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PubMed2004

The neurobehavioral changes induced by bilateral rotenone lesion in medial forebrain bundle of rats are reversed by L-DOPA.

Rotenone (an inhibitor of mitochondrial complex I) has been proposed as a model of Parkinson's disease (PD) as it induces nigrostriatal degeneration associated with alpha-synuclein inclusions. So far, only peripherally administered rotenone has been used as a model of PD. There has not been any investigation on the neurobehavioral changes induced by bilateral lesions of dopaminergic neurons by rotenone in rats. In the present study, rotenone (3 microg) was administered bilaterally stereotaxically into the medial forebrain bundle (MFB) to produce parkinsonian symptoms. Behavioural and biochemical data showed a strong increase in catalepsy, a decrease in locomotor activity and a significant depletion of dopamine levels in the striatum as compared to sham-lesioned animals. If the locomotor deficits are caused by the depletion of dopaminergic neurons, then L-DOPA should counteract motor deficits because L-DOPA therapy reverses mostly all motor deficits in human Parkinsonian patients. To examine the effectiveness of L-DOPA in reversing the motor deficit in rats, two different doses of L-DOPA (5 and 10 mg/kg) in combination with the peripheral amino acid decarboxylase inhibitor benserazide were daily administrated intraperitonially for a period of 31 days lesioned animals. L-DOPA plus benserazide counteracted catalepsy dose-dependently and increased locomotor activity. The results indicate that rotenone infused into the MFB destroys dopaminergic neurons, induces pakinsonian symptoms that are reversed by the clinically effective anti-parkinsonian drug L-DOPA. Therefore, sterotaxically infused rotenone may be useful for screening drugs for the treatment of PD.

Analysis of Variance↗
PubMed2004

Voluntary running provides neuroprotection in rats after 6-hydroxydopamine injection into the medial forebrain bundle.

Neurotoxic drugs such as 6-hydroxydopamine (6-OHDA) have been used to mimic a Parkinsonian state in a rat model. The toxic effect of 6-OHDA has been shown to be reduced in rats that were forced to use the impaired limb immediately after unilateral 6-OHDA injection. The aim of this study was to determine whether dopamine neurons in the substantia nigra are spared in rats that exercise voluntary. Two groups of rats were placed in cages with attached running wheels 7 days prior to injection of 6-OHDA (10 microg/4 microL saline) into the medial forebrain bundle. The running wheels of the control group were immobilized for the duration of the study. After 6-OHDA injection, the rats were returned to their respective cages where they remained for a further period of 14 days. Wheel revolutions during free running were recorded daily in the experimental group. At the end of this period the rats were injected with apomorphine (0.5 mg/kg, s.c.) and the number and direction of rotations was recorded. Rats that exercised in the running wheels did not rotate contralaterally in response to apomorphine injection, suggesting that dopamine neurons had been spared sufficiently from the toxic effects of 6-OHDA injection to prevent upregulation of postsynaptic dopamine receptors in the striatum.

Animals↗
PubMed1988

Excitability properties of medial forebrain bundle axons of A9 and A10 dopamine cells.

A9 and A10 units identified as dopaminergic were recorded with extracellular micropipettes. The units were antidromically activated by electrical stimulation at the level of the preoptic area. The absolute refractory periods ranged from 1.2 to 2.5 ms. During the 2-8 ms of the relative refractory period, conduction was slower than normal by up to 1.5 ms. The time constant, C, of the strength-duration curve ranged from 0.4 to 0.6 ms. The current (I)-distance (D) relationship, tested by moving the stimulating electrode past the axon, was approximately parabolic (I = K D exp 2), with the constant of the equation, K, ranging from 900 to 2000 microA/mm exp 2, for 0.5 ms pulses. This relationship allows calculation of the radius of the field of dopamine axon excitation at any current. These high K values show that axons of dopamine cells cannot be activated unless high current densities are delivered, even when electrodes are placed near the axons. These data allow determination of the extent to which dopamine axons can be the directly activated substrates for behaviors, such as self-stimulation and circling, which are evoked by electrical stimulation of the medial forebrain bundle or internal capsule.

Action Potentials↗
PubMed1990

Responses in the diagonal band of Broca, adjacent septal nuclei and the islands of Calleja of cats to stimulation of the subcallosal fornix, medial basal hypothalamus and medial forebrain bundle.

