Median Forebrain Bundle Research Articles

Diffusion and uptake of dopamine in rat caudate and nucleus accumbens compared using fast cyclic voltammetry

Fast cyclic voltammetry was used in the caudate and nucleus accumbens of anaesthetised rats to study the release and reuptake of dopamine following stimulation of the median forebrain bundle. Dopamine uptake was significantly slower in accumbens than caudate, indicating a lower number of functional uptake sites. This implies that dopamine may be able to diffuse further from its sites of release in nucleus accumbens than in caudate and thus may have a neuromodulator role in the region.

Accommodation of rat nigrostriatal dopamine neurones to high frequency electrical stimulation of the median forebrain bundle: in vivo voltammetric data.

The frequency response of nigrostriatal neurones to electrical stimulation of the median forebrain bundle was investigated in vivo using high-speed cyclic voltammetry to measure the evoked striatal dopamine overflow. It was found that the nerves could follow 25-50 Hz stimulation for at least 10 s, whereas the neurones were unable to respond to high frequencies (100-200 Hz) for more than 1-3 s. Accommodation, due to incomplete re-equilibration of ionic fluxes between successive stimuli, provides a possible explanation for these findings.

Presynaptic control of dopamine metabolism in the nucleus accumbens. Lack of effect of buspirone as demonstrated using in vivo voltammetry

Buspirone is a non-benzodiazepine drug with anxiolytic properties. It has been reported to induce a marked increase in the metabolism of dopamine in the striatum and the nucleus accumbens which is similar to that induced by neuroleptics. It has been suggested that the effect observed in the striatum reflects an action of buspirone on dopaminergic autoreceptors in both terminals and cell bodies. In the present study, presynaptic effects of buspirone on dopaminergic metabolism in the nucleus accumbens were investigated, and they were compared to the effects of the classical neuroleptic, haloperidol. Dopaminergic terminals were isolated by infusion of tetrodotoxin into the median forebrain bundle in order to evaluate the effects of buspirone and haloperidol on presynaptic receptors. Changes in dopamine metabolism were determined by in vivo voltammetry. Buspirone administered after interruption of the impulse flow did not affect dopamine metabolism. In contrast haloperidol treatment led to an increase in metabolism of dopamine. It is concluded that buspirone did not act at the presynaptic level and furthermore on dopaminergic autoreceptors.

Naloxone attenuation of the effect of cocaine on rewarding brain stimulation

Antagonism of the threshold lowering effect of cocaine for brain stimulation reward by naloxone was investigated. Rats with bipolar electrodes implanted in either the median forebrain bundle (MFB) or the ventral tegmental area (VTA) were trained on a rate-independent threshold procedure. Effective threshold lowering doses of cocaine (10–15 mg/kg i.p.) were determined for each subject. A moderate dose of naloxone (4 mg/kg i.p.) effectively blocked the threshold lowering action of the cocaine. Lower (2 mg/kg) and higher (8 mg/kg) doses of naloxone attenuated but did not completely block the cocaine effect. These results provide further evidence for a catecholamine/endogenous opioid interaction in central reward.

The relationship between descending serotonin projections and ascending projections in the nucleus raphe magnus: a double labeling study

The nucleus raphe magnus and rostral parts of the nucleus raphe obscurus were found to have extensive efferent projections: a major ascending non-serotonergic (5-HT) projection through the median forebrain bundle, and a descending system consisting of both 5-HT and non-5-HT neurons. Differences in the localizations of their cells of origin suggest that they form two distinct efferent systems from the caudal medullary raphe nuclei.

In vivo voltammetric characterization of low affinity striatal dopamine uptake: Drug inhibition profile and relation to dopaminergic innervation density

Electrical stimulation of the median forebrain bundle evoked dopamine release in the ipsilateral striatum which was monitored with high-speed cyclic voltammetry. After stimulation, the extracellular concentration of dopamine fell due to uptake in a biphasic manner, showing zero-order and first-order components. The zero-order phase corresponded to a V max of 42.8 ± 1.8nmol/min/g tissue. The uptake system could be blocked by d-amphetamine, methylphenidate and nomifensine, but not by benztropine, amfonelic acid or mazindol. The density of uptake sites showed a correlation with the density of striatal dopamine innervation.

