Library

Notes: BTS 74 398 (1-[1-(3,4-dichlorophenyl)cyclobutyl]−2-(3-diaminethylaminopropylthio)ethanone monocitrate) is a monoamine reuptake inhibitor that reverses motor deficits in MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmosets without provoking established dyskinesia. However, it is not known whether BTS 74 398 primes the basal ganglia for dyskinesia induction. In this study, the ability of BTS 74 398 to sensitize 6-hydroxydopamine (6-OHDA)-lesioned rats for the production of abnormal motor behaviours and the induction of striatal ΔFosB were determined in comparison with l-3,4-dihydroxyphenylalanine methyl ester (l-dopa). Acute administration of BTS 74 398 induced a dose-dependent ipsilateral circling response in unilaterally 6-OHDA-lesioned rats whereas l-dopa produced dose-dependent contraversive rotation. The ipsilateral circling response to BTS 74 398 did not alter during 21 days of administration. In contrast, l-dopa treatment for 21 days caused a marked increase in rotational response. Repeated administration of both l-dopa and BTS 74 398 increased general motor activity and stereotypic behaviour. In l-dopa-treated rats, orolingual, locomotive, forelimb and axial abnormal movements developed whereas BTS 74 398 produced only locomotion with a side bias but no other abnormal movements. Sensitization of circling responses and the development of abnormal movements in 6-OHDA-lesioned rats have been associated with the potential of dopaminergic drugs to induce dyskinesia. Furthermore, striatal ΔFosB immunoreactivity, shown to correlate with dyskinesia induction, was increased by l-dopa but was unaffected by repeated BTS 74 398 administration. The lack of such changes following repeated BTS 74 398 treatment suggests that it may be an effective antiparkinsonian therapy that is unlikely to produce involuntary movements.

Notes: l-3,4-dihydroxyphenylalanine methyl ester (l-DOPA)-induced dyskinesia in Parkinson's disease may result from aberrant glutamatergic stimulation of the striatum due to synaptic plasticity in the motor cortex or striatum as a consequence of adaptation of striatal output pathways. This might result from changes in NMDA receptor subunit or NMDA receptor associated postsynaptic density (PSD) scaffold protein expression. Using immunoautoradiography the expression levels of NR1 and NR2B subunits of the NMDA receptor and the postsynaptic density scaffold proteins, PSD-95, PSD-93, and neurofilament light (NFL) were examined in normal common marmosets (Callithrix jacchus) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned animals that exhibited high or low levels of l-DOPA-induced dyskinesia. Brains from MPTP-lesioned animals that were not primed for l-DOPA-induced dyskinesia were not included in this study. No alterations in the NR1 NMDA receptor subunit were observed. The NR2B NMDA receptor subunit was increased in caudal caudate nucleus and putamen, hippocampus, cingulate motor area (CMA), supplementary motor area (SMA) and dorsal primary motor cortex (dMI) of highly dyskinetic MPTP-lesioned marmosets, but not in animals with low levels of dyskinesia. PSD-93 was decreased in the globus pallidus of marmosets with high and low levels of dyskinesia and increased in the CMA, SMA and dMI of highly dyskinetic marmosets. PSD-95 was increased in the SMA of highly dyskinetic marmosets, but not in animals with low dyskinesia. NFL expression was elevated in the SMA and dorsal and ventral MI of highly dyskinetic marmosets. These results suggest that l-DOPA treatment of MPTP-lesioned marmosets can affect glutamatergic systems and indicate that altered NMDA receptor function may relate to dyskinesia.

Notes: [Auszug] Many dopamine agonists and antagonists have selective actions on D-l and D-2 systems, as determined by adenylate cyclase stimulation4'6 and membrane binding studies7^9, but examination of possible differences in motor, hormonal and other behavioural effects of these compounds in man has proved ...

Notes: [Auszug] We first investigated the changes in the biochemical charac-teristics of striatal dopamine receptors which take place during 12 months' continuous administration of the neuroleptic trifluoperazine dihydrochloride to rats in two separate experi-ments-in one of them the drug was subsequently ...

Notes: [Auszug] THE dialogue between Waddington1 and Martin and Haubrich2 emphasizes the complexity of the interaction between striatal dopamine systems and nigral ?-aminobutyric acid (GABA) mechanisms as recently pointed out by Arnt and Scheel-Kruger3. This is particularly true when interpreting behavioural ...