The projection of neurons in the septal nuclei and the insula magna of the islands of Callaja (IC) was explored together with their response to stimulation of the fornix. The septal nuclei all contained neurons projecting in the medial forebrain bundle (MFB). Only the diagonal band of Broca (DBB) and the lateral septal nucleus (LS) contained many neurons projecting toward the medial basal hypothalamus (MBH). The spatial distribution of neurons excited by stimulation of the fornix in the DBB was almost identical with the distribution of neurons projecting toward the MBH and there was considerable overlap (10/28 cells). In the medial septal nucleus the spatial distribution of neurons excited by stimulation of the fornix and neurons projecting in the MFB was similar and there was considerable overlap (6/21 cells). The connectivity of the IC resembled that of the MS but there was little overlap between the neurons excited by fornix stimulation and those projecting in the MFB (1/27 cells). In the LS there were almost equal numbers of neurons projecting in the MFB and toward the MBH but there was very little input from the fornix. Neurons were significantly more often excited by stimulation of the lateral fornix, carrying axons from the subiculum, than they were by medial stimulation exciting axons from Ammon's horn. Axons projecting toward the MBH or in the MFB had conduction velocities less than 1 m/s.

Animals↗
PubMed2000

The immunophilin ligand FK506, but not GPI-1046, protects against neuronal death and inhibits c-Jun expression in the substantia nigra pars compacta following transection of the rat medial forebrain bundle.

The immunophilin ligand FK506 (Tacrolimus) is used for prevention of graft rejection following organ transplantation. FK506 is a high-affinity ligand for FK506-binding proteins, an immunophilin subgroup of peptidyl-prolyl-cis/trans-rotamases abundant in the mammalian brain. Here, we demonstrate that FK506 is a potent survival factor that prevents neuronal cell death following axotomy of central intrinsic neurons. Administration of FK506 (2 mg/kg, s.c., per day for two days pre-axotomy and for up to eight days post-axotomy) effectively delayed and reduced the death of axotomized neurons in the substantia nigra pars compacta following transection of the medial forebrain bundle. In saline-treated controls, 75%, 89% and 92% of nigral neurons died after 25, 50 and 60 days post-axotomy, respectively. In contrast, application of FK506 resulted in survival of 46%, 44% and 28% of the axotomized nigral neurons, and the majority of these surviving neurons showed continuous expression of tyrosine hydroxylase, the pacemaker enzyme for dopamine synthesis. Moreover, FK506 significantly reduced the expression of the inducible transcription factor c-Jun and its N-terminal phosphorylation and prevented the axotomy-induced suppression of the constitutive transcription factor ATF-2 in neurons of the substantia nigra and mammillary body. The latter is also axotomized by the coincident transection of the mammillothalamic tract, but the mammillary neurons survive the axotomy. In contradistinction to FK506, the non-immunosuppressive FK506-binding protein ligand GPI-1046 (25 or 12.5 mg/kg, applied once or twice per day for two days pre-axotomy and for eight days post-axotomy) was completely ineffective for all these parameters investigated. Finally, FK506, but not GPI-1046, impressively accelerated the recovery from surgery. Our data provide the first evidence that FK506 acts as a neuroprotective molecule that rescues axotomized otherwise degenerating central intrinsic neurons in the adult mammalian brain by mechanisms that interfere with the transcriptional program of the axotomy-induced cell body response, such as activating transcription factor-2 suppression and c-Jun expression and phosphorylation.

Animals↗
PubMed1997

GDNF reduces drug-induced rotational behavior after medial forebrain bundle transection by a mechanism not involving striatal dopamine.

