Induction Of Dyskinesia Research Articles

Dynamic dopamine receptor interactions in the core and shell of nucleus accumbens differentially coordinate the expression of unconditioned motor behaviors.

Many neurochemical and behavioral functions mediated by dopamine require the dynamic interaction between dopamine receptors. We examined the behavioral effects evoked by microinjections of drugs with relative selectivity for specific dopamine receptors into the nucleus accumbens (Acb). The results showed that, at behaviorally inactive doses, the dopamine D1-class receptor agonist SKF 38393 switched the behavioral profile induced by injections of the dopamine D2-class receptor agonist quinpirole into the Acb, from sedation, yawning, and motor inhibition to hyperactive-like behavior. Further, the effects of injections of the dopamine D2-class receptor agonist (+)-PD 128907 into the shell of Acb, including suppression of rearing, locomotion, and grooming, and induction of oral dyskinesia, yawning, and sedation, could not be distinguished from those elicited by (+)-PD 128907 following infusions into the core of Acb. However, the behavioral effects elicited by coadministration of SKF 38393 and (+)-PD 128907 into the core or the shell of Acb showed a striking anatomical specificity. The infusion of SKF 38393 plus (+)-PD 128907 into the core, but not into the shell, of Acb modified the pattern of responses induced by (+)-PD 128907, inducing behavioral hyperactivity. These results suggest critical differences in the functional interaction between dopamine receptors in the core and the shell of the Acb and reveal a mechanism of behavioral switching in the core of Acb by virtue of which dopamine D1-class receptors regulate the transition from states of behavioral suppression to states of heightened psychomotor arousal.

Differential regulation of striatal preproenkephalin and preprotachykinin mRNA levels in MPTP-lesioned monkeys chronically treated with dopamine D1 or D2 receptor agonists.

Studies in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys and in parkinsonian patients show elevated preproenkephalin (PPE) mRNA levels, unaltered by chronic L-DOPA therapy, whereas preprotachykinin (PPT) mRNA levels are decreased by the lesion and corrected by L-DOPA. The relative contributions of the dopamine D1 and D2 receptors for PPE mRNA regulation were investigated in the present study and compared with those for PPT mRNA. In situ hybridization was used to measure peptide mRNA levels in the striatum of MPTP cynomolgus monkeys after chronic 1-month treatment with the D1 agonist SKF-82958, administered subcutaneously in pulsatile or continuous mode, compared with the long-acting D2 agonist cabergoline. Normal as well as untreated MPTP animals were also studied. PPE mRNA levels were elevated in the caudate nucleus and putamen of untreated MPTP monkeys compared with control animals with a more pronounced increase in the lateral as compared with the medial part of both structures. PPT mRNA levels showed a rostrocaudal gradient, with higher values in the middle of the caudate-putamen and more so in the medial versus the lateral parts. PPT mRNA levels were decreased in the caudate and putamen of untreated MPTP monkeys compared with control animals, and this was observed in the middle and posterior parts of these brain areas. Elevated PPE and decreased PPT mRNA levels observed after MPTP exposure were corrected after treatment with cabergoline (0.25 mg/kg, every other day), a dose that had antiparkinsonian effects and did not give sustained dyskinesia. In contrast, elevated PPE mRNA levels observed in untreated MPTP monkeys were markedly increased by pulsatile administration of SKF-82958 (1 mg/kg, three times daily) in two monkeys in which the parkinsonian symptoms were improved and dyskinesias developed, whereas it remained close to control values in a third one that did not display dyskinesias despite a sustained improvement in disability; a shorter duration of motor benefit (wearing off) over time was observed in these three animals. By contrast, pulsatile administration of SKF-82958 corrected the decreased PPT level observed in untreated MPTP monkeys. Continuous treatment with SKF-82958 (equivalent daily dose) produced no clear antiparkinsonian and dyskinetic responses and did not alter the denervation-induced elevation of PPE or decrease of PPT mRNA levels. The present data suggest an opposite contribution of the dopamine D1 receptors (stimulatory) as compared with the dopamine D2 receptors (inhibitory) on PPE mRNA, whereas a similar stimulatory contribution of D1 or D2 receptors is observed for PPT mRNA. An increase in PPE expression could be involved in the induction of dyskinesias and wearing off, whereas our data do not support this link for PPT. The antiparkinsonian response was associated with a correction of the lesion-induced decrease of PPT.

