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Chronic treatment of rat cortical slices with a relative low concentration of mitochondrial inhibitor malonate leads to cortical motoneuron (CMN) death. In the neurodegenerative disease amyotrophic lateral sclerosis (ALS) corticospinal neurons, CMNs projecting to the spinal cord, degenerate. In the present study we compared the effect of chronic mitochondrial inhibition on the survival of CMNs located in the dorsal cortical areas (including corticospinal neurons) with that on ventrally located CMNs (non-corticospinal neurons) in vitro. In the explant culture model used, the dorsally located CMNs were less vulnerable to a 2-week period of mitochondrial inhibition with malonate as compared to ventrally located CMNs. Treatment with 5 mM malonate resulted in 50% surviving CMNs in the dorsal part and only 16% in the ventral part. Neuroprotection of the CMNs could be achieved with co-administration of the non-NMDA antagonist CNQX, the NMDA antagonist MK-801, or the glutamate release inhibitor riluzole, suggesting that chronic energy shortage leads to excitotoxicity. In the dorsal cortical areas CNQX, MK-801, and riluzole had a neuroprotective effect on the CMNs, whereas in the ventral cortical areas only MK-801 was neuroprotective. The sensitivity to energy depletion and consequently excitotoxicity may be related to glutamate receptor density and subunit composition in various cortical areas, but also to the projection length and input of CMNs in vivo. The present investigation gives insight in mechanisms leading to excitotoxic cell death of CMNs and may therefore be important for the development of treatment strategies in protection and survival of cortical motoneurons in ALS.

From a Wistar population two rat lines were generated using as criterion the behavioral response to the dopamine agonist apomorphine. Rats of the apomorphine-susceptible (apo-sus) line revealed a vigorous gnawing response to apomorphine administration while the other rat line, the apomorphine-unsusceptible (apo-unsus) line, was selected for lack of response to the drug. In the present study using the 12th and 13th generation of these genetically selected lines, we have investigated whether this difference in apomorphine responsiveness was correlated with changes in dopamine neurochemistry. Therefore, we measured tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis, as well as dopamine D 1 and D 2 receptor mRNA levels in discrete brain regions by in situ hybridization. Dopamine ( D 2 /D 3 ) receptor binding was assessed with [ 125 I]iodosulpride in a membrane binding assay and by quantitative autoradiography on tissue sections. [ 3 H]SCH 23390 was used to analyze D 1 receptor binding. Apo-sus rats displayed significantly higher TH mRNA levels in the A 9 cell group of the substantia nigra pars compacta and in the A 12 cell group of the arcuate nucleus. No difference was found in the A 10 cell group of the VTA and the A 6 cell group of the locus coeruleus. The density of D 2/3 binding sites as well as D 1 receptor mRNA levels in the striatal projection area of the A 9 substantia nigra neurons, were significantly elevated in apo-sus rats. Dopamine D 2 receptor mRNA and D 1 receptor binding levels in caudate putamen and nucleus accumbens, however, were similar in rats of both lines. In conclusion, high apomorphine susceptibility is related to a potentially enhanced dopamine responsiveness selective for the nigrostriatal and tuberoinfundibular pathways.

The present study investigates the role of corticotropin-releasing hormone (CRH) neurons in stress regulation by a comparison of stress induced Fos-immunoreactivity and CRH-immunoreactivity in the hypothalamic paraventricular nucleus (PVH) of APO-SUS (apomorphine-susceptible), APO-UNSUS (apomorphine-unsusceptible), normal Wistar and adrenalectomized Wistar (ADX) rats. The first two types represent a good model to study the role of the PVH in stress regulation, since they show different stress responses and a differential synaptic organization of the PVH. After placement on an open field for 15 min all rats showed an increase in the number of Fos-immunoreactive nuclei compared to control handling. Interestingly, open field stress, but not control handling, induces significantly fewes Fos-immunoreactive nuclei in the PVH of APO-SUS rats (1255 ± 49) compared to APO-UNSUS rats (1832 ± 201). Experiments with ADX rats revealed that 93% of the CRH-immunoreactive neurons contained a Fos-immunoreactive nucleus, which suggests that the differential Fos-expression in APO-SUS and APO-UNSUS rats represents a differential activation of the CRH neurons. This hypothesis is discussed in relation to reported differences in stress responses, stress-induced ACTH levels and synaptic organization of the PVH.

