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PubMed1996

Burst stimulation of the medial forebrain bundle selectively increase Fos-like immunoreactivity in the limbic forebrain of the rat.

The present study was designed to evaluate the postsynaptic functional consequences of different presynaptic activity patterns in midbrain dopamine systems using electrical stimulation of the rat medial forebrain bundle and subsequent determination of c-fos expression, used as a marker for neuronal activation, in dopamine target areas, by means of Fos immunohistochemistry. Nerve terminal dopamine release evoked by electrical stimulation of the medial forebrain bundle was monitored in the same animals using in vivo voltammetry. A 5 Hz stimulation consisting of 60 trains of five pulses and lasting 1 min was applied to the medial forebrain bundle. This stimulation was repeated 15 times every 3 min. Its pattern was defined by the interpulse interval which was either 70 ms or 200 ms for burst or regularly spaced stimulation, respectively. Our results show that burst stimulation of the medial forebrain bundle, which increase release of dopamine in target areas, increases the basal Fos-like immunoreactivity in the stimulated hemisphere, while regular stimulation does not affect expression of this protein. Moreover, the increase in Fos-like immunoreactivity induced by burst stimulation is restricted to limbic related structures, i.e. nucleus accumbens shell and intermediate aspect of the lateral septum, and the major island of Calleja, but is not observed in motor related structures (nucleus accumbens core and striatum). Pretreatment with the D1 dopamine receptor antagonist, SCH23390 (0.1 mg/kg, i.p.), blocked the increase in Fos-like immunoreactivity induced by burst stimulation of the medial forebrain bundle, suggesting a role for these receptors in the observed effects. Pretreatment with the 5-hydroxytryptamine2A/2C receptor antagonist ritanserin (0.4 mg/kg, i.p.) did not affect the increase in Fos-like immunoreactivity induced by burst stimulation in the nucleus accumbens shell or in the lateral septum, although it blocked the stimulated enhancement of Fos-like immunoreactivity in the major island of Calleja. The present data indicate that, rather than the absolute mean discharge rate of midbrain dopamine neurons, the temporal organization of the action potentials they generate conveys information to their target areas.

Animals↗
PubMed1965

LESIONS IN THE MEDIAL FOREBRAIN BUNDLE: DELAYED EFFECTS ON SENSITIVITY TO ELECTRIC SHOCK.

Rats with bilateral lesions in the medial forebrain bundle demonstrate both an increased sensitivity to electric shock, as reflected by a lowered jump threshold, and a decrease in the concentration of serotonin in the brain. Both effects of the lesion are characterized by a delayed time of onset and gradual development, which approximates the time required for progressive nerve degeneration in the central nervous system. It is suggested that this behavioral effect of bilateral lesions in the medial forebrain bundle may be due to a central denervation supersensitivity.

Animals↗
PubMed1978

Cocaine: acute effects on reinforcement thresholds for self-stimulation behavior to the medial forebrain bundle.

Reinforcing thresholds for self-stimulation behavior to the medial forebrain bundle were determined in rats by means of rate-free psychophysical method. The acute administration of cocaine lowered the reinforcing thresholds independent of motor stimulatory effects. These results indicate that cocaine affects the sensitivity of the reward pathways in the brain, and further demonstrate the utility of rate-independent methods in the assessment of drug effects on self-stimulation behavior.

Animals↗
PubMed2000

Sequential changes of cholinergic and dopaminergic receptors in brains after 6-hydroxydopamine lesions of the medial forebrain bundle in rats.

