Motor effects of (-)-OSU6162 in primates with unilateral 6-hydroxydopamine lesions.

The effects of the novel compound, (-)-OSU6162 ((S)-(-)-3-methylsulfonylphenyl-1-propylpiperidine), on rotational behavior induced by dopamine receptor agonists was investigated in common marmosets (Callithrix jacchus) with unilateral 6-hydroxydopamine lesions. (-)-OSU6162 per se displayed no effect on the animals' behavior. On the other hand, pretreatment with (-)-OSU6162 attenuated rotational behavior induced by apomorphine (apomorphini hydrochloridum), L-DOPA (3,4-dihydroxyphenylalanine), and the dopamine D2 receptor agonist, quinpirole (trans-(-)-4aR-4,4a, 5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolol[3,4-g]quinoline hydrochloride), without inducing motor impairment such as akinesia or dystonia. In addition, treatment with (-)-OSU6162 for 5 consecutive days almost completely abolished the rotational behavior provoked by apomorphine and produced a transient subsensitization of such apomorphine-induced effects after it was discontinued. Moreover, pretreatment with (-)-OSU6162 in two monkeys augmented the rotational behavior elicited by the dopamine D1 receptor agonists, SKF-81297 (R(+)-6-chloro-7,8,dihydroxy-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrobromide) and A-77636 ((-)-(1R, 3S)-3-adamantyl-1-(aminomethyl)-3,4-dihydro-5, 6-dihydroxy-1H-2-benzopyran hydrochloride). The findings indicate that (-)-OSU6162 can exert indirect state-dependent effects that differentially affect dopamine D1 and dopamine D2 receptor agonist-induced behavior.

(-)-OSU 6162 inhibits levodopa-induced dyskinesias in a monkey model of Parkinson's disease.

We have studied the effects of two D2 dopamine receptor-selective compounds, (-)-OSU 6162 and raclopride, on levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmosets (Callithrix jacchus). Three monkeys developed a severe parkinsonian syndrome following administration of MPTP. In response to daily levodopa treatment the animals developed reproducible and idiosyncratic peak-dose dyskinesias. Pretreatment with (-)-OSU 6162 and raclopride, in doses increased by multiples of three, both dose-dependently relieved the levodopa-induced dyskinesias. However, in contrast to when raclopride pretreatment was given, (-)-OSU 6162 pretreatment did not induce akinesia. Our investigation suggests that (-)-OSU 6162 may be useful an an adjuvant treatment to levodopa in advanced Parkinson's disease to selectively combat levodopa-induced dyskinesias without affecting the antiparkinsonian response.

High frequency oral movements induced by long-term administration of amperozide but not FG5803 in rats.

Long-term studies of antipsychotic-induced oral movements may serve as a rat model of acute and tardive movement disorders. Vacuous chewing movements (VCM), tongue protrusions (TP), and jaw tremors (TR) were studied in rats during acute and chronic administration of two potential antipsychotics, amperozide and FG5803. Comparisons were made with haloperidol and vehicle. Single intraperitoneal injections of amperozide (0.2, 1, or 5 mg/kg) or FG5803 (1.2, 6, or 30 mg/kg) were without effect on oral behaviors. During long-term drug administration, withdrawal and readministration, endpoint analysis was focused on changes in supranormal oral movements. The maximal mean control frequencies found at 29 sessions during 14 months experiment +2 standard deviations were used to define the upper limit of the normal range. FG5803 (1.2, 6, or 30 mg/kg per day) administered via the drinking water for 12 months, did not produce significant deviations from this normal range with respect to VCM, TP, or TR, and this drug was not studied further. Rats receiving amperozide (0.2, 1, or 5 mg/kg per day) showed dose-related increases in oral movements over the year. The changes began after 3 months of treatment with amperozide 1 and 5 mg/kg per day, but became statistically significant only during the second half of the treatment year. Amperozide 0.2 mg/kg per day did not produce significant changes in oral movements during administration for a year, but drug withdrawal resulted in a significant rise in TP behavior. Haloperidol (1 mg/kg per day) produced increases in supranormal oral movements which tended to level out after 9 months. In all groups with significant elevations (i.e. haloperidol and amperozide 1 and 5 mg/kg per day), there was a persistence of such movements during a month of drug withdrawal. During treatment with amperozide (1 or 5 mg/kg per day), some rats developed a high frequency chewing behavior up to 175 VCMs/min. It is concluded that long-term treatment with amperozide, but not FG5803, produced a tardive pattern of supranormal oral movements. The importance of these findings for the clinical future of amperozide is difficult to predict, due to the unexpected finding of high-frequency chewing, which has not been noticed before during extensive studies of classical neuroleptics.

