Skilled motor deficits in rats induced by ventrolateral striatal dopamine depletions: behavioral and pharmacological characterization

Rats were tested in an instrumental lever pressing procedure, in which a computer program recorded detailed parameters of responding such as response initiation and duration. Initially, rats with ventrolateral striatal dopamine depletions and control rats were tested on days 3–5 after surgery. Dopamine depletions produced by local injections of 6-hydroxydopamine substantially reduced the number of lever presses emitted. Dopamine depleted animals showed significant increases in average response initiation times, average length of fast initiation times, average length of pauses and total pause time. The distribution of initiation times was altered so that DA depleted rats showed significant reductions in the relative number of very high rate responses and also showed increases in the relative number of pauses. On day 7 after surgery, dopamine-depleted rats received one of three drug treatments: injections of ascorbate vehicle, injections of 20.0 mg/kg

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-DOPA, and injections of 40.0 mg/kg

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-DOPA. Injections of 40.0 mg/kg

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-DOPA led to some improvement in several parameters of instrumental responding. Compared to the previous baseline day, the group that received 40.0 mg/kg

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-DOPA showed a significant increase in number of responses on the drug treatment day, and also showed significant decreases in average response initiation time and total pause time. The group that received 40.0 mg/kg

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-DOPA also showed significant increases in number of responses (expressed as a percent of the previous day) when compared to the control group that received injections of ascorbate vehicle. These results indicate that

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-DOPA can partially reverse the skilled motor deficits produced by ventrolateral striatal dopamine depletions, and suggest that this test may be useful for the assessment of antiparkinsonian drugs.     

Decreased striatal dopamine transporter density in JNCL patients with parkinsonian symptoms

OBJECTIVE: To explore whether striatal dopamine transporters are involved in juvenile neuronal ceroid lipofuscinosis (JNCL) with extrapyramidal signs. METHODS: Seventeen patients with JNCL entered the study (mean age, 15 years; age range, 10 to 31 years). For clinical evaluation, the authors used the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). For studying the density of dopamine transporters in the striatum, they employed iodine-123-labeled 2beta-carbomethoxy-3beta-(4-iodophenyl) tropane as a SPECT tracer. The SPECT images were evaluated visually, and tracer accumulation was semiquantified from transverse slices as striatum-to-cerebellum activity ratios. MRI (1.5-T) signal intensities of the striatum were measured and compared with those of the thalamus. RESULTS: The mean UPDRS score was 20 (range, 2 to 41). On SPECT, the mean striatum-to-cerebellum uptake ratio was lower in patients than in control subjects (3.1 +/- 0.6 versus 6.8 +/- 1.0; p < 0.001), with the decrease being more pronounced in the putamen than in the caudate nucleus. On MRI, the mean striatum-to-thalamus signal intensity ratio was higher in patients than in control subjects (1.14 +/- 0.02 versus 1.08 +/- 0.02; p < 0.001). There was a negative correlation between uptake ratios in SPECT and UPDRS scores, and a positive correlation between the MRI ratios and UPDRS. The SPECT and MRI ratios also correlated significantly, providing additional evidence for the contributions of nigrostriatal, striatal, and thalamic dysfunction to the parkinsonian symptoms. CONCLUSIONS: The observed decrease in the striatal dopamine transporter density in JNCL offers a rational basis for a trial of dopaminergic drugs in this disease.     

Behavioral asymmetries and recovery in rats with different degrees of unilateral striatal dopamine depletion

A detailed behavioral analysis during the first postoperative week was performed in rats which had sustained various degrees of unilateral neostriatal dopamine (DA) lesions by administration of the neurotoxin 6-hydroxydopamine into the substantia nigra. These animals were assigned to different groups according to their residual DA levels in the damaged neostriatum (as percentage of the intact side). On the first day after toxin injection into the substantia nigra, turning asymmetries (tight turns) toward the side of the lesion were observed in animals with a mean residual DA level of 32% or less. Out of these, the strongest asymmetries were observed in animals with a mean residual DA of 3%. After one week, the asymmetry in tight turns had totally recovered except in those groups with mean residual DA levels of 17% or less. Partial recovery was found in animals with mean residual DA of 9 and 17%, whereas no indication for recovery was found in animals with the most severe lesions (mean residual DA 3%). Measurement of thigmotactic scanning also revealed an asymmetry for the side of the lesion on the first post-operative day. This asymmetry was observed over a wider range of DA lesion than that observed in turning, namely up to a mean residual DA level of 78%. Furthermore, recovery to symmetry was observed in all lesion-groups except in those with more severe lesions (mean residual DA 17% or less). In contrast to turning, the strongest asymmetries were not displayed by the animals with the most severe lesions. Furthermore, locomotor activity was affected by the lesion, since on the first postoperative day locomotion was reduced in animals with mean residual DA of 39% or less. On day 7, this lesion-dependent deficit had recovered to control levels. Finally, the analysis of net turns allowed the prediction of lesion size in animals with residual DA levels of less than 15%. These results are discussed with respect to mechanisms of recovery, the role of lesion size, and the value of different behavioral measures to predict the degree of DAergic lesion.     