Apomorphine induces changes in GPi spontaneous outflow in patients with parkinson's disease

OBJECTIVE To determine the effect of a single dose of apomorphine on internal globus pallidus (GPi) neuronal discharge in patients with Parkinson's disease (PD). PATIENTS AND METHODS Nine PD patients who underwent microelectrode-guided posteroventral pallidotomy (PVP) were studied. After identification of a single GPi unit discharge with sufficient spike S/N ratio to allow reliable thresholding, basal recording was followed by a single 3-mg subcutaneous injection. One-minute samples were recorded 10′, 30′, and 60′ after apomorphine. RESULTS In four patients, recording was lost after 5–10 minutes. In two, changes were observed at peak-of-dose but recording was then lost, whereas three completed recording and returned to baseline, all five showing significant reduction in GPi firing rate (mean ± standard deviation for basal and post-apomorphine were 143 ± 55.6 and 52 ± 19.2, respectively; p <0.002). CONCLUSION In patients with PD, apomorphine induces changes in GPi spontaneous discharge and modifies firing rates resembling recordings in normal primates. These findings show that clinical improvement as well as induction of dyskinesias following DA administration could be mediated by reduction of GPi outflow.

Apomorphine induces changes in GPi spontaneous outflow in patients with Parkinson's disease.

To determine the effect of a single dose of apomorphine on internal globus pallidus (GPi) neuronal discharge in patients with Parkinson's disease (PD). Nine PD patients who underwent microelectrode-guided posteroventral pallidotomy (PVP) were studied. After identification of a single GPi unit discharge with sufficient spike S/N ratio to allow reliable thresholding, basal recording was followed by a single 3-mg subcutaneous injection. One-minute samples were recorded 10', 30', and 60' after apomorphine. In four patients, recording was lost after 5-10 minutes. In two, changes were observed at peak-of-dose but recording was then lost, whereas three completed recording and returned to baseline, all five showing significant reduction in GPi firing rate (mean +/- standard deviation for basal and post-apomorphine were 143+/-55.6 and 52+/-19.2, respectively; p <0.002). In patients with PD, apomorphine induces changes in GPi spontaneous discharge and modifies firing rates resembling recordings in normal primates. These findings show that clinical improvement as well as induction of dyskinesias following DA administration could be mediated by reduction of GPi outflow.

Preproenkephalin mRNA expression in the caudate-putamen of MPTP monkeys after chronic treatment with the D 2 agonist U91356A in continuous or intermittent mode of administration: comparison with l-DOPA therapy

The effect of chronic treatment with the D 2 dopamine agonist U91356A or l-DOPA therapy on the regulation of preproenkephalin (PPE) mRNA was investigated in the caudate-putamen of previously drug-naive cynomolgus monkeys Macaca fascicularis rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In MPTP monkeys, pulsatile treatment with either l-DOPA or U91356A relieved parkinsonian symptoms but caused progressive sensitization to treatment and, as expected, induced choreic dyskinesias. In contrast, U91356A given in a continuous mode led to partial behavioral tolerance without appearance of dyskinesias. Using in situ hybridization histochemistry, lesioning was shown to produce elevation of PPE mRNA levels in the lateral and medial parts of the putamen and in the lateral part of the caudate nucleus compared to control animals at the three rostrocaudal regions analyzed. In general, no change of PPE mRNA levels were observed in the medial caudate after MPTP lesioning with or without l-DOPA or U91356A treatments in the three rostrocaudal regions measured except for an increase in the caudal part of l-DOPA-treated MPTP monkeys. In the putamen and lateral caudate nucleus, elevated PPE mRNA expression by MPTP generally was not corrected (or only partially corrected) by chronic l-DOPA treatment except for the rostral medial putamen where correction to control values was observed. In general, pulsatile administration of U91356A partially corrected the lesion-induced elevation of PPE mRNA levels in the putamen and lateral caudate nucleus whereas the correction was more pronounced and widespread when MPTP monkeys received the continuous administration of this drug. These results indicate that the mode of administration of a D 2 dopamine receptor agonist, such as U91356A, although at a roughly equivalent dosage influences the extent of inhibition of the expression of PPE in the denervated striatum of monkeys. In addition, the general lack of correction of the MPTP-induced increase of PPE mRNA in the striatum of l-DOPA-treated monkeys compared to the decreases observed with the D 2 agonist treatments suggest that the D 1 agonist component of l-DOPA therapy opposes the D 2 agonist activity. Hence, D 1 receptor agonist activity would stimulate PPE mRNA expression whereas D 2 receptor agonists inhibit the expression of this peptide. Increases in PPE expression in the striatum may be implicated in the induction of dyskinesias since both groups of treated MPTP monkeys displaying dyskinesias had elevated striatal PPE mRNA levels whereas the MPTP monkeys with the lowest striatal PPE mRNA levels developed tolerance without dyskinesias.

