2 receptors in the brain of animals lesioned with 6-hydroxydopamine using quantitative receptor autoradiography. The rats were unilaterally lesioned in the medial forebrain bundle and the brains were analyzed at 1, 2, 4 and 8 weeks postlesion. Degeneration of the nigrostriatal pathway caused a significant loss of dopamine uptake sites in the ipsilateral striatum, substantia nigra (SN) and ventral tegmental area (VTA) in the lesioned animals. Dopamine D1 receptors were significantly increased in the ventromedial part of striatum of the ipsilateral side from 2 to 4 weeks postlesion. In the ipsilateral SN, a transient increase in dopamine D1 receptors was observed only 1 week after lesioning. However, the frontal cortex, parietal cortex and dorsolateral part of the striatum showed no significant change in dopamine D1 receptors throughout the experiments. On the other hand, dopamine D2 receptors were decreased increased in the ipsilateral SN and VTA from 1 week to 8 weeks postlesion. In the ipsilateral striatum, dopamine D2 receptors were increased in the dorsolateral part from 2 weeks to 8 weeks and in the ventromedial part from 2 weeks to 4 weeks. However, the frontal cortex and parietal cortex showed no significant change in dopamine D2 receptors during postlesion. In the contralateral side, most of regions examined showed no significant change in dopamine uptake sites, dopamine D1 receptors and dopamine D2 receptors during postlesion except for a transient change in a few regions. These results demonstrate that 6-hydroxydopamine can cause a severe functional damage in dopamine uptake sites in the striatum, SN and VTA. Our findings also suggest that the up-regulation in dopamine D2 receptors is more pronounced than that in dopamine D1 receptors in the brain after 6-hydroxydopamine treatment. Furthermore, our results support the existence of dopamine D2 receptors on the neurons of SN and VTA. Thus, our findings provide insights into the pathogenesis of Parkinson's disease.

Adrenergic Agents↗
PubMed1994

Glutamate receptors in striatum and substantia nigra: effects of medial forebrain bundle lesions.

We examined NMDA-sensitive [3H]glutamate, [3H]AMPA, [3H]kainate and metabotropic-sensitive [3H]glutamate binding sites in neostriatum and substantia nigra pars reticulata (SNr) in rats after unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. One week after the lesion, NMDA, AMPA, kainate and metabotropic receptors were decreased in the ipsilateral neostriatum, whereas at three months NMDA receptors were increased while AMPA, kainate and metabotropic receptors were not changed. In the SNr at one week, only AMPA and metabotropic receptors were significantly decreased whereas three months after the lesion NMDA, AMPA and kainate binding sites were decreased. The early decrease of excitatory amino acid receptors in the striatum is likely to reflect degeneration of dopaminergic fibers, suggesting that specific subpopulations of excitatory amino acid binding sites are located on dopaminergic terminals.

Animals↗
PubMed1984

Circling behaviour induced by electrical stimulation of the medial forebrain bundle, importance of stimulus parameters and dopaminergic processes.

Unilateral electrical stimulation of the substantia nigra or the ventral tegmental area produced postural asymmetry and increased locomotor activity respectively. Concurrent stimulation of the efferent pathways of these two areas (medial forebrain bundle) resulted in contraversive circling behaviour that was dependent upon the current intensity and frequency of the stimuli. The application of biphasic electrical pulses minimised the damage to the brain site stimulated; no decrease in circling intensity over time, nor spontaneous circling after administration of amphetamine or apomorphine without stimulation was observed. The contraversive circling behaviour was induced by activation of the ascending dopaminergic pathways as revealed by the close correlation between the site of stimulation and the localisation of this pathway, its antagonism by haloperidol and its abolishment by pretreatment with reserpine and alpha-methyl-p-tyrosine. Apomorphine likewise inhibited the electrical stimulation-induced circling behaviour. These results are discussed with regard to the influence of the stimulation parameters and the dopaminergic processes involved.