Lateralized deficits in visual attention in males with developmental dopamine depletion.

Children with early treated phenylketonuria (ETPKU), a disorder associated with developmental dopamine depletion, were tested with a visual orienting paradigm to determine the existence of lateralized deficits in specific attentional operations. Male ETPKU subjects showed a right visual field impairment in disengaging attention, indicating left hemisphere dysfunction, and overall slowed reaction times. Female ETPKU and normal subjects did not differ. The results suggest that for males, dopamine depletion disrupts left hemisphere function. This finding has important implications for disorders with suspected developmental dopamine abnormalities, and may also illustrate how sex differences in functional lateralization develop in the normal brain.     

Effects of dopamine depletion on the spontaneous activity of type I striatal neurons: relation to local dopamine concentration and motor behavior

The relation between the electrophysiological activity of Type I striatal neurons, local dopamine (DA) concentration, and motor behavior in rats was investigated using intraventricular administration of the neurotoxin 6-hydroxydopamine (6-HDA) and extracellular single-unit recording. Results are compared with findings of past experiments in which the activity of Type II striatal neurons was examined after comparable 6-HDA-induced lesions. Several differences between the present observations and the earlier results were found. First, although large depletions (greater than 50%) of DA local to the site of the recording were required before the spontaneous firing rate of either cell type was increased, the levels necessary for this effect were found to be less for Type I cells than for Type II neurons. Second, although DA depletions of greater than 50% always were associated with increased Type I cell activity, depletions of greater than 95% resulted in spontaneous firing rates that were lower than those observed after depletions of approximately 90%. Thus, the relation between extent of dopaminergic depletion and Type I cell firing rate was biphasic, whereas that relation previously was found to be monophasic for Type II neurons. Finally, whereas increased Type I cell activity in the lateral striatum was associated with the aphagia, adipsia, and akinesia induced by large DA-depleting brain lesions, increased Type II cell activity in the medial striatum was found to be associated with these impairments. Because accumulating evidence suggests that the functioning of the lateral striatum is more critical for these behaviors, however, it is proposed that the substrate of the behavioral dysfunctions resulting from DA depletion is the Type I cell population in lateral striatum.     

Neglect of contralateral visual stimuli in monkeys with unilateral striatal dopamine depletion.

Unilateral lesions of the nigrostriatal dopaminergic system were induced by injecting 6-hydroxydopamine into the substantia nigra of three monkeys trained to initiate arm movements in response to stimuli randomly presented at various locations in their immediate visual space. This procedure resulted in partial reduction of dopamine content, as compared to intact side, in both the putamen and caudate nucleus, with the exception of the putamen in one monkey. A concomitant reduction in the level of dihydroxyphenylacetic acid was observed, but less systematically than the dopamine decrease in the same striatal regions. All monkeys displayed a predominant contralateral arm hypokinesia consisting of a slowness in initiating movements, little or not affected by the hemispace of presentation of the trigger stimulus. Conversely, when the monkeys responded with the arm ipsilateral to the lesion, the movement was initiated more slowly when the trigger stimulus was presented to the hemispace contralateral to the striatal dopaminergic depletion as compared to the ipsilateral hemispace. The results suggest that the visual neglect is more conspicuous when monkeys performed with the arm ipsilateral to the damaged nigrostriatal system. This neglect may be described as a disorder in the ease with which stimuli presented to the side contralateral to the impaired dopaminergic transmission are able to elicit behavioral responses, possibly as the result of a lack of selective attention or defective movement initiation.     