D1 dopamine receptor activity of anti-parkinsonian drugs.

Clinical and preclinical investigations suggest that stimulation of D1 dopamine receptors may be responsible for dyskinesias induced by dopamine agonist treatment of Parkinson's Disease (PD), and that these dyskinesias may be decreased by treatment with a D1 antagonist (clozapine). Therefore, the effects of dopamine agonists and antagonists have been investigated in a primary cerebellar granule cell model of cAMP formation that seems to be highly responsive to the D1 receptors. SKF 38393, lisuride, apomorphine, pergolide, dopamine, bromocriptine and 7-OH-DPAT showed concentration-dependent increases in cAMP formation, with EC50s (in microM) of 0.013, 0.053, 0.25, 1.04, 2.18, 50.9 and 54.4, respectively. SKF 38393, apomorphine, dopamine and pergolide had similar intrinsic activity (100%), while the intrinsic activities of 7-OH-DPAT, bromocriptine and lisuride were 28.0%, 20.7% and 17.2%, respectively. SCH 23390, a selective D1 dopamine receptor antagonist, blocked an increase in cAMP formation produced by EC50 concentrations of all of the dopamine agonists investigated in this study. Clozapine concentration-dependently blocked pergolide-induced increases in cAMP and was approximately 1700-fold less potent than SCH 23390 (IC50: 0.97 microM and 0.56 nM, respectively). U-95666A (1-1000 microM), selective for the D2 receptors, showed no significant effect on cAMP, while pramipexole (0.1-100 microM), a D3 preferring agonist, did not elevate cAMP. These data suggest that primary cerebellar granule cell cultures are an excellent model for measuring D1 dopamine receptor-mediated changes in cellular cAMP. The results are discussed with reference to the relationship between the D1 receptor-stimulated increase in cAMP formation and the induction of dyskinesia in humans by these anti-parkinsonian drugs.

The effects of chronic levodopa treatment on pre- and postsynaptic markers of dopaminergic function in striatum of parkinsonian monkeys.

Therapeutic treatment of parkinsonian monkeys by chronic administration of levodopa (l-DOPA) leads to the development of dyskinesias and other motor fluctuations. It is unclear whether there are alterations in the dopamine system that are related to the induction of dyskinesias by l-DOPA, but recent attention has focused on the D1 receptor system. The present study assessed the consequences of chronic l-DOPA treatment in monkeys made parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on indices of the pre- and post-synaptic dopamine (DA) system. Treatment with therapeutic doses of l-DOPA led to the induction of dyskinesias in the MPTP-treated monkeys. High-pressure liquid chromatography was used for measurement of tissue levels of DA and its metabolites, and quantitative autoradiography was used to examine the regional integrity of the presynaptic DA system (by measuring [3H]mazindol binding to DA uptake sites). Quantitative autoradiography was used to measure the number of postsynaptic D1 receptors (using [3H] SCH 23390) in the striatum and pallidum of normal, MPTP alone, and MPTP monkeys treated chronically with l-DOPA. In both MPTP-treated monkeys, levels of DA and metabolites as well as [3H]mazindol binding were greatly reduced in the caudate and putamen, slightly more in dorsal than in ventral areas. However, the lack of increase in striatal DA levels along with higher [3H]mazindol binding in MPTP-plus-l-DOPA-treated monkeys suggested differences in the way DA was used after l-DOPA treatment In MPTP-treated monkeys, a significant increase (141-170% of normals) of D1 receptor numbers was observed in putamen and dorsal caudate. With l-DOPA treatment, the number of D1 receptor numbers was further elevated in caudal putamen (119-123%), dorsal caudate (110-130%), and in the internal segment of the globus pallidus (GPi; 164% of normals) of MPTP-treated monkeys as compared with MPTP treatment alone. This suggested that in MPTP-treated monkeys made dyskinetic by chronic pulsatile delivery of l-DOPA, there was enhanced production of D1 receptors in the direct striatal output to the GPi.