Notes: Summary The role of efferents in substantia nigra pars reticulata in the mediation of circling behaviour in the rat has been studied by means of lesions designed to interrupt these pathways or to damage nigral projection areas. The behavioural model used was the circling rodent with a prior 6-hydroxydopamine lesion of the left nigro-striatal pathway in which amphetamine induced ipsiversive rotation and apomorphine induced contraversive rotation. Removal of the left fronto-parietal cortex caused only a transient decrease in drug-induced rotation. An electrolytic lesion of the left, right or both parafascicular thalamic nuclei did not alter circling behaviour. Electrolytic lesioning of the left ventromedial thalamus decreased apomorphineinduced contraversive circling whereas a lesion of the right ventromedial thalamus decreased amphetamine-induced ipsiversive rotation. Bilateral electrolytic lesions of the ventromedial thalamus did not alter drug-induced circling. Unilateral or bilateral electrolytic lesioning of the medial superior colliculus did not alter the rotational response to apomorphine or amphetamine. However, an electrolytic lesion interrupting the dorsal tegmental decussation reduced apomorphine-induced circling but not amphetamine-induced circling. That a critical role for the nigro-thalamic and nigro-tectal pathways is not involved in the mediation of circling behaviour was confirmed by placing knife cuts so as to separate these structures from the substantia nigra; such lesions failed to alter the contraversive rotation induced by the ipsilateral injection of muscimol into substantia nigra pars reticulata. Electrolytic lesions of the ipsilateral nucleus reticularis gigantocellu laris or kainic acid lesions of the ipsilateral nucleus tegmenti pedunculopontinus did not alter drug-induced circling in animals with a prior 6-hydroxydopamine nigral lesion. In contrast, an ipsilateral lesion of the midbrain periaqueductal grey matter and adjacent midbrain reticular formation (the angular complex) decreased apomorphine-induced contraversive rotation in such animals, while bilateral lesions reduced both apomorphine-and amphetamine-induced circling; in each case the postural component of rotation was abolished. Unilateral kainic acid lesions of the angular complex in naive animals caused ipsiversive rotation which was enhanced by apomorphine. Unilateral kainic acid lesions of the angular complex with an ipsilateral 6-hydroxydopamine nigral lesion caused reversal of the previous contraversive rotation to apomorphine, and enhanced amphetamine-induced ipsiversive rotation. A nigro-reticular pathway to the midbrain reticular formation adjacent to the periaqueductal grey matter (the angular complex) appears critical in the mediation of the postural component of drug-induced rotation in animals with a prior unilateral 6-hydroxydopamine lesion of the dopaminergic nigro-striatal system. Nigro-thalamic pathways and pathways from nigra to the superficial and medial superior colliculus do not seem to be involved, although we cannot exclude a role for the deep lateral superior colliculus which, in any case, is anatomically and functionally closely related to the midbrain tegmental reticular formation.

Notes: Abstract Rats treated continuously for 4 months with haloperidol (1.4–1.6 mg/kg/day), trifluoperazine (4.5–5.1 mg/kg/day), or sulpiride (102–110 mg/kg/day), but not clozapine (23–26 mg/kg/day), exhibited an increased frequency of chewing jaw movements. Chewing in both control and haloperidol-treated rats was increased by acute administration of the cholinergic agents pilocarpine or physostigmine. Physostigmine or pilocarpine also induced abnormal gaping jaw movements; physostigmine-induced gaping was more prevalent in haloperidol-treated rats than control rats receiving physostigmine alone. Acute administration of the anticholinergic agents scopolamine and atropine decreased chewing in control animals and reduced haloperidol-induced chewing to control values or below. The effects of these cholinergic manipulations suggest that neuroleptic-induced perioral responses in rats do not resemble tardive dyskinesia in man.

