Comparison of adrenal and foetal nigral grafts on drug-induced rotation in rats with 6-OHDA lesions

Summary Separate groups of rats with unilateral 6-OHDA lesions of the nigrostriatal pathway received intrastriatal foetal (E14) substantia nigra suspension grafts, intrastriatal postnatal (P22–25) adrenal medulla suspension grafts using either collagenaseor trypsin-based dissociation procedures, intraventricular adrenal medulla grafts, or remained with lesions alone. Rats with nigral or adrenal suspension grafts, but not rats with adrenal solid grafts, showed reduced apomorphine-induced rotation in comparison with lesion rats. The nigral graft group alone showed substantial reduction of amphetamine-induced rotation, and this was the only group manifesting good long-term graft survival. These results indicate that nigral and adrenal grafts do not have comparable mechanisms of functional action, and suggest that adrenal grafts can ameliorate apomorphine-induced rotation by a non-specific mechanism.     

Long-term effects of caudate nucleus lesions on body weight in the rat

Lesions placed bilaterally in the caudate nucleus of albino rats produced only small transient depressions in body weight immediately after the operation. However over the following 240 days the lesioned animals grew more slowly and achieved lower and premature asymptotic weights compared to their matched controls. Logical and empirical considerations mitigate against sensory or motor interruption of feeding as a basis of these changes. Rather striatal influences on mechanisms which regulate and control growth are indicated.     

Nigrostriatal reconstruction after 6-OHDA lesions in rats: combination of dopamine-rich nigral grafts and nigrostriatal “bridge” grafts

Summary In an attempt to reconstruct the nigrostriatal dopamine (DA) pathway following 6-hydroxy-dopamine-induced degeneration in adult rats, a novel double graft procedure has been developed. Embryonic DA-rich grafts were implanted in the vicinity of the host substantia nigra by standard procedures. An intracerebral bridge was then implanted by injection of alternative tissues along a single oblique needle penetration through the frontal pole and neostriatum to the substantia nigra. Embryonic striatal tissue bridges provided a continuous column of tissue from the nigral DA graft to the host striatum. In 3 cases, tyrosine hydroxylase immunoreactive fibres grew the full length of the striatal bridge grafts and were seen to penetrate the host neostriatum. In these three animals alone, methylamphetamine-induced rotation was significantly reduced to 44% of the baseline lesion-induced turning rate. Alternative tissues or substrates (embryonic olfactory bulb, cultured astrocytes or laminin-coated microspheres) were not effective in promoting THir fibre growth from the nigral DA grafts to the host neostriatum.     

A comparison of frontal pole, anterior median and caudate nucleus lesions in the rat

Rats with frontal pole cortex, anterior median cortex, caudate nucleus or sham control lesions were tested on activity, spatial reversal learning and delayed response learning. Performance of the lesioned groups of rats was compared with that of higher mammals with frontal and caudate lesions on similar problems. Rats with either type of frontal lesion were significantly more hyperactive than controls during the first hour of testing but were not impaired on reversal or delayed response learning. Caudate lesioned rats were significantly more hyperactive than the frontally lesioned groups, were significantly impaired on the reversal task and showed some indication of impairment on the delayed response task.     

Delayed alternation in cats with lesions of the prefrontal cortex and the caudate nucleus

As in other species which have been examined, ablation of the cortical projection area of the mediodorsal thalamic nucleus in the cat impaired retention of delayed alternation. The same deficit was observed after coagulation of the part of caudate nucleus which is directly connected with the prefrontal cortex. In agreement with previous findings, lesions of the prefrontal cortex impaired cats less than monkeys. Normal cats readily learned delayed alternation in the Nencki Testing Situation.     

Dorsal but not ventral lesions of the caudate nucleus disrupt maze learning in the rat

Learning of a series of Hebb-Williams maze problems was investigated in rats with bilateral lesions of the anterior caudate nucleus. Rats with lesions restricted to the dorsal aspect of the anterior caudate nucleus were significantly more impaired than those with lesions restricted to the ventral aspect of the anterior caudate nucleus. Maze learning performance did not differ significantly between rats with lesions of the ventral caudate nucleus and sham-operated animals. The findings were interpreted as further evidence of the particular importance of the anterodorsal caudate nucleus in the processes of learning and remembering.     

Correlation of evoked potentials in the caudate nucleus and conditioned motor responses

The relevant participation of the caudate nucleus (CN) in motor conditioned responses has been described in different papers. This function could be reflected by changes in its electrical activity. In cats with implanted electrodes in the CN the evoked potentials produced by the conditioned stimulus (light or sound) appeared and increased during the performance of an approaching conditioned response (CR). Extinction of the CR caused decrease in amplitude, while reconditioning had the opposite effect. The potentials did not decrease as long as the conditioning sessions were repeated. The correct performance of the CR was positively correlated at the level of p<0.001 with the amplitude or the appearance of the evoked potentials. The increment of the evoked potentials seems to be independent of the cat's movements since the movements were much more frequent and vigorous during the first training sessions and besides that the increment of the potentials preceded the performance of the CR and persisted during the inhibitory conditioning. The recorded potentials seem to manifest the afferent changes capable of evoking responses in areas not directly connected with the sensory parthways and/or the integration of the information in the CN which subserved the performance of the learned response.     

