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At least 163 records · Page 9Linked to original sources
PubMed2005

Alteration of striatal [11C]raclopride and 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine uptake precedes development of methamphetamine-induced rotation following unilateral 6-hydroxydopamine lesions of medial forebrain bundle in rats.

We studied the positron emission tomography (PET) tracer distributions of ligands for dopamine D1 receptors ([11C]SCH23390) and D2 receptors ([11C]raclopride) and of the dopamine precursor analog 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]FDOPA) in the brain after 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle in rats. The number of methamphetamine-induced rotation was higher at 14 days than at 3 days after the 6-OHDA lesions. The brains of 6-OHDA-treated rats were analyzed by tissue dissection following i.v. bolus of each tracer at 3 days (acute stage) or 3 weeks (chronic stage) postlesion. [11C]Raclopride, but not [11C]SCH23390, showed higher accumulation in the striatum on the lesion side than on the non-lesion (intact) side both at 3 days and 3 weeks postlesion. On the other hand, lower accumulation of [18F]FDOPA was observed in the striatum on the lesion side at 3 days postlesion and in both the striatum and cerebral cortex on the lesion side at 3 weeks postlesion. Our studies demonstrate that an increase in [11C]raclopride and a decrease in [18F]FDOPA uptake in the denervated striatum is evident even at 3 days after the 6-OHDA lesions when the methamphetamine-induced rotational behavior is not established.

Animals↗
PubMed1998

Neurturin protects dopaminergic neurons following medial forebrain bundle axotomy.

To determine whether neurturin (NTN), a recently identified homologue of glial cell line-derived neurotrophic factor (GDNF), is able to preserve tyrosine hydroxylase immunoreactivity (TH-IR) in a rat model of Parkinson's disease, polymer encapsulated cells genetically engineered to release NTN were implanted near the substantia nigra 1 week before a unilateral medial forebrain bundle axotomy. Animals were allowed to survive for 1 week post-axotomy. Upon sacrifice, animals that received a NTN capsule had a significantly higher percentage of TH-IR (lesioned side vs non-lesioned side) than animals that had received a capsule containing non-transfected parent cells. However, in contrast to GDNF, no reduction of turning was observed upon amphetamine rotation with NTN. Nevertheless, these results suggest that NTN might have a therapeutic value for the treatment of Parkinson's disease.

Analysis of Variance↗
PubMed2004

NMDA receptor antagonists ameliorate the stepping deficits produced by unilateral medial forebrain bundle injections of 6-OHDA in rats.

RATIONALE AND OBJECTIVES: To test the hypothesis that excess glutamatergic transmission at NMDA receptors may contribute to the pathogenesis of Parkinson's disease (PD), we examined the effects of various NMDA receptor antagonists on a recently developed rat model of PD. METHODS: Following unilateral injections of 12 microg 6-OHDA into the medial forebrain bundle of male Long Evans rats, stepping with both front paws was measured separately as the paws were dragged backwards and laterally. The effects of i.p. injections of varying doses of L-dopa, the non-competitive NMDA receptor antagonist dizocilpine [(+)-MK-801], the competitive NMDA receptor antagonist CPP, and combinations of L-dopa and NMDA receptor antagonists were then examined on stepping in three separate groups of rats. RESULTS: The lesioned rats stepped less often with their contralateral paw than with their ipsilateral paw, and the magnitude of this stepping deficit was positively correlated with the amount of DA depletion in the ipsilateral dorsal striatum. L-dopa (1-25 mg/kg) dose dependently enhanced stepping with the contralateral paw, and 0.15-0.3 mg/kg dizocilpine and 1.5-6.25 mg/kg CPP enhanced stepping with the contralateral paw as much as did 8 mg/kg L-dopa. The combinations of L-dopa and each of the NMDA receptor antagonists did not significantly improve stepping more than either drug alone. Moreover, none of the drugs completely eliminated the stepping deficits, and high doses began to impair stepping with the ipsilateral paw by inducing turning. CONCLUSIONS: These data indicate that deficits in contralateral stepping are a reliable and sensitive measure of akinesia in unilateral 6-OHDA-lesioned rats, and they support the hypothesis that excess glutamatergic transmission at NMDA receptors may play a role in the expression of PD symptomology.

Adrenergic Agents↗
PubMed1976

Brain stem self-stimulation attenuated by lesions of medial forebrain bundle but not by lesions of locus coeruleus or the caudal ventral norepinephrine bundle.