Midline B3 Serotonin Nerves in Rat Medulla are Involved in Hypotensive Effect of Methyldopa

Previous experiments in this laboratory have shown that microinjection of methyldopa onto the ventrolateral cells of the B3 serotonin neurons in the medulla elicits a hypotensive response mediated by a projection descending into the spinal cord. The present experiments were designed to investigate the role of the midline cells of the B3 serotonin neurons in the medulla, coinciding with the raphe magnus. In spontaneously hypertensive, stroke-prone rats, microinjection of methyldopa into the area of the midline B3 serotonin cell group in the ventral medulla caused a potent hypotension of 30-40 mm Hg, which was maximal 2-3 h after administration and was abolished by the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) injected intracerebroventricularly. However, intraspinal injection of 5,7-DHT to produce a more selective lesion of only descending serotonin projections in the spinal cord did not affect this hypotension. Further, 5,7-DHT lesion of serotonin nerves travelling in the median forebrain bundle, one of the main ascending pathways from the B3 serotonin cells, did not affect the fall in blood pressure associated with a midline B3 serotonin methyldopa injection. It is concluded therefore that, unlike the ventrolateral B3 cells which mediate a methyldopa-induced hypotension via descending projections, the midline serotonin B3 cells in the medulla contribute to the hypotensive action of methyldopa, either by way of an ascending projection which does not pass through the median forebrain bundle, or through a projection restricted to the caudal brainstem.

Dopaminergic toxicity after the stereotaxic administration of the 1-methyl-4-phenylpyridinium ion (MPP +) to rats

The administration of the 1-methyl-4-phenylpyridinium ion (MPP +) stereotaxically into the left neostriatum or left median forebrain bundle of female rats resulted in a very large and highly significant loss of dopamine and of its metabolites in the left neostriatum. The effect of MPP + on neostriatal dopamine content was in general considerably greater than its effect on serotonin or on several amino acids. These results are consistent with the premise that MPP +, formed from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by the enzyme monoamine oxidase B, may be responsible for the toxicity observed after MPTP administration.

Behavioural effects in the rat after acute unilateral intranigral infusions of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced a dose-dependent contralateral circling in the rat when infused unilaterally into the central region of the pars reticulata of the substantia nigra. This action of MPTP seems to be nigral dopamine-mediated since rotation was potentiated by intranigral amphetamine (50 μg unilaterally) and blocked by haloperidol (5 μg bilaterally) as well as by picrotoxin (5μg bilaterally) and by unilateral lesions of the internal capsule. MPTP was not effective in inducing rotation in rats with unilateral 6-hydroxydopamine lesions of the median forebrain bundle in contrast to intranigral apomorphine which produced robust turning. The data suggest that MPTP may not act as a dopamine receptor agonist but induce rotation by other mechanisms, for example, by enhancing the accumulation of dopamine release from dendrites in the pars reticulata.

Electrochemical, pharmacological and electrophysiological evidence of rapid dopamine release and removal in the rat caudate nucleus following electrical stimulation of the median forebrain bundle

Fast cyclic voltammetry was used to monitor the release of electroactive material in the striatum following electrical stimulation of the median forebrain bundle. The released material was shown to be dopamine by electrochemical, pharmacological and neurophysiological means. The material gave a voltammogram identical to that of iontophoretically applied dopamine but not DOPAC. Release was increased by L-DOPA, the metabolic precursor of dopamine. NSD 1015, an inhibitor of dopa decarboxylase, and α-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor decreased release. Reserpine, which disrupts vesicular dopamine storage, abolished release. Parachlorophenylalanine, a tryptophan hydroxylase inhibitor, had no effect. Finally, square wave stimulation was only effective when pulses longer than 0.5 ms were used. This indicated stimulation of very fine unmyelinated fibres, consistent with the known morphology of nigrostriatal dopamine fibres.

Fluradoline (HP 494), a centrally acting analgesic with antidepressant properties: Antidepressant pharmacology

AbstractFluradoline (HP 494), a tricyclic dibenz (b, f) oxepine derivative with an analgesic profile, was tested for antidepressant activity. After oral administration, fluradoline was twice as potent as imipramine and similar in potency to desmethylimipramine in blocking tetrabenazine‐induced ptosis. Like standard antidepressants, fluradoline selectively increased response rates for electrical stimulation of the median forebrain bundle using internal capsule‐lesioned rats. Response rates in nonlesioned rats were unaffected. There was partial protection against yohimbine toxicity and no potentiation of 5‐hydroxytryptophan‐induced seizures in mice. When administered to squirrel monkeys, the EEG profile from cortically‐placed electrodes resembled that found for imipramine. Using in vivo and in vitro techniques, it was shown that fluradoline was not a monoamine oxidase inhibitor; however, the compound did block the reuptake of norepinephrine, serotonin and dopamine in brain homogenates. These results suggest that in addition to the analgesic profile, there is a concomitant antidepressant profile which may enhance the spectrum of activity of fluradoline.

Autoradiographic localization of tetrodotoxin-sensitive Na+ channels in rat brain.