Methamphetamine-induced Fos expression in the substantia nigra pars reticulata in rats with a unilateral 6-OHDA lesion of the nigrostriatal fibers

In rats with a unilateral 6-hydroxydopamine (6-OHDA)-induced lesion in the nigrostriatal fibers, methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity (FLI), which was inhibited by pretreatment with N-methyl-

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-aspartate antagonist MK-801 (1 mg/kg, i.p.), not only in the medial striatum contralateral to the lesion but also in the substantia nigra pars reticulata (SNr) ipsilateral to the lesion. Thus, hemispheric asymmetries in FLI were induced by methamphetamine in the medial striatum and the SNr in the 6-OHDA model of turning which may be related to the altered function of glutamatergic transmission.     

An electron microscopic study of the developing caudate nucleus in euthyroid and hypothyroid states

Summary Thyroid hormone exerts a powerful influence on CNS growth and maturation. Hypothyroidism early in life has long been known to cause disturbances in innate behavior, motor performance, severe and frequently irreversible mental retardation. In this deficiency, depressed caudate neurogenesis, cell migration and neuropil development during the rapid period of CNS growth may contribute to the clinical picture of perceptual handicaps often seen in cretins. Light microscopic and Golgi studies of the developing caudate nucleus in thyroid deficiency have been carried out to help attain insights into the mechanisms whereby the extrapyramidal system regulates motor function. The ultrastructural study of caudate nuclear cytogenesis and synaptogenesis in normal and hypothyroid states provides more detailed information for further analysis of the problem.Hypothyroidism was induced from birth by adding propylthiouracil to the food and drinking water of lactating dams. Linear development of the caudate nucleus of both normal and hypothyroid rats at ages 8, 14, 20, 30 and 42 days was studied by electron microscopy. Thyroid glands were examined by light microscopy to assess the normal and deficient states.Immature cells, primitive processes and synapses were the characteristic features of the 8-day-old normal caudate nucleus. Distinctively wide cisternae of the rough endoplasmic reticulum, loosely packed Golgi apparatus and chromatin clumps throughout the nuclei of the neurons were significant early morphologic variations. The dramatic cytoarchitectural maturation in the 14- and 20-day normal caudate neuropil points to the rapidity of developmental rate. After the growth spurt of the first three weeks a maturational plateau occurs which is characterized by well-formed neuronal cytoplasmic organelles, myelinated and non-myelinated axons, axon terminals, dendrites and their spines, and synapses.Thyroid deficiency causes a marked maturational delay of approximately 7 days in caudate neuronal proliferation, the elaboration of neuronal networks and the attainment of mature synaptic contents and membranes. This delay is evidenced by comparison of the structural similarities between 8-day-old normal and 14-day-old deficient rats; and additional comparisons between the 14-day-old normal and 20-day-old hypothyroid rats. A rapid catch up process in fine structural morphogenesis takes place in the period between days 14 and 30 in the deficient animals. Repression of thyroid function does not entirely prevent development of the caudate nucleus but allows a fairly extensive, though critically incomplete degree of maturation. This imperfection is manifested by a decrease in the number of synaptic contacts that persists even after the rapid catch up phenomenon of caudate synaptogenesis.Partially supported by USPHS Grant No. HD-05615     

Termination of cortical afferents on identified neurons in the caudate nucleus of the cat

Summary A combined Golgi/electron microscopic technique was used to investigate the fine structure and synaptology of Golgi-stained spiny neurons in the caudate nucleus of the cat. In order to study the termination sites of cortical afferents on Golgistained spiny neurons, cortical fibres were caused to degenerate by making extensive cortical lesions 3 days prior to fixation of the animals.When examined in the electron microscope, perikarya of labelled spiny neurons have a round nucleus, a few mitochondria and microtubules, and a poorly developed Golgi apparatus and rough endoplasmic reticulum. Only rarely are axo-somatic contacts seen. Labelled dendrites exhibit a moderate number of microtubules and sometimes elongated mitochondria. Numerous labelled spines are seen in the vicinity of their parent dendrites. They are contacted by smaller type I and type III boutons and larger type IV boutons (Hassler et al. 1978). Large boutons filled with clear round vesicles establish symmetric contacts with labelled dendritic shafts.Degenerating boutons of cortical afferents are seen in contact with spines and, more rarely, with dendritic shafts of Golgi-stained spiny neurons. All degenerating boutons synapsing with labelled structures are found some distance from the cell body. No contacts of degenerating cortical boutons with the soma or with stem dendrites of Golgi-stained spiny neurons are found.     