Midbrain tegmental intracranial self-stimulation (ICSS) was not attenuated by ipsilateral or bilateral locus coeruleus lesions. Certain of these lesions were followed by histochemical confirmation that the majority of locus coeruleus neurons was destroyed, and biochemical evidence that over 80% of the cortical norepinephrine was depleted. To test the possibility that the surviving ICSS was due to stimulation of another norepinephrine system, histochemically verified ipsilateral or bilateral lesions of the ventral norepinephrine bundle were administered to a second group of midbrain tegmental ICSS animals. These lesions resulted in marked loss of body weight, but had no effect on ICSS. In a third experiment, lesions were made in the medial forebrain bundle (MFB) ipsilateral to midbrain tegmental ICSS electrodes. These lesions resulted in attenuation of ICSS which was directly proportional to the extent of MFB damage. On the basis of these data alone, however, it was not possible to identify the ciritical fibers supporting ICSS. It was oncluded that the locus coeruleus does not play a necessary role in midbrain tegmental ICSS.

Animals↗
PubMed1996

The effects of acute and chronic haloperidol treatment on dopamine release mediated by the medial forebrain bundle in the striatum and nucleus accumbens.

The delayed therapeutic effects of neuroleptics have been attributed to D2-mediated depolarization inactivation (DI) of mesolimbic dopaminergic neurons and concomitant reduction in dopamine release. Several studies have suggested, however, that DI may not reduce dopamine release and have hypothesized that this is due to increased impulse independent release. To examine the mechanisms that modulate dopamine release during DI, tetrodotoxin (TTX) was infused into the left medial forebrain bundle (MFB) of Sprague Dawley rats. Three-methoxytyramine (3-MT) levels 10 minutes after pargyline (75 mg/kg) were used as a measure of dopamine release. A dose response study showed that infusions of 10(-5) mol/L and 10(-4) mol/L TTX reduced 3-MT levels on the infused side by 70% in the striatum and 50% to 60% in the nucleus accumbens. In a time course study, 10(-5) mol/L TTX reduced striatal 3-MT at 30, 90, and 120 minutes. After intraperitoneal injections of haloperidol (0.4 mg/kg) for 1 or 21 days, TTX infusions again reduced 3-MT levels by approximately 70% in the striatum and 53% to 59% in the nucleus accumbens on the infused side. Acute and chronic haloperidol treatment did not alter the percent of TTX-induced reductions. These data suggest that dopaminergic neuronal impulse flow modulates similar amounts of total transmitter release after both acute and chronic haloperidol treatment. The results do not support the notion that DI mediates the antipsychotic effects of neuroleptics by markedly reducing total basal dopamine release or increasing impulse independent release. Alternatively, DI could reduce psychotic symptoms by changing the responsiveness of the dopamine system to external stimuli or by reducing synaptic dopamine levels that have been hypothesized to be elevated in psychotic patients.

Animals↗
PubMed1996

Microinjections of phencyclidine (PCP) and related drugs into nucleus accumbens shell potentiate medial forebrain bundle brain stimulation reward.

Microinjections of phencyclidine (PCP) into the ventro-medial portion of nucleus accumbens in rats potentiated the rewarding impact of lateral hypothalamic brain stimulation. Similar effects were found with nomifensine, which shares with PCP the ability to block dopamine uptake and thus elevate synaptic dopamine levels but does not share with PCP the ability to block NMDA receptors. Similar effects were also seen with dizocilpine (MK-801) and [3-((+/-)2-carboxypiperazin-4-yl)propyl-1-phosphonate] (CPP), which share with PCP the ability to block NMDA receptors but not to block dopamine uptake. Thus PCP's properties as a dopamine uptake inhibitor and as an NMDA receptor antagonist each appear capable of producing reward-related actions in this brain region. The common denominator of these two PCP actions is decreased output of medium spiny neurons; these neurons are tonically activated by a glutamate projection from prefrontal cortex (PCP blocks this source of activation) and are tonically inhibited by a dopaminergic projection from the ventral tegmental area (PCP augments this inhibition).

Animals↗
PubMed1989

Forebrain neurons driven by rewarding stimulation of the medial forebrain bundle in the rat: comparison of psychophysical and electrophysiological estimates of refractory periods.

Psychophysically derived estimates of recovery from refractoriness were obtained at self-stimulation sites in the lateral hypothalamus and ventral tegmental area. The refractory periods of single units driven by the same stimulation electrodes and stimulation fields were then measured electrophysiologically. Antidromically driven units with refractory periods longer than those of the neurons responsible for the rewarding effect were concentrated in the septal complex. Units with refractory periods that overlapped the estimates for the reward-related neurons were found in this region as well but were also encountered in neighboring structures lateral, ventral, and/or caudal to the septal nuclei. It is argued that this latter class of units should be considered as possible constituents of the directly stimulated substrate for the rewarding effect because they are driven by rewarding stimulation, have refractory periods similar to those of the reward-related neurons and arise in or near regions in which lesions have been effective in decreasing the rewarding effect of stimulating the medial forebrain bundle.

Animals↗