We studied sequential changes in muscarinic cholinergic receptors, high-affinity choline uptake sites and dopamine D2 receptors in the brain after 6-hydroxydopamine lesions of the medial forebrain bundle in rats. The animals were unilaterally lesioned in the medial forebrain bundle and the brains were analyzed at 1, 2, 4 and 8 weeks postlesion. [3H]Quinuclidinylbenzilate (QNB), [3H]hemicholinum-3 (HC-3) and [3H]raclopride were used to label muscarinic cholinergic receptors, high-affinity choline uptake sites and dopamine D2 receptors, respectively. The degeneration of nigrostriatal pathway produced a transient decrease in [3H]QNB binding in the parietal cortex of both ipsilateral and contralateral sides at 2 and 8 weeks postlesion. [3H]QNB binding also showed a mild but insignificant decrease in the ipsilateral striatum throughout the postlesion periods. No significant change was observed in the substantia nigra (SN) of both ipsilateral and contralateral sides throughout the postlesion periods. In contrast, [3H]HC-3 binding showed no significant change in the parietal cortex of both ipsilateral and contralateral sides during the postlesion. However, [3H]HC-3 binding was upregulated in the ipsilateral dorsolateral striatum throughout the postlesion periods. The ventromedial striatum also showed a significant increase in [3H]HC-3 binding at 1 week and 2 weeks postlesion. On the other hand, no significant change in [3H]raclopride binding was found in the parietal cortex of both ipsilateral and contralateral sides during the postlesion. [3H]Raclopride binding showed a conspicuous increase in the ipsilateral striatum (35-52% of the sham-operated values in the lateral part and 39-54% in the medial part) throughout the postlesion periods. In the contralateral side, a mild increase in [3H]raclopride binding was also found in the striatum (10-15% of the sham-operated values in the lateral part and 22% in the medial part) after lesioning. However, a significant decline in [3H]raclopride binding was observed in the ipsilateral SN and ventral tegmental area during the postlesion. The present study indicates that 6-hydroxydopamine injection of medial forebrain bundle in rats can cause functional changes in high-affinity choline uptake site in the striatum, as compared with muscarinic cholinergic receptors. Furthermore, our studies demonstrate an upregulation in dopamine D2 receptors in the striatum and a decrease in the receptors in the SN and ventral tegmental area after the 6-hydroxydopamine injection. Thus, these findings provide further support for neurodegeneration of the nigrostriatal pathway that occurs in Parkinson's disease.

Animals↗
PubMed1981

Suppression of the late component of the carotid occlusion reflex by lesion of the medial forebrain bundle in the rat.

1. The pressor response to a prolonged carotid occlusion in the rat has two components: an early, fast increase in blood pressure, and a late, slow and sustained hypertension. Since the second component can be blocked by a disconnecting lesion near the medial side of the medial forebrain bundle, the hypothesis that this complex structure is involved in the integration of the late pressor reflex was tested. 2. The medial forebrain bundle was partially or completely destroyed, or a disconnecting lesion was made to interrupt some of its medially running afferents and/or efferents. Incomplete lesion caused a transient suppression of the second component in 4 rats, whereas complete lesion in 5 rats or probable interruption of the medial efferent pathways in 3 rats led to suppression of the late component when the one-minute occlusion was performed within one hour after the lesion. 3. The data show that the medial forebrain bundle plays an important role in the integration of the late component of the pressor response to prolonged carotid occlusion.

Animals↗
PubMed1983

The ultrastructural localization of serotonin immunoreactivity in myelinated and unmyelinated axons within the medial forebrain bundle of rat and monkey.

Myelinated and unmyelinated serotonin-containing axons were demonstrated in the medial forebrain bundle of rats and monkeys with an antibody against serotonin (5-HT) conjugated to hemocyanin. The level of 5-HT in the brain was increased by pretreatment of animals with pargyline and L-tryptophan. The addition of nickel salts to the diaminobenzidine-peroxidase reaction mixture increased the intensity of the reaction product. Specific 5-HT immunoreactivity was observed to be localized to membrane-enclosed and membrane-attached compartments. 5-HT immunoreactivity was seen predominantly in unmyelinated axons (0.2 to 1.25 micron in diameter) surrounded by unlabeled processes. More than half of these 5-HT-immunoreactive fibers were in apposition with unreactive myelinated axons in the hypothalamus of both the rat (55%) and the monkey (54%). These appositions may provide the anatomical substrate for the observations that sprouting serotonergic fibers in the adult brain use myelinated axons for contact guidance. In addition to the unmyelinated fibers, intensely labeled myelinated axons (1.0 to 2.1 micron) were seen in the medial forebrain bundle of both rats and monkeys. The percentage of 5-HT-immunoreactive myelinated axons appeared greater in the monkey than in the rat (25.4% versus 0.7% of the total number of 5-HT-immunoreactive fibers, respectively). the observation of an increased number of myelinated 5-HT-immunoreactive axons in the monkey hypothalamus as compared to the rat supports the general hypothesis of a trend toward increased myelination during evolution.

Animals↗
PubMed1991

The effect of medial forebrain bundle lesion on thyrotropin secretion in the rat.