Animals↗
PubMed1980

Ascending and descending components of the medial forebrain bundle in the rat as demonstrated by the horseradish peroxidase-blue reaction. I. Forebrain and upper brain stem.

The ascending and descending components of the medial forebrain bundle (MFB) were investigated by means of horseradish peroxidase (HRP) with a sensitive substrate. The HRP was injected iontophoretically into the MFB at various levels from the anterior commissure to the posterior hypothalamus. In order to prevent the diffusion of HRP to other brain areas, a double micropipette system was used. The descending components of the MFB are derived from (1) the anterior cingulate area, infra- or prelimbic area, and sulcal cortex, (2) the lateral septal nucleus and diagonal band, (3) the bed nucleus of the stria terminalis, (4) the paraventricular nucleus (5) the substantia innominata, (6) the amygdaloid complex (AM), (7) the ventromedial (VM) and dorsomedial (DM) hypothalamic nuclei, (8) the entopeduncular nucleus and (9) nucleus periventricularis stellatocellularis. The ascending components of the MFB originate in: (1) the medial preoptic nucleus, (2) the nucleus periventricularis stellatocellularis and rotundocellularis, (3) the posterior hypothalamic nucleus, (4) the parafascicular nucleus, (5) the ventral premammillary nucleus, (6) the substantia grisea periventricularis, (7) the lateral habenular nucleus, (8) the VM and DM, (9) the paratenial nucleus, (10) the AM and (11) the arcuate nucleus.

Animals↗
PubMed1989

The effect of uptake inhibition on dopamine release from the nucleus accumbens of rats during self- or forced stimulation of the medial forebrain bundle: a microdialysis study.

Changes in dopamine (DA) release were measured in microdialysis samples taken from the nucleus accumbens (NAC) of rats pretreated with the DA uptake inhibitor, nomifensine (1 mg/kg, i.p.) during self- or forced stimulation of the medial forebrain bundle (MFB). Self-stimulation of the MFB in nomifensine-pretreated rats caused an increased release of DA in the NAC. In the same rats, similar increases in DA release were also found during forced stimulation, that is, during MFB stimulation in the absence of lever-pressing, but at current and rate parameters identical to those recorded in the previous self-stimulation session. The results indicate that self-stimulation of the MFB activates the mesolimbic DA system; similar neurochemical changes observed during self- and forced stimulation of the MFB suggest that the operant lever-pressing behavior itself did not influence DA release in the NAC.

Animals↗
PubMed1998

Lesions of pontomesencephalic cholinergic nuclei do not substantially disrupt the reward value of medial forebrain bundle stimulation.

This study examines the effects of lesioning the pedunculopontine tegmentum (PPTg) and laterodorsal tegmentum (LDTg) on the reward effectiveness of medial forebrain bundle (MFB) stimulation. Although the focus is on the effects of unilateral lesions made ipsilateral to stimulation sites in the hypothalamic and ventral tegmental MFB, the effects of contralateral lesions of both targets are also investigated. Reward effectiveness was assessed using the rate-frequency curve shift paradigm. In nine rats with unilateral PPTg lesions and five rats with unilateral LDTg lesions, the frequency required to maintain half-maximal response rats was generally not changed by more than 0.1 log units relative to prelesion baseline mean. In three rats with contralateral PPTg lesions and four rats with contralateral LDTg lesions, required frequency was also not substantially changed. The results are interpreted in terms of a previously proposed hypothesis regarding the role in MFB self-stimulation of ascending cholinergic input from the pontomesencephalon to ventral tegmental dopaminergic neurons.

Animals↗
PubMed1995

Medial forebrain bundle stimulation in rats activates glycogen phosphorylase in layers 4, 5b and 6 of ipsilateral granular neocortex.