Parkinson's disease (PD) is characterized by the progressive loss of the substantia nigra (SN) dopaminergic neurons projecting to the striatum. Neurotrophic factors may have the potential to prevent or slow down the degenerative process occurring in PD. To that end, we examined whether low amounts of glial cell line-derived neurotrophic factor (GDNF) continuously released from polymer-encapsulated genetically engineered cells are able to prevent the loss of tyrosine hydroxylase immunoreactivity (TH-IR) in SN neurons and ameliorate the amphetamine-induced rotational asymmetry in rats that have been subjected to a unilateral medial forebrain bundle (MFB) axotomy. Baby hamster kidney (BHK) cells transfected with the cDNA for GDNF were encapsulated in a polymer fiber and implanted unilaterally at a location lateral to the MFB and rostral to the SN. ELISA assays before implantation show that the capsules release approximately 5 ng of GDNF/capsule per day. One week later, the MFB was axotomized unilaterally ipsilateral to the capsule placement. Seven days later, the animals were tested for amphetamine-induced rotational asymmetry and killed. The striatum was excised and analyzed either for catecholamine content or TH-IR, while the SN was immunostained for the presence of TH-IR. GDNF did not prevent the loss of dopamine in the striatum. However, GDNF significantly rescued TH-IR neurons in the SN pars compacta. Furthermore, GDNF also significantly reduced the number of turns per minute ipsilateral to the lesion under the influence of amphetamine. Improvement of rotational behavior in the absence of dopaminergic striatal reinnervation may reflect neuronal plasticity in the SN, as suggested by the dendritic sprouting observed in animals receiving GDNF. These results illustrate that the continuous release of low levels of GDNF close to the SN is capable of protecting the nigral dopaminergic neurons from an axotomy-induced lesion and significantly improving pharmacological rotational behavior by a mechanism other than dopaminergic striatal reinnervation.

Animals↗
PubMed2002

Effect of bilateral 6-hydroxydopamine lesions of the medial forebrain bundle on reaction time.

Overt symptoms of Parkinson's disease do not manifest themselves until there is a substantial loss of the dopaminergic nigrostriatal projection. However, as neuroprotective strategies are developed, it will be essential to detect the disease in its preclinical phase. Performance on conditioned reaction time tasks is known to be impaired by extensive 6-hydroxydopamine-induced lesions of the nigrostriatal dopamine pathway. However, the effect of smaller lesions on a reaction time task has not been systematically assessed. We, therefore, used this test to examine behavioral deficits as a function of striatal dopamine loss. When injected at doses that produced striatal DA depletion <50%, 6-hydroxydopamine infused in the medial forebrain bundle produced no reliable impairment in the reaction time task. Higher doses producing > or = 60% DA depletion in the striatum produced a decrease in the percent correct responding throughout the 5 week testing period and akinetic deficits expressed by an increase in delayed responding. In addition, larger DA depletions (> or = 95%) profoundly altered motor control with decreases in percent correct responses, increases in delayed responses and increases in reaction time. These results suggest that reaction time may be a relatively sensitive measure of preclinical or subtle deficits, although it might be even more useful in quantitating the severity of depletion once overt deficits or symptoms appear and has the advantage of measuring such deficits over time to follow recovery of function. Furthermore since reaction time deficits required extensive loss of dopamine, these results are consistent with a predominant role of extrasynaptic dopamine in the mediation of relatively skilled motor tasks.

Adrenergic Agents↗
PubMed1982

Behaviorally derived measures of conduction velocity in the substrate for rewarding medial forebrain bundle stimulation.

The results of collision and refractory period tests were used to compute conduction velocity estimates for reward-relevant neurons activated by electrodes aimed approximately 3 mm apart along the trajectory of the medial forebrain bundle (MFB). Collision tests consisted of delivering pairs of pulses in alternating fashion to the lateral hypothalamus and ventral tegmental area. As the interval between pulses was increased the behavioral effectiveness of double-pulse stimulation abruptly increased and then levelled off at longer pulse-pair intervals. In 6 subjects the C-T interval at which the abrupt rise was observed ranged from 1.0 to 3.0 ms. Refractory periods were estimated using an analogous paradigm but with both pulses applied through the same electrode. Recovery was first evident at pulse-pair intervals greater than 0.4-0.6 ms. Conduction velocity was determined for each subject by dividing the interelectrode distance by the difference between the collision interval and the refractory period; a range of 1.0-4.5 m/s was obtained, values that are inconsistent with the reported conduction velocities for catecholaminergic fibers. It is proposed that the substrate for brain-stimulation reward in the MFB consists of small, myelinated, non-catecholaminergic fibers.

Animals↗
PubMed2000

On the altered expression of tyrosine hydroxylase and calbindin-D 28kD immunoreactivities and viability of neurons in the ventral tegmental area of Tsai following injections of 6-hydroxydopamine in the medial forebrain bundle in the rat.