Acute intranigral homocysteine administration produces stereotypic behavioral changes and striatal dopamine depletion in Sprague-Dawley rats

Homocysteine has been considered a major risk factor for cardiovascular diseases, and patients with hyperhomocystinemia exhibit neurological and psychological abnormalities. Elevated level of this molecule in the blood of Parkinson's disease patients receiving long-term l-DOPA therapy prompted us to investigate whether homocysteine is neurotoxic to the nigrostriatal dopaminergic system in Sprague-Dawley rats. Animals infused unilaterally with different doses of homocysteine (0.25-1 micromol in 1 microl) intranigrally exhibited significant and dose-dependent decrease in dopamine levels in the ipsilateral striatum as assayed employing an HPLC coupled with electrochemical detector, 19 days post-infusion. While 3,4-dihydroxyphenylacetic acid level in the striatum showed a dose-dependent decrease, homovanillic acid was found to be inhibited only for the highest dose. Amphetamine administration in these animals on the 14th day caused stereotypic turning behavior ipsilateral to the side of infusion. Apomorphine challenge on the 16th day elicited stereotypic contralateral circling behavior. Neurotransmitter levels in the serotonergic perikarya or terminals were unaltered 19 days following intraraphe infusion of homocysteine, which suggested the specificity of its action to dopaminergic neurons. These results indicate nigrostriatal lesions similar to that observed following intranigral infusion of the dopaminergic neurotoxin, 6-hydroxydopamine and suggest its closeness to the parkinsonian animal model. Furthermore, these findings provide evidence for the neurotoxic nature of homocysteine to dopaminergic neurons and suggest that elevated level of this molecule in parkinsonian patients may be conducive to accelerate the progression of the disease.     

Scoliosis in rats with experimentally-induced hemiparkinsonism: dependence upon striatal dopamine denervation.

Rats suffering from experimental hemiparkinsonism induced by a unilateral injection of 6-hydroxydopamine into the left area ventralis tegmenti showed a strong ipsilateral deviation and scoliosis-like skeletal deformity. The rats often showed single rotatory curves affecting the thoracic and lumbar regions, although cases with multiple curves were also found. The severity of the scoliosis was closely related to a decrease in extracellular striatal dopamine measured with microdialysis and to the development of postsynaptic dopamine receptor supersensitivity, functionally evaluated with rotational behaviour elicited with apomorphine. Indeed, rats with the strongest dopamine depletion (greater than 95%) and the strongest rotational responses showed the sharpest spinal deviation and skeletal deformity. These findings agree with the clinical observations that scoliosis occurs in patients with Parkinson's disease and its direction is correlated with the side of the major signs and symptoms of parkinsonism.     

Substantia nigra and pentylenetetrazol threshold in rats: correlation with striatal dopamine metabolism.

The time course of the metrazol threshold in rats with electrolytic lesions of the substantia nigra presents variations inversely proportional to the changes in dopamine and its metabolites in the neostriatum. Thus initially dopamine is increased and the threshold lowered, then a progressive decrease in dopamine and its metabolite is accompanied by a progressive increase in metrazol threshold. This supports the hypothesis that changes in functional activity of the caudate nucleus are reflected in variations of the brain's susceptibility to generalized seizures. When cobalt chloride was injected into the substantia nigra there were biochemical changes in the neostriatum similar to those observed with electrolytic lesions, but the pentylenetetrazol threshold steadily decreased. This is probably due to the fact that cobalt induces a lesion which changes in extent with time to involve adjacent brain stem nuclei sensitive to its epileptogenic action.     

Upregulation of striatal dopamine-2 receptors in Brattleboro rats with prepulse inhibition deficits.

BACKGROUND: Brattleboro rats (BRATs) have natural deficits in prepulse inhibition (PPI) of the startle response similar to those exhibited by schizophrenia patients, which are reversed by antipsychotics. We sought to determine whether they also have increases in striatal dopamine-2 (D2) receptors found in some studies examining the brains of schizophrenia patients. METHODS: Several days after startle testing, the brains of BRAT and Long Evans (LE) rats were removed, and D1 and D2 receptor levels were measured by autoradiography. RESULTS: PPI was lower in BRATs consistent with previous reports. D2, but not D1, receptor binding was significantly higher in the nucleus accumbens shell and the dorsomedial caudate of BRAT compared with LE rats, consistent with some findings in schizophrenia patients. Furthermore, individual rat PPI was inversely correlated with D2 binding density. CONCLUSIONS: These findings suggest that the dopamine system in BRATs is dysregulated and these abnormalities may contribute to the PPI deficits observed in these rats.     