Notes: Abstract Administration of haloperidol (1.4–1.6 mg/kg/day) for up to 12 months or sulpiride (102–109 mg/kg/day) for between 6 and 12 months increased the frequency of purposeless chewing jaw movements in rats. N,n-propylnorapomorphine (NPA) (0.25–2.0 mg/kg SC) did not induce hypoactivity in haloperidol-treated rats at any time; sulpiride treatment for 9 and 12 months caused a reduction in the ability of NPA to induce hypoactivity. Haloperidol, but not sulpiride, treatment enduringly inhibited low dose apomorphine effects (0.125 mg/kg SC). After 12 months, sterotypy induced by high doses of apomorphine (0.5–1.0 mg/kg) was exaggerated in haloperidol-, but not sulpiride-treated rats. Bmax for specific striatal 3H-spiperone binding was increased by haloperidol, but not sulpiride, treatment throughout the study. Bmax for 3H-NPA binding was elevated only after 12 months of both haloperidol and sulpiride treatment. Bmax for 3H-piflutixol binding was not alfered by chronic haloperidol or sulpiride treatment. Striatal dopamine-stimulated adenylate cyclase activity was inhibited for the 1st month of haloperidol treatment, thereafter returning to control levels; dopamine stimulation was increased after 12 months of sulpiride treatment. Striatal acetylcholine content was increased after 3 and 12 months of treatment with haloperidol, but was not affected by sulpiride. Chronic administration of sulpiride does not induce identical changes in striatal dopamine function to those caused by haloperidol.

Notes: Abstract Rats received therapeutically equivalent doses of either haloperidol (1.7–1.9 mg/kg/day), sulpiride (112–116 mg/kg/day) or clozapine (30–35 mg/kg/day) continuously for 4 weeks. Treatment with haloperidol, but not sulpiride or clozapine, caused inhibition of stereotyped behaviour induced by apomorphine (0.125–0.25 mg/kg SC). Following drug withdrawal for up to 7 days, haloperidol and sulpiride, but not clozapine treatment caused an exaggeration of stereotyped behaviour induced by apomorphine. Bmax values for striatal 3H-spiperione binding were erevated in animals treated for 2 and 4 weeks with haloperidol, but not with sulpiride or clozapine. Following drug withdrawal, haloperidol, but not sulpiride or clozapine, treatment caused an increase in Bmax for striatal 3H-piperone binding. Bmax values for striatal 3H-NPA binding revealed no change during haloperidol or clozapine treatment. Sulpiride treatment for 1 week caused an increase in Bmax for 3H-NPA binding, which returned to control levels at 2 and 4 weeks. Following drug withdrawal, there was an increase in Bmax for 3H-NPA binding in rats treated with haloperidol and sulpiride, but not clozapine. On continuous treatment and following withdrawal from haloperidol, sulpiride, or clozapine the ability of dopamine to stimulate striatal adenylate cyclase activity did not differ from that in control animals. Repeated administration of sulpiride or clozapine may not induce striatal dopamine receptor supersensitivity when given in clinically relevant doses, although haloperidol does.

Notes: Summary Unilateral kainic acid lesions of the globus pallidus in the rat caused weak spontaneous circling at 3 and 10 days after surgery. Unilateral kainic acid lesions of the entopeduncular nucleus caused no spontaneous circling at any time after surgery. Systemic administration of apomorphine to such lesioned animals caused ipsiversive circling in both groups. Pallidal lesions in animals with a prior ipsilateral 6-OHDA lesion of the medial forebrain bundle attenuated apomorphine-induced, but not amphetamine-induced, circling. Entopeduncular nucleus lesions in the 6-OHDA lesioned animal attenuated both apomorphine- and (+)-amphetamine-induced circling. Kainic acid lesions of the globus pallidus or entopeduncular nucleus did not alter nigral glutamic acid decarboxylase (GAD) activity. Unilateral electrolytic lesions of the globus pallidus or entopeduncular nucleus caused ipsiversive circling in response to apomorphine. An electrolytic lesion of the globus pallidus in animals with a prior 6-OHDA lesion did not alter (+)-amphetamine-induced circling but reversed the direction of apomorphine-induced circling. Electrolytic lesions of the entopeduncular nucleus enhanced (+)-amphetamine-induced circling and attenuated apomorphine-induced circling. Nigral GAD activity was reduced by electrolytic lesions of the globus pallidus but not by those of the entopeduncular nucleus. Large kainic acid lesions in the area of the substantia nigra caused weak spontaneous contraversive circling 3 days after surgery, and ipsiversive circling in response to the systemic administration of apomorphine. Similar lesions in animals with a prior ipsilateral 6-OHDA lesion of the medial forebrain bundle initially attenuated the response to (+)-amphetamine, but the response returned with time. The direction of apomorphine-induced circling was reversed in these animals. The strio-nigral pathway and nigral efferents are confirmed to be involved in circling induced by dopamine agonists in rats with a unilateral lesion of the medial forebrain bundle. Both the globus pallidus and the entopeduncular nucleus also appear to be involved in this dopamine-mediated circling behaviour.