Combined effects of cabergoline and L-dopa on parkinsonism in MPTP-treated cynomolgus monkeys.

The behavioral effects of L-dopa or cabergoline alone were compared with those of the joint administration of the two drugs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity and dyskinesia. Cabergoline alone at 0.2 mg/kg or less improved in a dose-dependent fashion the parkinsonism without inducing hyperactivity and dyskinesia following a single subcutaneous injection. L-dopa alone improved the parkinsonism, but induced hyperactivity and dyskinesia, depending on the dose applied. Doses required for 50% amelioration by L-dopa and cabergoline were 10 and 0.038 mg/kg, s.c., respectively. With low doses (50%-amelioration doses), cabergoline or L-dopa alone improved the parkinsonism without induction of hyperactivity and dyskinesia, but the duration of action was brief. Cabergoline in combination with L-dopa was highly effective in improving motor disability without induction of hyperactivity and dyskinesia. Moreover, the duration of action was more prolonged with the coadministration than with the single administration of each drug. These findings suggest that the combined therapy with low doses of L-dopa and cabergoline is beneficial for treating patients with advanced Parkinson's disease.

Haloperidol and its tetrahydropyridine derivative (HPTP) are metabolized to potentially neurotoxic pyridinium species in the baboon.

The in vivo metabolic fate of haloperidol (HP) and its tetrahydropyridine analog HPTP have been examined in the baboon to investigate the formation of potentially neurotoxic pyridinium metabolites that have been observed previously in humans. Urine samples collected from baboons treated with HPTP were shown to contain, in addition to the parent drug, the corresponding reduced HPTP (RHPTP), generated by reduction of the butyrophenone carbonyl group. RHPTP was characterized by comparison with a synthetic standard using HPLC with electrochemical detection and HPLC/MS/MS. Another compound identified by LC/MS/MS was a glucuronide metabolite of RHPTP. The HP pyridinium (HPP+) and reduced pyridinium (RHPP+) metabolites were shown to be present in urine from both HP and HPTP treated baboons by HPLC using fluorescence detection. The urinary excretion profile of HPP+ and RHPP+ in both groups was essentially identical and, in contrast to that observed in rodents, closely paralleled the profile found in humans treated with HP. These data in the baboon suggest that the metabolic processes involved in the production of the pyridinium metabolites of HP are similar to those in humans. Furthermore, the HPTP-treated baboon may be an appropriate model in which to study the role of pyridinium metabolites in the induction of tardive dyskinesia.

Risk Factors for Peak Dose Dyskinesia in 100 Levodopa-treated Parkinsonian Patients

No clinical parameter other than "sufficient" dopamine denervation and exposure to exogenous levodopa has been unquestionably linked to dyskinesia in levodopa-treated Parkinson's disease patients. We retrospectively analyzed data on 100 consecutive patients treated with levodopa for 1 to 18 years to identify clinical risk factors for dyskinesia. The cumulative dyskinesia-free survival probability in relation to levodopa therapy was assessed using the Kaplan-Meier method. Overall, 56% of patients developed dyskinesia after a mean of 2.9 years, a figure similar to the average duration of levodopa treatment in the non-dyskinetic group. Dyskinetic patients were significantly younger at disease onset, but their mean latency to dyskinesia induction after levodopa initiation was not different from older dyskinetic individuals and the overall dyskinesia-free survival of younger subjects was not worse either. Dyskinetic patients were on a higher daily levodopa dose than non-dyskinetic subjects when dyskinesia emerged, but the cumulative levodopa dose used prior to dyskinesia did not discriminate dyskinetic from non-dyskinetic patients. A delay in initiating levodopa therapy of more than three years after disease onset and levodopa treatment initiation in Hoehn-Yahr stage II compared to stage I patients did not increase the probability of developing dyskinesia over time. Since withholding levodopa therapy did not increase the risk for dyskinesia in our patients and can delay the emergence of dyskinesia after onset of parkinsonian symptom, a trial with a dopaminomimetic agonist as initial treatment appears logical.

Is striatal dopaminergic receptor imbalance responsible for levodopa-induced dyskinesia?