Affective-prosodic deficits in schizophrenia: comparison to patients with brain damage and relation to schizophrenic symptoms [corrected

OBJECTIVE: Although affective prosody seems to be a dominant and lateralised communication function of the right hemisphere, focal lesions of either hemisphere may cause problems with its modulation. When impairment occurs after brain damage, the profiles of affective-prosodic disturbances differ depending on the hemisphere injured. Patients with left brain damage (LBD) improve their performance whereas patients with right brain damage (RBD) do not when the verbal-articulatory demands of the test stimuli are reduced systematically. One of the major arguments for a right hemispheric contribution to schizophrenia has been the documentation of affective prosodic deficits under the assumption that these abnormalities reflect right hemispheric dysfunction. Thus, an essential question to resolve is whether the profile of affective prosodic disturbances in schizophrenia is similar to LBD or RBD, or represents a unique variation. METHODS: Data were collected from four subject groups: 45 chronic, medication-stabilised, schizophrenic patients, 10 patients with focal LBD, nine patients with focal RBD, and 19 controls. All groups were tested on the aprosodia battery, which uses stimuli having incrementally reduced verbal-articulatory demands. Schizophrenic and aphasic symptoms were evaluated using standard assessment tools. RESULTS: For patients with impaired performance on the aprosodia battery, schizophrenic patients were statistically identical to patients with RBD and robustly different from those with LBD. Thirty eight schizophrenic patients (84.4%) were found to have some type of affective prosodic deficit with the predominant pattern indicating, at minimum, right posterior sylvian dysfunction (57.8%). When schizophrenic symptoms and aprosodic deficits were examined using a principal component analysis, affective comprehension and repetition loaded uniquely as separate factors. CONCLUSIONS: The profile of affective-prosodic deficits found in impaired schizophrenic patients is characteristic of RBD, supporting the concept that schizophrenia is a bihemispheric disease process. These deficits may also represent cardinal symptoms of schizophrenia as they are highly prevalent and, except for spontaneous affective prosody, are not associated statistically with traditional clusters of schizophrenic symptoms.     

Nerve terminal degeneration after a single injection of D-amphetamine in iprindole-treated rats: relation to selective long-lasting dopamine depletion

A single injection of D-amphetamine has recently been shown to produce long-lasting dopamine (DA) deficits in rats pretreated with iprindole, an agent which interferes with the metabolism of amphetamine and prolongs its half-life. The basis for these persistent DA deficits has not been determined. The present results suggest that amphetamine produces prolonged DA depletions in iprindole-treated rats by destroying DA nerve terminals.     

Systemic 3-nitropropionic acid: Behavioral deficits and striatal damage in adult rats

Previous animal studies have demonstrated that systemic administration of 3-nitropropfonic acid 3-NP) leads to neuropathological changes similar to those seen in Huntington's disease (HD). Recently, we reported hypeactivity in 6- and 10-week old rats treated with systemic 3-NP OP, 10 mg/kg/day) once every 4 days for 28 days. Although these behavioral results seem to differ from the observed hyperactivity in most excitotoxic models of HD, 3-NP may provide a better model of juvenile onset and advanced HD. In the present study, older rate were similarly treated with 3-NP to further characterize the reported age dependency of striatai neuronal death caused by 3-NP. Hypoactivtty was observed In 14- and 28-week old rats with the latter demonstrating more profound features. The present study also provided the first direct evidence of a 3-NP affect on passive avoidance behavior. Experimental and control animals showed no sigraficant difference in daytime acquisition and retention of a passive avoidance task. However, when the retention tests were conducted during the night time (in contrast to previous daytime tests), 3-NP-treated animals exhibited significant retention deficits. M addition, the neuropathological effects of 3-NP were determined by Nissi, ACNE and NADPH-diaphorase histochemistry. Metabolic activity was studied using cytochroms oxidase activity as an index. Results revealed striatal glial infiltration, lose of intrinsic striatai Cholingergic neurons, but some sparing of large ACNE positive neurons, minimal damage of NADPH-disphorase-containing neurone, and very slight, if any, alterations in cytochrome oxidese activity. In summary, the present results revealed that long-term systemic administration of 3-NP leads to a) an age-dependent hypoactivity, b) a contextual retention deficit in paasive avoidance, and c) a selective destruction of striatal neuronal populations.     

Choline acetytransferase activity and striatal dopamine receptors in Parkinson's disease in relation to cognitive impairment