Calbindin-D 28kD is a calcium binding protein reported to protect neurons from degeneration by buffering intracellular calcium. It is expressed in midbrain dopaminergic neurons reported to be relatively resistant to degeneration in Parkinson's disease and certain of its animal models. Lesions of the nigrostriatal pathway produced in rats following injection of 6-hydroxydopamine result in a neurochemical profile similar to that seen in patients with Parkinson's disease. In the present study, brains were processed to exhibit tyrosine hydroxylase- and calbindin-D 28kD immunoreactivities in sections through the ventral mesencephalon at 3, 7, 10, 14 and 21 days after 6-hydroxydopamine had been injected into the medial forebrain bundle. Numbers of ventral mesencephalic calbindin-D 28kD immunoreactive neurons were significantly reduced ipsilateral to the lesions at 3 days post-lesion and, following slight recovery, remained significantly depleted through post-lesion day 21. The densities of calbindin-D 28kD and tyrosine hydroxylase immunoreactive neurons were different only at the 3 day post-lesion time point, when the apparent loss of calbindin-D 28 kD immunoreactive profiles was significantly greater. A lesion-induced increase in the proportion of neurons exhibiting both calbindin-D 28kD and tyrosine hydroxylase immunoreactivities, expected if calbindin-D 28kD is neuroprotective, was observed in the substantia nigra, pars compacta, but not in the ventral tegmental area. It is concluded that, while the observed losses of tyrosine hydroxylase and calbindin-D 28kD immunoreactivities do not necessarily reflect neuronal degeneration, they are not consistent with CB confering a neuroprotective advantage in the ventral tegmental area following 6-OHDA lesions as administered in this study.

Animals↗
PubMed2005

Comparison of 6-hydroxydopamine-induced medial forebrain bundle and nigrostriatal terminal lesions in rats using a lateralised nose-poking task with low stimulus-response compatibility.

Experimental therapies for Parkinson's disease are commonly validated in unilateral rat lesion models using simple tests of motor asymmetry such as rotation. However, the human disorder is considerably more complex than this, and alternative tests that yield a more relevant evaluation of the lesion-induced deficit could provide a powerful behavioural tool for analysis of novel therapies. This study evaluated the potential of a lateralised nose-poking task for detailed assessment of the deficit in rats with complete unilateral and partial nigrostriatal terminal lesions induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) or striatum, respectively. To maximise the task's potential for revealing chronic deficits, a version of the task that requires rats to nose-poke away from visual stimuli associated with food rewards was used. Because of its low stimulus-response compatibility, performance of this version is not mediated by the rats innate tendencies, and thus, is less likely to spontaneously recover after partial lesions. Two weeks and 4 months after lesion surgery, both groups of lesioned rats developed an ipsilateral responding bias with a corresponding drop in contralateral accuracy. Rats with complete (but not partial) lesions also developed a deficit in attempting trials, reacting to stimuli requiring a contralateral nose-poke and executing movements bilaterally. This experiment suggests that the version of the lateralised nose-poking task requiring an arbitrary stimulus-response association may be a powerful behavioural tool for assessment of complete or partial dopamine lesions, and any subsequent dopamine replacement strategy.

Animals↗
PubMed1998

Angiotensin II receptor binding sites in the ventral portion of the bed nucleus of the stria terminalis are reduced by interruption of the medial forebrain bundle.

Many techniques have been utilized to discern the localization of angiotensin II (Ang II) receptors to specific cellular components (glia, neuronal cell bodies and nerve terminals) in the brain. In the present study, we used lesioning techniques to localize Ang II receptors to cellular components in the rat forebrain. In the first experiment, axons ascending to the hypothalamus and forebrain from neurons in the brainstem were destroyed by unilaterally cutting the medial forebrain bundle (MFB). In the second experiment, a single injection of the neurotoxin, ibotenic acid, was injected unilaterally into the ventral portion of the bed nucleus of the stria terminalis (BSTV) to destroy neuronal cell bodies, thus determining if Ang II receptors are present on neuronal cell bodies. In both experiments, the animals were sacrificed after two weeks recovery and the brains processed for in vitro receptor autoradiography using 125I-sar1,ile8 Ang II (125I-SI Ang II). Unilateral knife-cut lesions of the MFB caused a significant reduction in 125I-SI Ang II binding in the BSTV (30+/-6%) and the piriform cortex (PC; 26+/-4%) ipsilateral to the knife cut. Unilateral injection of the neurotoxin into the BSTV failed to alter 125I-SI Ang II binding in this nucleus. These experiments suggest that at least a subpopulation of Ang II receptors in the BSTV and PC are located on terminals of neurons that have their cell bodies in the brainstem and their axons in the MFB.

Animals↗
PubMed2004

Comparison of 6-hydroxydopamine-induced medial forebrain bundle and nigrostriatal terminal lesions in a lateralised nose-poking task in rats.