The medial forebrain bundle (MFB) was partially lesioned with 6-hydroxydopamine (6-OHDA) in order to investigate the effect of deficient central noradrenergic regulation on thyrotropin (TSH) secretion in the rat. 6-OHDA injection into the MFB significantly reduced the noradrenaline (NA), dopamine (DA) and serotonin (5-HT) content of the whole hypothalamus. NA and 5-HT concentrations were also significantly decreased in the paraventricular nucleus (PVN). The MFB lesion did not affect the clonidine (250 micrograms/kg, i.p.) induced stimulation of TSH release or the isoproterenol (1 mg/kg i.p.) induced decrease in TSH levels. Thyrotropin releasing hormone (TRH, 5 micrograms/kg i.v.) caused a similar significant stimulation of TSH secretion in lesioned and non-lesioned rats. The present results do not support the hypothesis that the blunted TSH response to TRH observed in depressed patients results from a deficiency in noradrenergic neurotransmission.

Animals↗
PubMed1976

Deficient passive and one-way active avoidance acquisition following medial forebrain bundle lesions in rats.

Cathodal electrolytic lesions of the medial forebrain bundle (MFB) at posterior hypothalamic levels in male hooded rats produced a mild, transient hypodipsia and lowered jump thresholds to footshock. The lesions produced marked deficits in passive avoidance performance in a paradigm that paired discrete, linearly incrementing footshock intensities with contact of a water spout following 48 hr of water deprivation. Intraperitoneal injections of DL-5-hydroxytryptophan (75 mg/kg), the immediate metabolic precursor of serotonin, had no effect on the passive avoidance performance of either experimental or operated control subjects. Lesions of the MFB also resulted in deficient acquisition in a one-trial step-through passive avoidance paradigm not using motivation to drink and caused a severe acquisition deficit in a one-way active avoidance task. Lesions of the septal nuclei produced lowered jump thresholds but did not affect acquisition in the first passive avoidance task. The results are interpreted as indicating a lesion-induced deficiency in fear learning, independent of the serotonergic functions of the MFB.

5-Hydroxytryptophan↗
PubMed1985

Modifications of adrenocortical responses following frontal cortex simulation in rats with hypothalamic deafferentations and medial forebrain bundle lesions.

With the purpose of delineating the neural pathways in the rat which mediate adrenocortical responses following frontal cortex stimulation, the effects of partial hypothalamic deafferentations and medial forebrain bundle lesion were studied. In intact and sham-operated animals, cortical stimulation through permanently implanted electrodes caused a significant increase in plasma corticosterone levels. In rats with anterior hypothalamic deafferentation and bilateral medial forebrain bundle lesions the adrenal response to cortical stimulation was blocked completely, while in animals with posterior hypothalamic deafferentation there occurred a normal rise in plasma corticosterone. These studies demonstrate that the frontal cortex effects on adrenocortical secretion are neurally mediated and involve an anterior hypothalamic input, more specifically the medial forebrain bundle.

Adrenal Cortex↗
PubMed1999

Alterations of second messenger systems in the rat brain after 6-hydroxydopamine lesions of the medial forebrain bundle.

We studied the sequential changes in second messenger systems in the striatum and substantia nigra (SN) after 6-hydroxydopamine lesions of the medial forebrain bundle in rats. The animals were unilaterally lesioned in the medial forebrain bundle and the brains were analyzed at 1, 2, 4 and 8 weeks postlesion. [3H]Phorbol-12, 13-dibutyrate (PDBu), [3H]forskolin and [3H]rolipram were used to label protein kinase C (PKC), adenylyl cyclase and calcium/calmodulin-independent cyclic-AMP phosphodiesterase, respectively. The degeneration of nigrostriatal pathway produced a significant increase in [3H]PDBu binding in the ventromedial part of the ipsilateral striatum from 2 to 8 weeks postlesion. In the contralateral side, [3H]PDBu binding showed a transient increase in the SN only 4 weeks after lesioning. [3H]Forskolin binding showed a significant increase in the ipsilateral and contralateral striatum from 2 to 4 weeks postlesion. In the ipsilateral SN, a significant increase in [3H]forskolin binding was observed at 4 weeks after lesioning. However, no significant change in [3H]forskolin binding was observed in the contralateral SN during postlesion. On the other hand, [(3)H]rolipram binding showed no conspicuous alteration in the brain during postlesion. These results demonstrate that rats made hemiparkinsonism by unilateral 6-hydroxydopamine injection have a significant increase in [3H]PDBu and [3H]forskolin binding in the striatum and/or SN, whereas no significant change in [3H]rolipram binding is observed in these areas during postlesion. Our findings also suggest that the increase in [3H]forskolin binding is more pronounced than that in [3H]PDBu binding in the brain after unilateral 6-hydroxydopamine injection. Thus, our studies may provide valuable information concerning degeneration of the nigrostriatal pathway such as Parkinson's disease.