Abnormal involuntary movements (dyskinesias) of variable intensity eventually emerge in the majority of Parkinson's disease patients chronically treated with standard oral levodopa. They create social and physical embarrassment and narrow the therapeutic options normally proposed to improve Parkinsonian symptoms. Thus far, indirect clinical and experimental evidence has implicated the potential role of dopamine D1 receptor activation in the generation of dopa dyskinesia. In recent years, our group has tested several dopaminergic agonists of variable half-life and selectivity in monkeys rendered parkinsonian following toxic exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These monkeys readily develop dyskinesia when treated with levodopa and provide the best animal model to study this complication. Our results in "drug-naive" and "dyskinesia-primed" MPTP animals suggest that pathological sensitisation of D2 receptor-mediated striatal outflow is necessary and sufficient for the induction of dopa dyskinesia, with perhaps a synergistic contribution from D1 receptors, and that repeated short-lived stimulation is important in the sensitisation process. This model supports the hypothesis that more continuous forms of dopaminomimetic therapy represent the best therapeutic approach for Parkinson's disease and calls for the development of novel D1 agonists for further clinical testing.

Mesencephalic grafts partially restore normal nigral dynorphin levels in 6-hydroxydopamine-lesioned rats treated chronically withl-dihydroxyphenylalanine

An increase of dynorphin levels is commonly observed in the substantia nigra of 6-hydroxydopamine-lesioned rats chronically treated with daily injections of L-DOPA. This study investigates the potential of fetal mesencephalic grafts to restore normal levels of dynorphin in such cases. After 19 consecutive days of treatment with L-DOPA, lesioned rats with the most severe nigral cell loss showed increased levels of dynorphin in the substantia nigra ipsilateral to the lesion, as expected. The changes were assessed by standard immunohistochemical techniques combined with the use of an image analysis system. Such changes were not observed in the substantia nigra of rats that received fetal mesencephalic cells in the striatum six months prior to the beginning of the chronic treatment. However, only animals displaying heavy loss of dopaminergic neurons in the substantia nigra pars compacta showed significant changes of dynorphin levels in the substantia nigra following drug treatment. Our results show that fetal nigral cells transplanted into the striatum have the potential to prevent biochemical changes observed in the basal ganglia induced by the lesion of the nigrostriatal pathway and chronic treatment with L-DOPA. It is still hypothesized from studies in rodents that this peptide may play a role in the appearance of DOPA-induced dyskinesia, because dynorphin levels increase in the substantia nigra pars reticulata after L-DOPA treatment. If this happens to be the case, then the use of fetal nigral grafts could therefore be an important step to prevent the induction of dyskinesia after chronic L-DOPA treatment.

Amantadine versus biperiden: A double-blind study of treatment-efficacy in neuroleptic EPS

Anticholinergic treatment of neuroleptic EPS has been associated with induction of tardive dyskinesia. Also an increasing abuse of anticholinergics by schizophrenic patients is noted. Since positive effects of amantadine on neuroleptic EPS have been described as early as 1976, a controlled study of these reports seemed worthwhile. Thirty-five schizophrenic patients in three centres were treated for EPS in a double-blind design: 18 (! 1 m, 7 f) with amantadine (A) and 17 (8 m, 9 f) with biperiden (B). Identical preparations of A (100 rag, rid) and B (2 mg tid) were used in treatment of halopefidol induced EPS (A: mean 22,4 mg haloperidol, B: mean 19,6 mg halopefidol). Effects of treatment and possible side effects were rated: EPS for the intensity of EPS, BPRS for quantification of psychotic symptoms, FSUCL for rating the side effects and KUSTA to document patients mood. Ratings were recorded on days 0, 3, 7, 14, 28 end at discontinuation respectively. All patients were treated with haloperidol and levomepromazine (for tranquilization / sleepinduction) and the respective anti-parkinsonian agent for 4 weeks. Patient characteristics did not differ significantly in either group, in treatment-group A (amantadine) 2 patients dropped out for non-compliance, in group B 5 (3 no effect, I non-compliance, ! agitation). There were no significant differences in results as recorded with the different rating-instruments, notably the treatment-effect of both drags on EPS was similar. Thus, the application of amantadine in cases of neuroleptic EPS seems justified and is a useful alternative to anticholinergic chugs. Certain advantageous aspects of amantadine-treatment of EPS with regard to the glutamate-hypothesis of schizophrenia and tardive dyskinesia are discussed.