The nigrostriatal degeneration underlying Parkinson's disease (PD) is commonly modeled in experimental animals by injection of the neurotoxin 6-hydroxydopamine (6-OHDA). Although a wide variety of simple behavioural screens exist to assess the impact of such dopamine lesions, more complex tasks that assess multiple parameters of an animal's performance may provide a more sensitive measure of the resulting functional impairment. This study assessed the performance of two unilateral lesion models of PD in a lateralised nose-poking task in the nine-hole box test apparatus. This task assesses the accuracy and speed of movements to either side of a rats' head, as well as a number of errors of performance. Rats with complete unilateral dopamine depletion (induced by injection of 6-OHDA into the medial forebrain bundle (MFB)) attempted fewer trials and committed more procedural errors than controls. They developed a marked ipsilateral responding bias, with a reduced accuracy for contralateral stimuli. They were also slower to react to contralateral stimuli and to complete movements bilaterally. Rats with unilateral nigrostriatal terminal lesions (induced by multiple injections of 6-OHDA in the striatum) developed a similar pattern of deficits, but they were significantly less impaired and spontaneously recovered to pre-operative levels by 4 months post-lesion. This experiment confirms that the lateralised nose-poking task may be a powerful tool for assessment of the nature of deficit and recovery in rats with complete but not partial unilateral dopamine lesions.

Adrenergic Agents↗
PubMed1986

Evidence implicating descending fibers in self-stimulation of the medial forebrain bundle.

The role of ascending and descending fibers in self-stimulation of the lateral hypothalamus and ventral tegmental area in the rat was assessed by noting whether anodal hyperpolarization of one of these sites could reduce the rewarding effect of stimulating the other site. Strength-duration curves were obtained by psychophysical means, with one of the depth electrodes serving as the cathode and the other as the anode. It was anticipated that at long pulse durations, conduction in some of the fibers stimulated at the cathode would be blocked at the anode. At shorter durations, the anodal hyperpolarization should have dissipated before the arrival of the action potentials triggered by the cathode. Thus, the predicted effect of the block was to bend the strength-duration curves obtained with two depth electrodes upward at long pulse durations, provided that the anode lay between the cathode and the efferent stages of the pathway responsible for the rewarding effect. To control for possible differences in the density of the reward substrate in the lateral hypothalamic and ventral tegmental areas, the strength-duration curves obtained with a given cathode and a depth anode were compared to curves obtained with the same cathode but with an anode consisting of a set of skull screws. It was expected that the concentrated current entering from the depth anode would much more effectively block conduction in the medial forebrain bundle than the diffuse current entering from the large, distant skull screws. The predicted change in the shape of the strength-duration curves was observed only when the ventral tegmental electrode served as the anode and the lateral hypothalamic electrode as the cathode. This is consistent with the notion that in at least some of the neurons responsible for the rewarding effect, action potentials elicited by the lateral hypothalamic electrode had to pass through the ventral tegmental area in order to reach the efferent stages of the reward pathway. In the simplest anatomical arrangement consonant with this view, the somata of these cells lie in the forebrain and give rise to descending axons. As a test of the hypothesis that anodal block was responsible for changing the shape of the strength-duration curve obtained with the ventral tegmental anode, a psychophysical version of the collision test was used to determine whether the tips of the lateral hypothalamic and ventral tegmental electrodes were indeed linked by a common set of reward-related fibers.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1999

Differential regulation of AP-1 DNA-binding activity by D1 and D2 dopamine receptor antagonists in the rat caudate-putamen and globus pallidus following a unilateral 6-OHDA lesion of the medial forebrain bundle.

The effect of D1 and D2 dopamine receptor antagonists on the DNA-binding activity of the AP-1 transcription factor was studied in the rat caudate-putamen and globus pallidus following a unilateral 6-OHDA lesion of the medial forebrain bundle. In the caudate-putamen, vehicle-treated rats showed increased AP-1 DNA-binding activity, which appeared to be reversed completely by treatment with the D1 receptor antagonist SCH23390 (1 mg kg-1 i.p.) and partially by the D2 antagonist sulpiride (50 mg kg-1 i.p.). In the globus pallidus, vehicle and sulpiride did not induce AP-1, while SCH23390 increased it significantly. This induction was much more prominent in the 6-OHDA-lesioned hemisphere than in the intact hemisphere. The present study suggests that in the caudate-putamen, dopamine-depletion induces long-lasting enhancement of AP-1 DNA-binding activity via activation of D1 receptors and the simultaneous activation of D2 receptors facilitate it. However, in the globus pallidus of the 6-OHDA-lesioned hemisphere, D1 but not D2 antagonism induces AP-1 in certain cell populations which may be distinct from those expressing AP-1 upon stimulation of D2 receptors.