Animals↗
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↗
PubMed1999

Lesions of midline midbrain structures leave medial forebrain bundle self-stimulation intact.

Previous work with psychophysically-based collision methods and pharmacological manipulation suggests a role in medial forebrain bundle (MFB) self-stimulation for neurons lying along the midline between the cerebral hemispheres, in the mid- and/or hindbrain. Also, recently-proposed models of the anatomical substrate for medial forebrain bundle stimulation reward suggest that at least part of the directly-activated axons of this substrate arise from mid- and/or hindbrain somata, bifurcate, and send bilateral projections to the MFB of each hemisphere. Branches of these axons are thought to cross the midline at some point near the ventral tegmental area. This study examines the effects on MFB stimulation reward of lesioning midbrain structures that lie along the midline between hemispheres. In 13 rats, lesions of the median raphe, the decussation of the superior cerebellar peduncle, or the interpeduncular nucleus were all ineffective in altering the stimulation frequency required to maintain half-maximal levels of operant responding for stimulation reward. These results are discussed in terms of implications for recent models of the anatomical substrate for brain stimulation reward.

Animals↗
PubMed2000

Acute immediate-early gene response to 6-hydroxydopamine infusions into the medial forebrain bundle.

Although the long-term neurobiological and behavioral effects of nigrostriatal lesions are well characterized, the events occurring soon after injury are not. These acute events can provide insight into the mechanisms underlying long-term adaptations to nigrostriatal lesions. The present experiments examined the basal ganglia immediate-early gene response to infusions of the catecholamine neurotoxin 6-hydroxydopamine into the nigrostriatal pathway in rats. Following 6-hydroxydopamine infusions into the medial forebrain bundle in awake, behaving rats, there was a rapid and transient induction of striatal c-fos and zif/268 messenger RNAs. Both immediate-early genes were maximally induced by 45min post-infusion, and returned to control levels by 1.5h (c-fos) or 3h (zif/268) post-infusion. Double-labeling experiments revealed that striatal c-fos expression occurred preferentially in preproenkephalin-expressing neurons. 6-Hydroxydopamine-induced c-fos messenger RNA was also observed in the substantia nigra pars reticulata and entopeduncular nucleus, but not the globus pallidus, 45 min after medial forebrain bundle 6-hydroxydopamine infusions. Finally, the role of ionotropic striatal glutamate receptors in nigrostriatal injury-induced striatal c-fos was examined by combining medial forebrain bundle 6-hydroxydopamine infusions with intrastriatal glutamate antagonist infusions. Both the N-methyl-D-aspartate antagonist, (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, and the non-N-methyl-D-aspartate antagonist, 6,7-dinitroquinoxaline-2, 3-dione, blocked striatal induction of c-fos messenger RNA following 6-hydroxydopamine infusions into the medial forebrain bundle. These results provide evidence of rapidly developing, glutamate-dependent molecular responses in the basal ganglia which may contribute to some of the well-described long-term adaptations of this system to nigrostriatal injury.

Animals↗
PubMed1987

Dopaminergic neurons: simultaneous measurements of dopamine release and single-unit activity during stimulation of the medial forebrain bundle.

Simultaneous electrical and chemical recordings have been made of dopamine neuronal activity in the rat brain during electrical stimulation of the medial forebrain bundle. Tungsten recording electrodes were placed at the level of the substantia nigra and carbon-fiber, Nafion-coated, voltammetric electrodes were placed in the neostriatum. Dopamine units, verified by histology to be in the zona compacta of the substantia nigra, were identified by previously established electrophysiological criteria. Dopamine release was detected by fast-scan cyclic voltammetry, a technique which allows dopamine to be determined in vivo on a sub-second time scale. The majority of dopamine cells examined (7 out of 10) were antidromically activated by 60 Hz stimulation of the medial forebrain bundle. The same stimulus also elicits dopamine overflow in the caudate nucleus. Following stimulation, dopamine concentrations in the extracellular fluid of the neostriatum rapidly declined to prestimulus levels. In addition, impulse flow in dopaminergic neurons was inhibited for 20 s following stimulation. These measurements represent the first direct observation from a neuronal tract of simultaneous unit activity and chemical release of a neurotransmitter in real time.