Dopamine D 1 receptors in the sub-commissural part of the globus pallidus and their role in oro-facial dyskinesia in cats

The possible role of dopamine D 1 receptors in the sub-commissural part of the globus pallidus in the induction of oro-facial dyskinesia was studied in cats. The present study reveals two findings. Firstly, bilateral injections of the D 1 agonist (±)-SK& F38393 into the ventral pallidal area elicited oro-facial dyskinesia, which was quantified in terms of numbers of tongue protrusions. The results show that the dose-effect curve was bell-shaped (1.0, 1.75, 2.5, 5.0 μg/μ0.5 μl (±)-SK&F 38393). The oro-facial dyskinesia elicited by (±)-SK& F38393 was highly comparable to the oro-facial dyskinesia elicited by injections of the GABA antagonist picrotoxin or the acetylcholine agonist carbachol into the sub-commissural part of the globus pallidus. Secondly, the inactive enantiomer of SK&F38393, i.e. S(-)-SK& F38393, was found to be ineffective in eliciting oro-facial dyskinesia when injected in a dose equivalent to 50% of the most effective dose of the racemic mixture of (±)-SK& F38393. Furthermore, the effect elicited by 2.5 μ/0.5 μl (±)-SK& F38393 was significantly attenuated by local injection of the D 1 antagonist R(+)-SCH23390 in a dose which had no effect itself (1.0 μg/0.5 μl). These findings indicate that the effects elicited by (±)-SK& F38393 are D 1-specific. The present results thus clearly indicate that dopamine D 1 receptors within the sub-commissural part of the globus pallidus are involved in mediating oro-facial dyskinesia in cats.

Nigrostriatal Damage is Required for Induction of Dyskinesias by l-DOPA in Squirrel Monkeys

We examined the ability of L-DOPA to induce dyskinesias in MPTP-treated and normal squirrel monkeys to establish whether the underlying neuropathology associated with parkinsonism is an absolute requirement or merely promotes the development of drug-induced dyskinesias. Administration of L-DOPA (5-40 mg/kg p.o., following a 60 min pretreatment with carbidopa 2.5-20 mg/kg p.o.) induced a range of dopamine-mediated behaviours including locomotor activity, stereotyped scratching, and climbing in both lesioned and nonlesioned animals. However, the dose-response curves showed a marked (three- to fourfold) shift to the left in lesioned animals, indicating behavioural supersensitivity. In contrast, L-DOPA-induced dyskinesias were only observed in MPTP-treated monkeys. Doses required for induction of dyskinesias were lower than those required to induce climbing. These findings provide further evidence that nigrostriatal damage is essential for the genesis of L-DOPA-induced dyskinesias.

Oro-facial dyskinesia and the sub-commissural part of the globus pallidus in the cat: role of acetylcholine and its interaction with GABA.

The possible role of cholinergic mechanisms in the sub-commissural part of the globus pallidus (scGP) in the induction of oro-facial dyskinesia (OFD) was studied in cats. Local injections of the cholinergic agonist carbachol into the scGP elicited tongue protrusions in a dose dependent way (100-1000 ng/0.5 microliters). The effect elicited by 1000 ng carbachol was selectively antagonized by the cholinergic antagonist scopolamine (10 micrograms/0.5 microliters); this dose of scopolamine was ineffective when injected alone. The tongue protrusions resulted from both normal and abnormal movements: whereas normal movements simply consisted of protruding the flat tongue, abnormal movements implied a variety of movements, especially curling upwards the lateral side(s) or tip of the tongue inside or outside the oral cavity. The abnormal carbachol-induced tongue protrusions formed part of a syndrome marked by dyskinetic movements of the muscles of the eye, ear and cheek, and were identical to those seen previously after local injections of picrotoxin (250-500 ng). Intra-pallidal injections of the abovementioned dose of scopolamine had no effect on the tongue protrusions induced by local injections of 375 ng picrotoxin. However, local injections of 100 ng muscimol, which was previously found to attenuate significantly the effect of 375 ng picrotoxin and which was ineffective when injected alone, significantly attenuated the tongue protrusions induced by local injections of 1000 ng carbachol. These data suggest that the cholinergic effects are mediated via a GABAergic mechanism, but not vice versa. The results are discussed in view of GABAergic and anti-cholinergic therapies used in oro-facial dyskinesia.