Animals↗
PubMed1990

Regulation of the synthesis and metabolism of striatal dopamine after disruption of nerve conduction in the medial forebrain bundle.

1. After physical (knife-cut) or chemically-mediated (tetrodotoxin 300 nM, 1.5 microliters; 1.0 microliters min-1) interruption of nerve conduction in the nigrostriatal tract, there was a marked increase in the synthesis and metabolism of dopamine in the isolated dopaminergic nerve terminals of the striatum. The effect peaked at 4 h post-transection, at which time 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased by 300% and 700% respectively (DOPAC: 27 +/- 13 vs 80 +/- 17 nmol g-1; HVA: 6.66 +/- 3.57 vs 54 +/- 18 nmol g-1). The increases in dopamine content and metabolism are secondary to an increase in the rate of synthesis on the lesioned side, versus the intact, control side. 2. In both experimental situations, haloperidol (1.0 mg kg-1, i.p.) retained its known ability to induce a significant increase in DOPAC and HVA in the striatum, despite the interruption of nerve conduction in the nigrostriatal tract. 3. Six days after cutting the left nigrostriatal tract, dopamine in the left striatum was reduced to less than 5% of the control value, and DOPAC and HVA were not detectable. In the denervated, left striatum, the synthesis of dopamine (from injected L-DOPA), and its metabolism to DOPAC and HVA, occurred to the same degree as in the intact right side. In these DOPA-treated rats, haloperidol (1.0 mg kg-1, i.p.) caused a further increase in DOPAC and HVA in the intact striatum, but not in the denervated striatum. 4. Under non-stressful conditions, using a combination of anaesthetic treatments, electrical stimulation (400 muA, 0.4 ins, 15 Hz, 15 min) of the nigrostriatal tract did not increase DOPAC or HVA in the striatum on the stimulated side. 5. It is concluded (a) that there is a significant presynaptic, and/or local circuit mechanism capable of activating the synthesis and metabolism of dopamine in the isolated, striatal, dopaminergic nerve terminals. Furthermore, haloperidol can act directly on the striatal, dopaminergic nerve terminal, to cause an increase in the synthesis and metabolism of striatal dopamine. (b) After degeneration of the striatal dopaminergic nerves, the denervated striatum retains the ability to synthesize (from L-DOPA) and metabolize dopamine, to the same degree as the intact, innervated, contralateral striatum. (c) When stress is minimized, and release of dopamine is induced by electrical stimulation of the medial forebrain bundle, the catabolism of dopamine (to DOPAC and HVA) during the release-uptake cycle may not be a significant factor under physiological conditions. (d) When dopamine synthesis is increased in the striatum, the normal blood concentration of tyrosine is adequate to sustain the increased synthesis, and precursor availability is not a limiting factor. (e) These results suggest that some of the basic concepts about the neurochemical/neurophysiological regulation of monoaminergic neurones may require further reevaluation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2002

Gamma-aminobutyric acidA and benzodiazepine receptor alterations in the rat brain after unilateral 6-hydroxydopamine lesions of the medial forebrain bundle.

Gamma-aminobutyric acidA (GABA(A)) and benzodiazepine (BZ) receptors and dopamine uptake sites in 6-hydroxydopamine-treated rat brains were studied by receptor autoradiography using [3H]muscimol, [3H]flunitrazepam and [3H]mazindol binding, respectively. The rats were unilaterally lesioned in the medial forebrain bundle and the brains were analyzed at 1, 2, 4 and 8 weeks post-lesion. Degeneration of the nigrostriatal pathway after 6-hydroxydopamine treatment caused a significant loss of dopamine uptake sites in the ipsilateral striatum and substantia nigra (SN) in the lesioned animals. In the contralateral side, however, dopamine uptake sites showed no significant changes in the brain throughout the experiments. On the other hand, no significant changes in GABA(A) receptors were observed in the brain of both the ipsilateral and contralateral sides during post-lesion. In contrast, BZ receptors were observed significantly increased in the ventromedial part of striatum of the ipsilateral side from 2 to 4 weeks post-lesion. Furthermore, a transient increase in BZ receptors was found in the ipsilateral SN only at 2 weeks post-lesion. In contralateral side, most regions examined showed no significant changes in BZ receptors throughout the experiments except for a transient increase in the SN at 1 week post-lesion. These results demonstrate that 6-hydroxydopamine can cause severe functional damage in dopamine uptake sites in the nigrostriatal pathway. Our results also suggest that the change in BZ receptors is more pronounced than that in GABA(A) receptors in the brain after 6-hydroxydopamine treatment. Furthermore, our findings suggest that the increase in BZ receptors in the brain of 6-hydroxydopamine-treated model may be due to the additional disruption of the nigrostriatal dopamine system. Thus, investigations into possible changes in neurotransmitter receptors other than dopaminergic receptors appear to be important for the elucidation of pathogenesis of Parkinsons disease.