Losartan pretreatment reduces neurodegeneration and behavioural symptoms in 6-hydroxydopamine induced unilateral rat model of Parkinson's disease

Losartan is an angiotensin II receptor antagonist which is mainly used to treat hypertension. It has been shown that angiotensin II involves in NADPH-dependent oxidase activation. In this study, the effect of losartan in 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease was investigated. The rats were daily pre-treated i.p. with losartan (90 mg/kg), for the duration of six days before the 6-OHDA injection in the left substantia nigra pars compacta (SNC), until one day afterwards. Losartan administration caused a significant decrease in the rotational and rigidity score in the lesioned rats after 2 weeks. Furthermore, the pretreatment with losartan significantly lowered the value of the markers of oxidative stress after 24 h. Moreover, losartan protected SNC dopaminergic neurons against toxicity of 6-OHDA. The results therefore suggested that losartan pretreatment attenuated the symptoms of Parkinson's disease probably by preventing 6-OHDA induced oxidative stress and neurodegeneration.     

Microinjection of different doses of norepinephrine into the caudate putamen produces opposing effects in rats

It has been proven that norepinephrine (NE) regulates antinociception through its action on alpha-adrenoceptors located in brain nuclei, spinal cord, and peripheral organs. However, the supraspinal mechanism of noradrenergic pain modulation is controversial. The present study was aimed at investigating the nociceptive effects induced by injecting different doses of NE and phentolamine into the caudate putamen (CPU) of rats. The thermal pain threshold of the rats was measured by performing a tail-flick test. The tail-flick latency (TFL) was measured at 2–60 min after microinjection of the drugs. Our results revealed that the thermal pain threshold increased (long TFL) after the administration of a low dose of NE (2 μg/2 μl) and decreased (short TFL) after injection of a high dose of NE (8 μg/2 μl). In contrast, the pain threshold decreased after the administration of a low dose of phentolamine (1 μg/2 μl), while it increased after injection of a high dose of phentolamine (4 μg/2 μl). These results indicated that the injection of different doses of NE in the CPU of the rats produced opposite effects on the pain threshold, as determined by the tail-flick tests.     

Neural pathway mediating somatic evoked responses in the caudate nucleus of cats

The course of somatic afferents to caudate nucleus (CN) was investigated. In curaized cats discrete lesions in intralaminar nuclei, n. centralis medialis (NCM) affect evoked response (ER) in CN to radial nerve stimulation. NCM lesions totally abolish these somatic responses, while after subthalamic lesions ER appear only when a high stimulus intensity is used. Lesions in the specific relay nuclei, ventralis posterior lateralis (VPL) have no effect on somatic ER in CN. Barbiturates (10 mg/kg) abolish somatic ER in CN. Stimulation of the ponto-mesencephalic reticular formation (RF) in a region where visual and somatic responses are recorded shows lowest threshold values for eliciting evoked responses in NCM and CN. The potentials in CN to RF stimulation are restricted to this nucleus and disappear in the internal capsule.     

Dominance behavior in the rat following lesions of the caudate nuclei.

Rats with bilateral lesions of the anterior caudate nucleus or the dorsolateral frontal cortex were tested against sham-operated rats in a straight-alley dominance situation. In 91% of encounters the caudate lesion rats forced the sham-operated animals to retreat. The frontal lesion rats won only 56% of their encounters, a proportion no different to that expected by chance. The performance of the caudate-damaged rats could not be explained satisfactorily in terms of increased motivation, changes in activity, motor impairments, or perseverative tendencies. It seemed more likely that the apparent increase in dominance was associated with changes in the level of aggression.     

Nigral grafts in neonatal rats protect from aphagia induced by subsequent adult 6-OHDA lesions: the importance of striatal location

Summary Previous studies have shown that dopamine-rich nigral grafts, implanted bilaterally into the intact neonatal brain, will provide some protection from the eating disorders induced by subsequent nigrostriatal 6-OHDA lesions. This has been repeated in the present study using unilaterally transplanted nigral grafts. Following adult lesions, the control animals displayed the full syndrome of aphagia, adipsia and akinesia. By contrast, 37% of the rats in the transplanted group recommenced eating following the adult lesion. Recovery was related to the size and position of the graft: protection was associated in particular with transplants located in the posterior-ventral neostriatum. The results are discussed in terms of specific patterns of graft-host interaction that may underlie protection of the regulation of eating from the loss of forebrain dopamine systems.     

Food, water and saccharin solution intake in trats with posterior striatal lesions

Albino rats either received bilateral electrolytic lesions in the posterior striatum or were subjected to a control operation. Striatal damage was not found to influence food intake, water intake, the differential consumption of a saccharin solution and water, or body weight, the data being expressed in relation to preoperative body weight. An interpretation of the results is presented, and their bearing on some previously reported findings is noted.     