Functional activation in human brain produces an increase in glycolytic metabolism. Animal studies suggest activation-induced glycolysis is coupled to brain glycogenolysis. Medial forebrain bundle (MFB) stimulation activates the release of neurotransmitters which promote neocortical glycogenolysis in vitro. In the present study, active glycogen phosphorylase (GP), an index of glycogenolysis, is assessed histochemically in rat brain after 15 min of MFB self-stimulation. Active GP increased significantly in layers 4, 5b and 6 of granular neocortex ipsilateral to MFB self-stimulation. Restriction of increased glycogenolysis to granular neocortex suggests an important functional interaction between sensory neocortical processing and ascending MFB systems.

Animals↗
PubMed2003

[Correlation between iron levels and degeneration of dopaminergic neurons in rat nigrostriatal system during the early 6-OHDA lesions in medial forebrain bundle].

In the present study, using fast cyclic voltammetry (FCV), atomic absorption/flame emission spectrophotometry and immunohistochemistry, we investigated the correlation between iron levels and degeneration of dopaminergic neurons in rat nigrostriatal system during the early 6-OHDA lesions in the medial forebrain bundle (MFB). The results showed that 1 d or 3 d after lesions in MFB, there was a 45% or 66% reduction, respectively, in the density of tyrosine hydroxylase (TH) immunoreactive cells in the substantia nigra (SN) of the lesioned side accompanied by an increase in iron staining intensity and iron concentration; while there was no change in dopamine (DA) release in the striatum (Str) of the lesioned side compared with the unlesioned side and the normal rats. There was no difference in the iron staining and concentration of SN and DA release of Str on the lesioned side between one-day group and three-days group. These results suggest that an iron level elevation in SN may be involved at the early stage of degeneration of DA neurons in SN. However, DA release in Str was unchanged due to the immense compensatory mechanism of DA system.

Animals↗
PubMed1979

Evaluation of the non-specific effects of catecholamine and serotonin neurotoxins by injection into the medial forebrain bundle of the rat.

Low doses of 6-hydroxydopamine (6-OHDA), 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT) that have previously been shown to produce behavioral change following intracerebral infusion were injected into the medial forebrain bundle of the rat. This site contains serotonin (5-HT), norepinephrine (NE), and dopamine (DA) fibers whose anatomical locations have been described. Damage to these fiber systems was quantified by measuring depletion of telencephalic 5-HT, NE and DA. The effects of infusions of 6-OHDA, 5,6-DHT and 5,7-DHT were compared to the effects of unequivocally non-specific electrolytic lesions and copper sulfate infusions. Survival time was varied to evaluate the amount of regeneration that could be expected over periods from 8 to 60 days. Amine levels were found to be stable over the time period examined. With the doses used, evidence was found to support the position that non-specific damage caused by general cytotoxic effects of 6-OHDA and 5,7-DHT is minimized sufficiently to permit the acquisition of useful data on the function of central catecholamine and indoleamine systems.

5,6-Dihydroxytryptamine↗
PubMed2000

Comparison of perirhinal cortex ablation and crossed unilateral lesions of the medial forebrain bundle from the inferior temporal cortex in the rhesus monkey: effects on learning and retrieval.

Seven monkeys learned new object-reward associations and scene problems and were overtrained on 100 problems of each type. Four monkeys received crossed lesions of the medial forebrain bundle (MFB) and inferior temporal cortex, with the later addition of a fornix section ipsilateral to the MFB lesion. The remaining 3 monkeys received bilateral perirhinal cortex ablation. Disconnection of the MFB from the inferior temporal cortex impaired postoperative new learning, but the retrieval of problems overtrained preoperatively was relatively preserved. Subjects with perirhinal cortex ablation were severely impaired in new learning and at the retrieval of scene problems, but retention of object-reward associations was relatively well preserved. The results support the hypothesis that isolation of the inferior temporal cortex from basal forebrain and midbrain afferents results in dense anterograde amnesia, whereas the role of the perirhinal cortex in learning is dependent on the perceptual difficulty of the task.

Amygdala↗
PubMed1996

Changes in [3H]AMPA and [3H]kainate binding in rat caudate-putamen and nucleus accumbens after 6-hydroxydopamine lesions of the medial forebrain bundle: an autoradiographic study.