Animals↗
PubMed1985

Gamma-aminobutyric acid and benzodiazepine receptor changes induced by unilateral 6-hydroxydopamine lesions of the medial forebrain bundle.

Quantitative autoradiography was used to ascertain alterations in [3H]muscimol, [3H]flunitrazepam (FLU), [3H]naloxone, [3H]D-alanine-D-leucine-enkephalin (DADL), and [3H]spiroperidol binding in basal ganglia 1 week, 4 weeks, and 5 months after unilateral 6-hydroxydopamine lesions of the medial forebrain bundle (MFB) in the rat. At 1 and 4 weeks following lesions, [3H]spiroperidol binding increased 33% in striatum. At 5 months, [3H]spiroperidol was only nonsignificantly increased above control. At 1 week, [3H]muscimol binding decreased 39% in ipsilateral globus pallidus (GP), but increased 41% and 11% in entopeduncular nucleus (EPN) and substantia nigra pars reticulata (SNr), respectively. At 4 weeks, [3H]muscimol binding was reduced 19% in striatum and 44% in GP and remained enhanced by 32% in both EPN and SNr. These changes in [3H]muscimol binding persisted at 5 months. [3H]FLU binding was altered in the same direction as [3H]muscimol binding; however, changes were slower in onset and became significant (and remained so) only at 4 weeks after lesions. Decreases in [3H]naloxone and [3H]DADL binding were seen in striatum, GP, EPN, and SNr. Scatchard analyses revealed that only receptor numbers were altered. This study provides biochemical evidence for differential regulation of striatal GABAergic output to GP and EPN/SNr.

Animals↗
PubMed1998

Medial forebrain bundle lesions fail to structurally and functionally disconnect the ventral tegmental area from many ipsilateral forebrain nuclei: implications for the neural substrate of brain stimulation reward.

Lesions in the medial forebrain bundle rostral to a stimulating electrode have variable effects on the rewarding efficacy of self-stimulation. We attempted to account for this variability by measuring the anatomical and functional effects of electrolytic lesions at the level of the lateral hypothalamus (LH) and by correlating these effects to postlesion changes in threshold pulse frequency (pps) for self-stimulation in the ventral tegmental area (VTA). We implanted True Blue in the VTA and compared cell labeling patterns in forebrain regions of intact and lesioned animals. We also compared stimulation-induced regional [14C]deoxyglucose (DG) accumulation patterns in the forebrains of intact and lesioned animals. As expected, postlesion threshold shifts varied: threshold pps remained the same or decreased in eight animals, increased by small but significant amounts in three rats, and increased substantially in six subjects. Unexpectedly, LH lesions did not anatomically or functionally disconnect all forebrain nuclei from the VTA. Most septal and preoptic regions contained equivalent levels of True Blue label in intact and lesioned animals. In both intact and lesioned groups, VTA stimulation increased metabolic activity in the fundus of the striatum (FS), the nucleus of the diagonal band, and the medial preoptic area. On the other hand, True Blue labeling demonstrated anatomical disconnection of the accumbens, FS, substantia innominata/magnocellular preoptic nucleus (SI/MA), and bed nucleus of the stria terminalis. [14C]DG autoradiography indicated functional disconnection of the lateral preoptic area and SI/MA. Correlations between patterns of True Blue labeling or [14C]deoxyglucose accumulation and postlesion shifts in threshold pulse frequency were weak and generally negative. These direct measures of connectivity concord with the behavioral measures in suggesting a diffuse net-like connection between forebrain nuclei and the VTA.

Animals↗