Single unit activity in frontal cortex and caudate nucleus of young and old rats

Spontaneous neuronal activity was recorded extracellularly from isolated single units in frontal neocortex and caudate nucleus of young and aged F344 rats anesthetized with urethane. Average firing rates, mean interspike intervals (ISI)±standard deviations, and ISI frequency histograms were computed and analyzed by microprocessor. For frontal cortex cells (N=226), there was a nonsignificant trend toward slower average discharge rates in the old group. However, a significantly longer mean ISI and proportionally more very slow firing cells (<I Hz) were observed in old rats. A laminar analysis of frontal cortex unit activity in young animals showed average discharge rates to be distributed somewhat evenly throughout the cortical mantle with the exception of the zone 1200–1400 μ beneath brain surface. This depth corresponds approximately to layer V where a 50% increase in mean firing rate in young animals was observed. In aged animals, this increased cell firing in layer V was absent, while mean discharge rates in other laminae remained essentially the same in the young and old rat groups. Caudate nucleus cells (n=70) showed a significant shift towards fewer fast discharging cells in old rats, with the average firing rate diminished by one-third. Although more brain regions need to be examined in a similar fashion, the consistency of the present results with those previously reported for the brainstem and cerebellum suggests that slower firing rates and longer ISIs are likely to be wide-spread throughout the brains of aged rats.     

Lack of centripetal connection between the lateral olfactory tract and the caudate nucleus. Evoked potential study in the rat

Summary In rats under alpha-chloralose or without general anesthesia the effect of a lateral olfactory tract stimulus on the caudate nucleus electric activity was explored by bipolar macroelectrodes. The stimulation effectiveness and the reactivity of recording sites to somatic stimuli were systematically tested. Under these conditions, no functional connection from the lateral olfactory tract to the caudate nucleus was demonstrated.     

Degeneration of pre-labelled nigral neurons induced by intrastriatal 6-hydroxydopamine in the rat: behavioural and biochemical changes and pretreatment with the calcium-entry blocker nimodipine

Intrastriatal application of 6-hydroxydopamine (6-OHDA) initiates a delayed and progressive loss of nigral dopaminergic neurons and therefore may better resemble the slowly developing neuropathology of Parkinson’s disease. We investigated the anatomical, behavioural and biochemical consequences of intrastriatal 6-OHDA after prior labelling of nigral dopaminergic neurons in rats and whether the dihydropyridine L-type calcium channel blocker nimodipine protected from the induced deficits. Adult rats received bilateral intrastriatal injections of the retrograde fluorescence tracer fluorogold and nimodipine (n=12) or placebo (n=9) pellets implanted subcutaneously. One week later all rats were injected unilaterally with 6-OHDA (20 μg) at the same intrastriatal site. Placebo-treated rats displayed relatively few d-amphetamine-induced ipsilateral net rotations (R) (1.3±1.4 R/min; mean±SEM) 1 week after the lesion with a slight but non-significant decline thereafter (after 2, 3 and 4 weeks). In nimodipine-treated rats the rotation behaviour after 1 week was more prominent (3.5±0.8 R/min; mean±SEM) with a similar slight decline until week 4. Fluorescent and immunocytochemical analysis of the midbrain after 4 weeks revealed a 35% and 39% loss of tyrosine hydroxylase positive cells and a 62% and 56% (placebo and nimodipine, respectively) loss of fluorogold-labelled cells in the ipsilateral substantia nigra pars compacta. Striatal dopamine levels were reduced to 47% (placebo) and 43% (nimodipine) of the control side and the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid to about 50%. Pretreatment with nimodipine failed to antagonize or to ameliorate any of the lesion-induced deficits. We conclude that pretreatment with 80 mg nimodipine pellets does not prevent nigrostriatal damage induced by intrastriatal 6-OHDA. Received: 5 August 1996 / Accepted: 20 March 1997     

Apomorphine-induced ipsilateral turning in rats with unilateral lesions of the parafascicular nucleus

Summary Apomorphine, 2 mg/kg i.p., produced ipsilateral turning in rats with unilateral lesions in the parafascicular nucleus of the thalamus. The effect was completely blocked by the administration of haloperidol, 0.3 mg/kg i.p. There were no asymmetries by the lesions alone or after administration of haloperidol, 2 mg/kg i.p. to lesioned animals. In control experiments apomorphine produced a marked contralateral turning in animals with unilateral degeneration of the fasciculus retroflexus.Supported by the Swedish Humanities and Social Sciences Research Council (F203/79), The Swedish Medical Research Council (14X-502), Magnus Bergvall Foundation, Albert Nilsson Foundation, and Anna Ahrenbergs Foundation