Brain tissue from 44 patients with Parkinson's disease (PD) and 36 age-matched controls was examined for choline acetyltransferase (ChAT) activity, and for densities of D1 and D2 dopamine receptors. Brain samples were examined for Alzheimer' disease (AD) type changes and for Lewy bodies (LBs), and for apolipoprotein E genotype. Patients were evaluated for the stage of cognitive impairment using Reisberg's global deterioration scale. ChAT activity in PD was reduced in all brain areas examined, being 51% of the control mean in the hippocampus (P<0.001), 57% in the prefrontal cortex (P< 0.001) and 64% in the temporal cortex (P<0.001). The number of LBs had a significant negative correlation with ChAT activity in both prefrontal (r=-0.33, P<0.05) and temporal cortex (r=-0.32, P<0.05). The reduction in ChAT activity in the prefrontal cortex had a significant negative correlation (r=-0.38, P=0.012) with the extent of cognitive impairment. When the CERAD class 'C' was excluded, cognitive impairment correlated significantly with both prefrontal ChAT activity (r=-0.52, P=0.0051) and the density of D1 dopamine receptors in the caudate nucleus (r=-0.40, P=0.037). The number of D1 and D2 dopamine receptors was reduced in both caudate nucleus and putamen in PD patients without neuroleptics as compared to controls. An increased D2 receptor number was found in the caudate nucleus and putamen in PD patients treated with neuroleptics. The present study showed that cognitive decline in PD is associated with reduced ChAT activity in the prefrontal cortex and the D1 dopamine receptor number in the caudate nucleus, even in the absence of AD-type pathology.     

Serotonin depletion during synaptogenesis leads to decreased synaptic density and learning deficits in the adult rat: a possible model of neurodevelopmental disorders with cognitive deficits

Studies in the past have revealed serotonin to play a role in regulating the development and maturation of the mammalian brain, largely through the release of the astroglial protein S-100β. S-100β plays a role in neurite extension, microtubule and dendritic stabilization and regulation of the growth associated protein GAP-43, all of which are key elements in the production of synapses. Depletion of serotonin, and thus of S-100β, during synaptogenesis should lead to a loss of synapses and the behaviors dependent on those synapses. The current study was undertaken to test this hypothesis. In order to assess the influence of serotonin we have looked at the synaptic density in the adult after depletion, by using immunodensitometry of synaptic markers (synaptophysin and MAP-2) and by studying behaviors thought to be highly dependent on synaptic plasticity and density. Male Sprague–Dawley rats were depleted of serotonin on postnatal days (PND) 10–20 by treating with the tryptophan hydroxylase inhibitor parachlorophenylalanine (PCPA; 100 mg/kg, s.c.). On PND's 30 and 62, animals were perfused for immunodensitometry. Littermates were used for behavioral testing. At PND 55–62, the animals were tested in an interchangeable maze with olfactory cues and in an eight-arm radial maze. Our results show a loss of both synaptic markers in the hippocampus on PND 30. At PND 62, the only remaining loss was of the dendritic marker MAP-2. The animals had deficits in both behaviors tested, suggestive of spacial learning deficits and of the failure to extinguish learned behaviors or to re-learn in a new set. Our findings show the long-term consequences of interfering with the role of serotonin in brain development on the morphology and function of the adult brain. These findings may have implications for human diseases, including schizophrenia, thought to be related to neurodevelopmental insults such as malnutrition, hypoxia, viruses or in utero drug exposure. Moreover, they provide further insights into the functioning of serotonin and S-100β in development and aging.     

Intrahippocampal grafts of cholinergic-rich striatal tissue ameliorate spatial memory deficits in rats with fornix lesions.

Previous studies have shown that cholinergic grafts derived from the medial septal nucleus are capable of restoring behavioral function in rats with lesions that sever the cholinergic inputs to the hippocampal formation. In this study, we demonstrate that intrahippocampal grafts of cholinergic-rich striatal tissue also ameliorate spatial memory deficits of rats with fornix lesions. We also found that atropine administration dramatically disrupted spatial navigation performance of rats with striatal grafts and control rats, thus suggesting that the striatal graft effects are mediated by cholinergic mechanisms of action. Measurements of high affinity choline uptake (HACU) and muscarinic receptor binding revealed that intrahippocampal striatal grafts increased HACU and normalized muscarinic receptor binding in animals with fornix lesions. Regression analyses demonstrated significant correlations between the amelioration of spatial memory deficits and hippocampal HACU and receptor binding. We conclude that intrahippocampal grafts of cholinergic-rich striatal tissue can ameliorate spatial memory deficits and that this amelioration is associated with the reinstatement of functional cholinergic terminations.     

Decreased striatal D2 dopamine receptors in obese Zucker rats: changes during aging.

The specific binding of [3H]YM-09151-2 was used to investigate the possible differences in age-associated changes in striatal D2 dopamine (DA) receptor properties in genetically obese (fa/fa) Zucker rats and their lean (Fa/?) littermates. The maximal binding sites (Bmax) of D2 DA receptors was found to decline with age in both obese and lean rats; the rate of decline in receptor Bmax was slightly higher in lean than obese rats. However, the Bmax of D2 DA receptor in 6-, 12- and 18-month-old obese rats was significantly lower compared to the age-matched lean rats. These data indicate that obesity decreases the number of striatal D2 DA receptors without affecting the rate at which receptor number decreases with age.