Action Potentials↗
PubMed1999

Serotonin hyperinnervation in the adult rat ventral mesencephalon following unilateral transection of the medial forebrain bundle. Correlation with reactive microglial and astroglial populations.

We have previously studied changes in the serotoninergic and dopaminergic nigrostriatal systems following transection of the medial forebrain bundle and found a long-term axotomy-induced increase in the levels of serotonin and its main metabolite, 5-hydroxyindolacetic acid in substantia nigra [Venero et al. (1997) J. Neurochem. 68, 2458-2468]. In an attempt to find a rationale for this effect, we have performed an immunohistochemical study. Transection of the medial forebrain bundle of the rat interrupted most of the ascending serotoninergic pathways from the raphe nuclei as revealed by serotonin immunoreactivity. While serotonin immunostaining was almost absent in striatum, it doubled in the ventral mesencephalon at 21 days postlesion. This axotomy-induced increase was accompanied by an increased density of the serotonin nerve terminal network in the ipsilateral substantia nigra and ventral tegmental area. The increase in serotonin immunoreactivity was in line with the measured levels of serotonin and 5-hydroxyindolacetic acid in substantia nigra. In addition, the distribution pattern of glial fibrillary acidic protein-immunoreactive astrocytes and OX42-immunoreactive microglia correlated highly with the location of increased serotonin fibre density in the ventral mesencephalon, especially in ventral tegmental area and in the most medial part of substantia nigra. We suggest that a pruning effect may underly the axotomy-induced increase in serotonin immunoreactivity in the ventral mesencephalon, and further, that activated astroglia and microglia may play a role in directing serotoninergic axonal regeneration following axotomy.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1975

Disappearance of supra-ependymal 5-HT axons in the rat forebrain after electrolytic and 5,6-DHT-induced lesions of the medial forebrain bundle.

The present study was intended to demonstrate the origin of supra-ependymal 5-hydroxytryptamine axons in the rat forebrain. Electrolytic lesions and injections of 5,6-dihydroxytryptamine (10 mug in 4 mul) were carried out unilaterally in and close to the medial forebrain bundle in the posterior hypothalamus of rats. Ten to 14 days later, terminal axons and formaldehyde-induced indolealkylamine fluorescence had virtually disappeared supra-ependymally in the lateral ventricles and interventricular foramina ipsilateral to the lesion if the indolealkylamine axons passing through the medial part of the medial forebrain bundle had been destroyed. No changes were observed, electron microscopically or fluorescence histochemically, in ventricles contralateral to the lesion. It is concluded that the supra-ependymal serotonergic nerve terminals in the lateral ventricles and interventricular foramina originate, uncrossed, from non-terminal axons passing through the medial forebrain bundle in the posterior hypothalamus.

5,6-Dihydroxytryptamine↗
PubMed1985

Electrical self-stimulation deficits in the anterior and posterior parts of the medial forebrain bundle after ibotenic acid lesion of the middle lateral hypothalamus.

The aim of the present study was to analyse the involvement of the intrinsic neurons located in the middle lateral hypothalamus in electrical self-stimulation measured with electrodes in the anterior and posterior parts of the medial forebrain bundle. In rats without hypothalamic lesions, self-stimulation rates from both anterior and posterior electrodes were similar on either side of the brain. For all rats with ibotenic acid-induced lesions in the lateral hypothalamus, self-stimulation rates were lower with electrodes in the area of the lesion, while self-stimulation on the contralateral side was normal. In rats with electrodes in the anterior hypothalamus, the lesion produced a large deficit when stimulation was applied to the anterior electrode ipsilateral to the lesion. Only three rats showed a decrease in self-stimulation with stimulation of the posterior hypothalamic electrode ipsilateral to the lesion; self-stimulation of the other three rats was normal. These results suggest that self-stimulation in the anterior part of the medial forebrain bundle is supported by long fibers originating in the middle part of the lateral hypothalamus, while self-stimulation in the posterior part of the lateral hypothalamus can be influenced by another system not involved in reward processes observed in the rostral part of the medial forebrain bundle.

Animals↗