The binding parameters of [3H] alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and [3H]kainate binding were examined in caudate-putamen and nucleus accumbens of rat striatum after unilateral lesions of the right medial forebrain bundle (MFB) using in vitro receptor autoradiography. Lesioning of the dopaminergic fibres in the MFB with 6-hydroxydopamine (6-OHDA) resulted, after one or four weeks, in a significant decrease in the levels of [3H]GBR 12935 (1-[2-diphenylmethoxy)-ethyl]-4-(3-phenylpropyl) piperazine) in ipsilateral caudate-putamen and nucleus accumbens (62 and 43%, respectively). A comparison of the dissociation constants (Kd) of [3H]AMPA and [3H]kainate binding in caudate-putamen and nucleus accumbens between control and MFB-lesioned side did not indicate any significant change. However, the maximum number of [3H]AMPA and [3H]kainate binding sites (Bmax) were significantly decreased in caudate-putamen and nucleus accumbens of the MFB-lesioned side of the brain. This decrease was between 17 and 26%. Our results suggested that at least one-fourth to one-fifth of AMPA and kainate receptors in rat caudate-putamen and nucleus accumbens are localized on the presynaptic endings of dopamine fibres that follow the MFB. A role of non-NMDA glutamate receptors in the presynaptic regulation of dopamine release in rat striatum is therefore supported.

Animals↗
PubMed2006

Muscimol inactivation of the septo-preoptic complex affects medial forebrain bundle self-stimulation only when directed at the complex's ventrolateral components.

Elements of the septo-preoptic basal forebrain complex, particularly the lateral and medial septum, the diagonal band of Broca, and the magnocellular preoptic area, have been linked to medial forebrain bundle (MFB) self-stimulation. This study examines the roles of these areas in MFB self-stimulation by temporarily inactivating them with 25 and 50ng doses of the GABA(A) receptor agonist muscimol. Changes in performance capacity and stimulation reward effectiveness were evaluated with the rate-frequency curve shift paradigm. When infused into the lateral and medial septum and the vertical limb of the diagonal band of Broca, both doses of muscimol were as ineffective as saline in altering either the rats' maximum rate of response for stimulation or the frequency required to maintain half-maximal response rate (required frequency). However, when infused into the horizontal limb of the diagonal band of Broca or the magnocellular preoptic area, muscimol substantially decreased maximal response rate and modestly increased required frequency. Changes in maximum rate were dose-dependent, but changes in required frequency were not. Muscimol infusions contralateral to the stimulated hemisphere were as effective as ipsilateral infusions; bilateral infusions tended to so suppress responding that resulting rate-frequency curves were often invalid. These results suggest a role in MFB self-stimulation for only the ventrolateral components of the septo-preoptic complex, and support past observations of considerable bilaterality in the neural systems that support self-stimulation.

Animals↗
PubMed1982

Conditioned suppression of medial forebrain bundle and septal intracranial self-stimulation in the rat: evidence for a fear-relief mechanism of the septum.

A conditioned emotional response (CER) paradigm was presented to two groups of rats during intracranial self-stimulation (ICSS). One group bar pressed for medial forebrain bundle (MFB) stimulation reward; the other group bar pressed for septal stimulation reward. The MFB ICSS was found to be suppressed by the CER procedure, but this procedure failed to suppress septal ICSS. This difference between the two sites was found only when both MFB and septal ICSS current intensities were available at their optimal levels. When ICSS current intensities were lowered to either threshold or medium level, both groups exhibited the CER suppression effect. The animals were also tested for a possible analgesic effect produced by the ICSS. The MFB stimulation was found to produce some degree of analgesia, but septal stimulation failed to produce any analgesic effect. Thus, the possibility that the attenuation of the CER suppression effect in the septal group was due to analgesia was excluded. The difference in MFB and septal ICSS behavior during the presentation of the aversive stimulus suggested a possible qualitative distinction between the reward functions of these two sites, and a possible fear-reduction property of the septal area.