The localization of tetrodotoxin-sensitive Na+ channels in rat brain was studied using a tritiated derivative of tetrodotoxin. The autoradiographic distribution of a tritiated ethylenediamine derivative of tetrodotoxin [( 3H]en-TTX) binding showed a high concentration of sites in cortical layers, hippocampus, globus pallidus, substantia nigra and the molecular layer of the cerebellar cortex. Lower levels were found principally in the striatum and median forebrain bundle. The white matter was not labelled. The characteristic distribution of tetrodotoxin-sensitive Na+ channels was compared to that of nitrendipine-sensitive Ca2+ channels and to that of apamin-sensitive Ca2+-dependent K+ channels.

Striatal dopamine uptake in the rat: In vivo analysis by fast cyclic voltammetry

Electrical stimulation of the median forebrain bundle of the chloral hydrate anaesthetised rat evoked dopamine release in the ipsilateral striatum, which was monitored with fast cyclic voltammetry. On cessation of stimulation, the extracellular concentration of dopamine fell to sub-detectable levels over a period of about 15 s. This fall appeared to be due to a saturable, low affinity uptake system that could be inhibited by nomifensine (20 mg/kg i.p.). These experiments constitute the first characterisation of a dopamine uptake mechanism obtained in the intact animal.

The effects of putative 5-hydroxytryptamine receptor active agents on d-amphetamine self-administration in controls and rats with 5,7-dihydroxytryptamine median forebrain bundle lesion

Animals in which 5,7-dihydroxytryptamine (5,7-DHT) was bilaterally injected into the median forebrain bundle (MFB) and sham lesioned animals were allowed access to an apparatus which delivered, upon lever pressing, intravenous d-amphetamine injections. MFB lesioned rats achieved stable self-injections patterns and self-administered more drug per test session than controls. A number of agents known to either directly or indirectly affect 5-hydroxytryptamine (5-HT) receptor function were administered prior to d-amphetamine access. The responses to these pretreatments in lesioned vs non-lesioned rats were markedly different. Pretreatment with l-tryptophan reduced the number of d-amphetamine self-injections in sham lesioned rats but had no effect in MFB lesioned animals. Fluoxetine pretreatment, likewise, reduced responding in non-lesioned rats and had no observable effect in lesioned animals. Quipazine markedy reduced self-injection in control rats but was not evaluated in the lesioned group. The putative 5-HT antagonists utilized, cyproheptadine and methysergide, unpredictably reduced self-injection frequency of non-lesioned animals in a dose related manner. When MFB lesioned animals were pretreated with cyproheptadine, rapid bursts of lever pressing were observed and 3 of 6 animals thus treated died as a result (presumably amphetamine overdose). In the remaining animals, methysergide produced a similar marked increase in self-injection rate. While these data may suggest that, in some instances, non-serotonergic mechanisms are involved, for the most part it would appear that 5-HT containing neurons are of major import in some aspect of d-amphetamine self-administration.

Evidence that nigral substance P controls the activity of the nigrotectal GABAergic pathway

The unilateral intranigral application of either of two substance P (SP) analogs with antagonist properties ([ dPro 2, d-Phe 7, d-Trp 9]-SP and [ d-Pro 2, d-Trp 7,9]-SP) induced a significant (37%) decrease in GABA turnover in the target region of the nigrotectal projections, namely the deep layers of the superior colliculus in the homolateral hemisphere, and was without any effect in the superficial layers. This action was not prevented by coinjection of the GABA antagonist bicuculline-methiodide. There was no effect of these SP analogs on GABA turnover in the deep layers of superior colliculus when they were microinjected in the ipsilateral median forebrain bundle or in the contralateral substantia nigra. These results are consistent with the proposal that nigral SP exerts a tonic excitatory action on efferent GABAergic projections from pars reticulata of substantia nigra.

Location of adenosine release and adenosine A2 receptors to rat striatal neurons

Three types of striatal lesions were performed to determine the site of adenosine synthesis and release and the location of adenosine A2 receptors: decortication; injection of 6-hydroxydopamine (6-OHDA) into the median forebrain bundle; and injection of kainic acid into the striatum. The parameters measured in the striatum were content of adenosine, activation of adenylate cyclase by N 6-(L-phenylisopropyl) adenosine (PIA) and release of endogenous adenosine from a perfused slice. Decortication and 6-OHDA had only minimal affects on the parameters measured. In contrast, kainic acid injection into the striatum decreased the content of adenosine, the release of adenosine from a slice preparation and diminished the ability of PIA to activate adenylate cyclase. We postulate that neurons which synthesize and release adenosine, originate in the striatum. The adenosine receptors appear to be of the adenosine A2 type and they may be located on adjacent neurons or on the adenosine releasing neurons themselves.