Biochemical and behavioural properties of clozapine

The selection and early development of clozapine was based upon its gross behavioural, arousal-inhibiting, sleep-promoting, and caudate spindle-prolonging properties. Compared to classical neuroleptics, clozapine causes only a short-lasting elevation of plasma prolactin levels, elevates both striatal homovanillic acid and dopamine content, is devoid of marked apomorphine-inhibitory or cataleptogenic activity and fails to induce supersensitivity of striatal dopaminergic systems after chronic administration. Clozapine's intrinsic anticholinergic activity, while stronger than that of other neuroleptic agents, does not appear to underlie either its failure to induce tardive dyskinesias or its superior antipsychotic activity. Furthermore, the overlap between clozapine and several classical neuroleptics with regard to alpha-adrenergic-, serotonin- and histamine-blocking activity makes it unlikely that one or more of these properties is the key to its atypical characteristics. More recent findings show that clozapine and classical neuroleptics differ with regard to their indirect effects on nigral GABA-ergic mechanisms implicated in the induction of tardive dyskinesias and, possibly in keeping with this, that clozapine and similar agents exhibit preferential blockade of D-1 dopamine receptors in the whole animal. Such an action of clozapine in man could well explain both its low EPS liability and, in some subjects, its superior antipsychotic activity.

Motor fluctuations in Parkinson's disease: central pathophysiological mechanisms, Part II.

The contribution of central pharmacodynamic mechanisms to the pathogenesis of motor fluctuations in advanced Parkinson's disease was studied in 29 patients by evaluating their acute response to intravenously injected levodopa. While the threshold dose for an antiparkinsonian effect did not change, that for induction of dyskinesia showed a progressive reduction in 4 groups: (1) levodopa-naive patients, (2) those with a stable response to oral administration, and (3) those with wearing-off or (4) on-off fluctuations. Concomitantly, the therapeutic window for levodopa narrowed and the levodopa dose-antiparkinsonian response slope increased. The antiparkinsonian threshold dose correlated best with duration of symptoms; the dyskinesia threshold dose, therapeutic window, and dose-response slope related most closely with the duration of levodopa treatment. The differing dose-response profiles for the antiparkinsonian and dyskinetic effects suggest involvement of separate pharmacological mechanisms. The present results, taken together with previous observations that the wearing-off phenomenon responds promptly to plasma levodopa stabilization while on-off fluctuations tend to diminish over several days, suggest that postsynaptic modifications, presumably at the receptor level, serve as the major determinant for the increasing difficulty with optimal dose adjustment and the motor fluctuations, especially of the on-off type, which complicate levodopa therapy of patients with advanced Parkinson's disease.

Kindling: a model for the development of tardive dyskinesia?

Tardive dyskinesia (TD) from long-term neuroleptic treatment may be irreversible; therefore prevention has become a major concern. A controversial issue with regard to the clinical use of neuroleptic drugs is the possible influence on the development of TD of drug holidays. The major characteristics of kindling, theories of TD and the role of multiplicity in the development of TD are described. Some clinical studies point to interruption of neuroleptic therapy being a risk factor for development of irreversible TD. Induction of dyskinesia in non-human primates has been demonstrated after repeated administration of haloperidol. Rodent studies have not been conclusive. Several experimental results link TD with kindling: both conditions involve repeated stimulations, both seem to involve increased receptor responsiveness and in both conditions does depression in GABA transmission in SNR (substantia nigra; pars reticulata) play an important role. It is concluded that the kindling hypothesis is relevant to the investigation of TD.

Kindling: A Model for the Development of Tardive Dyskinesia?

Tardive dyskinesia (TD) from long-term neuroleptic treatment may be irreversible; therefore prevention has become a major concern. A controversial issue with regard to the clinical use of neuroleptic drugs is the possible influence on the development of TD of drug holidays. The major characteristics of kindling, theories of TD and the role of multiplicity in the development of TD are described. Some clinical studies point to interruption of neuroleptic therapy being a risk factor for development of irreversible TD. Induction of dyskinesia in non-human primates has been demonstrated after repeated administration of haloperidol. Rodent studies have not been conclusive. Several experimental results link TD with kindling: both conditions involve repeated stimulations, both seem to involve increased receptor responsiveness and in both conditions does depression in GABA transmission in SNR (substantia nigra; pars reticulata) play an important role. It is concluded that the kindling hypothesis is relevant to the investigation of TD.