Previous studies have shown that the feline caudate nucleus contains DPI-sensitive (caput nuclei caudati, anterodorsal part; r-CRM) and DPI-insensitive (caput nuclei caudati, rostromedial part; CRM) regions. Stimulation of dopamine receptors within the r-CRM by dopamine or DPI are known to elicit oro-facial dyskinesia (OFD), i.e. a syndrome of tic-like contractions of the facial muscles in combination with tonque protrusions. OFD is also elicited from the sub-commissural part of the globus pallidus (scGP), a first order output station of the r-CRM, but not from the CRM. On the basis of these data it has been hypothetized that (1) OFD is a specific feature of the r-CRM, but not the CRM; (2) effects elicited from the r-CRM are funneled via the scGP, and that (3) r-CRM and CRM are differentially innervated. Cats were bilaterally equipped with cannulas directed at the CRM or r-CRM and scGP. Following recovery from the operation the cats received bilateral injections of DPI into CRM (5 μg/5μl) or r-CRM (5 and 10 μg/5 μl), the latter in combination with muscimol (50 and 100 ng/1 μl) into the scGP or its solvent. Subsequentl, behaviour was analayzed. OFD, quantified in number of tongue protrusions, was only elicited from the r-CRM, but not from the CRM confirming previously reported data in this respect. Furthermore the effect varied according to the dose used. The OFD elicited from the r-CRM was found to be blocked at the level of the scGP by local injections of muscimol, a GABA agonist. Furthermore it was found that the OFD elicited from the scGP by injections of picrotoxin or carbachol, i.e. a syndrome which was previously studied, was highly comparable with that elicited from the r-CRM. These data together allow the conclusion that effects elicited from the r-CRM such as OFD are anyhow funneled via the scGP. Finally, it was found in retrograde tracing experiments that r-CRM and CRM are differentially innervated by mesencephalic A8 and A9 cells. In sum, the present study provides direct evidence that OFD is a characteristic feature of a particular subregion within the caudate nucleus which has its own input and output channels.

The present study provides a detailed report about similarities and dissimilarities between the effects of neostriatally applied dopaminergic (apomorphine, 250–300 ng; haloperidol, 250–500 ng), cholinergic (carbachol, 50–100 ng; scopolamine, 200–500 ng), and GABAergic (muscimol, 1–2 ng; bicuculline, 5–35 ng) drugs upon swimming behavior or rats. The used swimming test7 consisted of 4 parts: (a) open-field test for analyzing drug-induced changes in normal behavior; (b) ‘swimming without escape’ test for analyzing drug-induced changes in the ability to switch from one type of behavior to another; (c) ‘swimming with escape’ test for analyzing drug-induced changes in the ability to switch from ongoing swimming behavior to climbing behavior by allowing the rats to escape via a rope; and (d) ‘rope’ test for analyzing drug-induced changes in the kind of contact behaviors needed to switch to the latter climbing behavior. In the open-field test the drugs produced neither abnormal behavior nor motor disturbances, which prevented the display of normal behavior in the remaining tests. Both apomorphine and carbachol produced identical effects in all tests. Muscimol produced overall effects which were not only opposite to those of apomorphine and carbachol, but also comparable to those of scopolamine. All effects elicited by apomorphine, carbachol and muscimol were antagonized by their corresponding antagonists; haloperidol, scopolamine and bicuculline respectively, whereas the effects of the latter were suppressed by their corresponding agonists. These data globally show that dopamine and acetylcholine act in the same direction but opposite to that of GABA as far as it concerns the regions investigated. The finding that haloperidol injected into the GABA target area produced effects which were not only similar to those of haloperidol injected into the dopamine target area, but also dissimilar to those of muscimol and bicuculline injected into the GABA target area, shows that the effects were drug-specific rather than region-specific. Though 3 distinct cholinergic regions were investigated, cholinergic-specific effects could only be elicited from one region, suggesting that the neostriatum is heterogeneous in this respect. Finally, well-delineated dissimilarities between haloperidol-, scopolamine-, and muscimol-treated rats were found in the rope test. These data show that behavior-relevant information transmitted by GABAergic drugs surmounted that transmitted by cholinergic drugs which, in turn, surmounted behavior-relevant information transmitted by dopaminergic drugs.

In order to investigate the role of neostriatal dopamine receptors in muscular rigidity we have studied catalepsy and spontaneous muscle tone in rats receiving haloperidol injections into various parts of the neostriatum. It was found that low doses of haloperidol (250-750 ng/0.5 microliter) induced a tonic activity in the EMG of the gastrocnemius-soleus muscle when injected into the most rostral part of the neostriatum (A 8620-9650). This tonic EMG activity was found to be both dose-dependent and dopamine-specific: the haloperidol effect of 500 ng could be inhibited by 500 ng apomorphine. No muscular rigidity could be observed when haloperidol (500 ng/0.5 microliter) was injected further caudally into the neostriatum or into the medial part of the nucleus accumbens. With regard to the haloperidol-induced catalepsy as measured by means of the bar test, a similar distribution of effective and ineffective injection sites was observed; however, higher doses of haloperidol (1.5-2.5 micrograms/0.5 microliter) were required. Thus catalepsy and muscular rigidity were found to be closely related phenomena within the neostriatum. Finally, it is discussed how information relevant to tonic EMG activity is transmitted from the substantia nigra pars compacta to the superior colliculus and the ventromedial thalamus via the neostriatum and the substrate nigra pars reticulata.

Behavioral effects of electrical stimulation of the medial part of the caput caudati were studied in freely moving cats in chronic experiments. These electrically evoked effects were also studied in animals locally pretreated with dexamphetamine, apomorphine, dopamine, 3-methoxytyramine, noradrenaline, serotonin, haloperidol, α -methyl-p-tyrosine, and procaine. Our data show that electrical stimulation of the medial part of the caput caudati results in behavioral responses similar to those evoked by dopamine application into the area, and that these responses are inhibited by blockade of the striatal dopamine system on the one hand, and facilitated by activation of the striatal dopamine system on the other hand. The importance of these data is discussed in view of the hypothesis that dopamine released from the ascending nigro-striatal pathways activates small inhibitory interneurons connecting the medial part with the anteroventral part of the caput caudati.