Localization of GRF-like immunoreactive neurons in the rat brain

The localization of human GRF 1–44-immunoreactive neurons was studied in the rat brain. A dense accumulation of GRF-containing fibers was noted in the external layer of the median eminence. Cell bodies were observed in colchicine-treated rats. The most intensely fluorescent cluster of cells was contained in the arcuate nucleus. Other cells were seen on the base of the hypothalamus, within the median forebrain bundle, dorsal and ventral aspects of the ventromedial nucleus, zona incerta and dorsal part of the dorsomedial nucleus. These cells may influence the pulsatile release of pituitary growth hormone.

An electrophysiological study of the forebrain projection of nucleus commissuralis: Preliminary identification of presumed A2 catecholaminergic neurons

Using a double-labeling technique (HRP combined with catecholamine fluorescence), up to 80% of all CA-containing neurons visualized in the nucleus commissuralis were found to project to or through the median forebrain bundle area (MFB). In addition at least 90% of all nucleus commissuralis neurons projecting through the MFB were found to be catecholaminergic. In a series of chloral hydrate-anesthetized rats, nucleus commissuralis neurons projecting through the MFB were identified with single-unit recordings by antidromic (AD) activation. These cells had a conduction velocity of about 0.5 m/s and a firing rate of 0–14 spikes/s. The pattern of discharge of these neurons was not correlated with the heart rate; they were unaffected by single-unit stimulation applied to the sciatic nerve but were powerfully excited by vagus nerve stimulation. For comparative purposes, NE-containing neurons were also recorded in the locus coeruleus (A6) in the course of the same experiments; in contrast with MFB-activated commissuralis neurons, A6 neurons were excited by both visceral (vagus nerve) and somatic (sciatic nerve) stimulation. The spontaneous firing rate of MFB-activated commissuralis neurons was inhibited by the intravenous administration of a low dose of the centrally acting antihypertensive agent clonidine (ED 50: 28 μg/kg).

Neurogenic hypertension after depletion of norepinephrine in anterior hypothalamus induced by 6-hydroxydopamine administration into the ventral pons: Role of serotonin

Destruction of the ventral noradrenergic pathway elicited by administration of 6-hydroxydopamine (6-OHDA, 5 μg into each side of the ventral pons) reduced the content of norepinephrine (NE) in the anterior hypothalamus (−80%) and induced an increase in arterial blood pressure (ABP) and in heart rate. These hypertensive rats, showed hypersensitivity to the hypotensive effect of NE (0.5–2 μg) and clonidine (0.75–1.5 μg) administered into the anterior hypothalamic preoptic (AH/PO) region. Methysergide (1–2 μg) and, to a lesser extent, ketanserin (1–2 μg) administered into the anterior hypothalamic preoptic region also reduced the arterial blood pressure in these rats treated with 6-OHDA. Bilateral administration of 5,7-dihydroxytryptamine (5,7-DHT, 8 μg) into the median forebrain bundle decreased the content of serotonin (5-HT) in the hypothalamus (−85%) without change in arterial blood pressure but largely prevented the development of hypertension after treatment with 6-OHDA in the ventral pons. These results suggest that neurogenic hypertension is produced after the removal of NE tonic depressor activity in the anterior hypothalamus and that serotonergic mechanisms play a major role in the development of the increased arterial blood pressure in this preparation.

Effect of lesioning dopamine, noradrenaline and 5-hydroxytryptamine pathways on tremorine-induced tremor and rigidity

The effects of lesioning monoamine pathways in the rat brain on tremorine-induced hindlimb tremor and rigidity were studied. Nigro-striatal and mesolimbic dopamine (DA) neurones were lesioned unilaterally by injecting 6-hydroxydopamine (6-OHDA) into the median forebrain bundle. Tremor was reduced in the contralateral leg and rigidity was prevented in the ipsilateral leg. Injection of 6-OHDA into the nucleus accumbens affected tremor but not rigidity. In general, nigral DA neurones may influence rigidity whilst mesolimbic DA neurones affect tremor. A unilateral locus coeruleus electrolesion which destroys noradrenaline (NA) fibres reduced both tremor and rigidity. A median raphe electrolytic lesion affecting 5-hydroxytryptamine (5-HT) neurones had no effect on tremor and rigidity. whereas lesioning the dorsal raphe electrolytically or by injecting 5,6-dihydroxytryptamine prevented rigidity without affecting tremor. Electrical stimulation of the dorsal raphe increased transiently the hindlimb tone of normal rats. The findings demonstrate that the monoamines, especially 5-HT, are differently involved in the mechanisms of tremor and rigidity produced by tremorine.