Animals↗
PubMed2004

Vulnerabilities of ventral mesencephalic neurons projecting to the nucleus accumbens following infusions of 6-hydroxydopamine into the medial forebrain bundle in the rat.

The terminal arbors of dopaminergic projections in the nucleus accumbens (Acb) core degenerate more rapidly, completely and permanently in a variety of neurotoxic circumstances than do those in the medial shell. It is unknown if this always reflects purely losses of the distal parts of axons from the core (as proposed in methamphetamine intoxication), or whether, in some circumstances, the disproportionate loss of core axons may also stem from an intrinsic vulnerability to degeneration of core-projecting neuronal perikarya. Experiments described here addressed this issue in the following manner. Three days after Fluoro-Gold (FG), a retrogradely transported tracer, had been iontophoresed selectively into the core or medial shell of male Sprague-Dawley rats, each received an infusion of saline vehicle containing or lacking 6-hydroxydopamine (6-OHDA) in the ipsilateral medial forebrain bundle (MFB). Twenty-one days later the brains were processed to exhibit ventral mesencephalic neurons containing FG. Application of an unbiased sampling method revealed substantially greater losses of FG labeled neurons relative to controls in rats that had received 6-OHDA lesions and deposition of FG in the Acb core as compared to the medial shell. Of the few core-projecting neurons that remained in the ventral mesencephalon after these lesions, 54% did not co-localize tyrosine hydroxylase immunoreactivity (TH-ir) and, thus, were not expected to degenerate. The capacity to selectively remove core-projecting dopaminergic neurons may be useful in the determination of molecular correlates of vulnerability and resistance to neurotoxicity and to possibly test the role of the core in reinforcement paradigms.

Adrenergic Agents↗
PubMed1983

Brain stimulation reward in the lateral hypothalamic medial forebrain bundle: mapping of boundaries and homogeneity.

The boundaries and relative fiber concentration of the brain stimulation reward (BSR) sustaining system coursing through the lateral hypothalamic medial forebrain bundle (MFB) were mapped using a dorso-ventral moveable electrode. High response rates for BSR were found in a region extending dorso-ventrally from the zona incerta (ZI) to the base of the brain and medio-laterally from the fornix to the medial tip of the internal capsule (IC). Self-stimulation associated with perifornical area and self-stimulation associated with the tip of the internal capsule were mixed with aversion and forced movements, respectively. Current intensity threshold variations suggest: (i) that the reward system has a well-defined dorsal boundary ventral to the ZI, and (ii) that the core of the MFB contains a relatively higher concentration of reward relevant fibers than do its lateral, medial, dorsal and ventral components. No evidence was seen of independent mid-lateral and far-lateral MFB systems, though independent BSR sites in the dorsomedial and ventromedial hypothalamus were seen.

Animals↗
PubMed1982

Responses of preoptic thermosensitive neurons to medial forebrain bundle stimulation.

Single-unit responses of neurons in the preoptic and anterior hypothalamus (PO/AH) to local thermal stimulation and electrical stimulation of the medial forebrain bundle (MFB) were studied in urethane-anesthetized male rats. In a total of 286 units (112 warm-units, 37 cold-units and 137 thermally insensitive units), 109 units (49 warm-units, 13 cold-units and 47 thermally insensitive units) responded to single pulse stimulation of MFB. The units initially inhibited by MFB stimulation corresponded to 64.2% (70 of 109), the units with facilitatory responses were 27.5% (30 of 109) and the antidromically activated units were 8.3% (9 of 109). High incidence of inhibition by noradrenaline (NA) applied iontophoretically was observed in the neurons inhibited by the MFB stimulation. Iontophoretic application of dichloroisoproterenol to 2 warm-units blocked both the NA-induced inhibition and the MFB-induced inhibition. These ascending and descending connections of the MFB with PO/AH thermosensitive neurons may be part of the neural circuits responsible for thermoregulation.

Animals↗