Neuroleptics differentially modulate central dopamine D1-receptor binding.

The effect of the classical neuroleptic, fluphenazine, on dopamine D1-receptor binding was examined in different regions of the basal ganglia. Whereas exposure to fluphenazine for 18 months reduced [125I]SCH-23982 binding to D1-receptors in the caudate putamen, nucleus accumbens and olfactory tubercle, binding in the entopeduncular nucleus was enhanced after fluphenazine treatment. Competition studies indicated that the region-dependent changes in [125I]SCH-23982 binding after fluphenazine exposure were not due to differences in the affinity of fluphenazine or other dopamine ligands for D1-binding sites. These data suggest that in addition to modulating striatal function, classical neuroleptics may also alter neurotransmission in the basal ganglia by enhancing dopamine receptor binding in the entopeduncular nucleus.

Chronic treatment with a classical neuroleptic alters excitatory amino acid and GABAergic neurotransmission in specific regions of the rat brain.

The purpose of the following experiments was to describe some of the neurochemical changes that occur in the basal ganglia of rats exposed chronically to a classical neuroleptic, fluphenazine, and to relate these changes to extrapyramidal motor dysfunction. For these studies a combination of behavioural, receptor autoradiographic and in situ hybridization methods were employed. Preliminary pharmacological studies on GABA receptors showed that incubation in Tris-acetate rather than Tris-citrate buffer increased the number of binding sites labelled by [3H]muscimol by over 120% without affecting binding affinity or selectivity. The results of experiments with fluphenazine showed that treatment for six months increased the frequency of vacuous chewing movements compared to controls. In the striatum, changes in GABA transmission were observed in fluphenazine-treated rats with increases in glutamate decarboxylase mRNA levels in the caudate nucleus, dorsal shell and core of the accumbens and decreases in [3H]muscimol binding in the caudate and dorsal shell regions. These data suggest that fluphenazine treatment increased GABA transmission in specific subregions of the caudate and accumbens nuclei. In addition, glutamate decarboxylase mRNA levels were elevated in the entopeduncular nucleus of fluphenazine-treated animals. Autoradiographic analysis of excitatory amino acid binding showed that fluphenazine exposure decreased [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding in entopeduncular nucleus and in the ventrolateral thalamic nucleus and decreased [3H]dizocilpine maleate binding in the medial geniculate nucleus. These experiments show that in addition to altering GABA transmission, chronic neuroleptic exposure alters excitatory amino acid transmission in specific regions of the basal ganglia-thalamocortical motor system. The neuroleptic dependent increases in glutamate decarboxylase mRNA levels in the entopeduncular nucleus may reflect changes in neurotransmission in the indirect pathway connecting the major input and output nuclei of the basal ganglia. Changes in some of these brain regions may be related to the occurrence of extrapyramidal motor disturbances.

Modulation of oral movements by intranigral 5-hydroxytryptamine receptor agonists in the rat.

Bilateral infusion of 5-hydroxytryptamine (5-HT) agonists into the substantia nigra pars reticulata (SNr) of awake rats was shown to influence oral behavior. The 5-HT1A agonist (R)-8-hydroxy-2-(di-propylamino)- tetralin (8-OH-DPAT) (1.3-13 nmol on each side) produced a dose-dependent depression of vacuous chewing movements (VCMs) that lasted about 20 min. The (R)-8-OH-DPAT-induced depression of VCMs was blocked by the simultaneous intranigral infusion of a specific 5-HT1A antagonist [(-)-(S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin HCl (UH-301)], which had no effect when given alone. Another 5-HT1A agonist [(5-methoxy-N,N-dimethyltryptamine hydrogen oxalate (5-MeO-DMT)] also reduced VCM frequencies. Intranigral infusion of the nonspecific 5-HT-agonists 1-(3-triflouro-methylphenyl) piperazine (TFMPP) and 1(m-chlorophenyl)-piperazine (mCPP) and a 5-HT3 agonist [2-methyl-5-hydroxytryptamine (2-Me-5-HT)] increased VCM after 5- to 10-nmol doses. Another 5-HT3 agonist (1-phenylbiguanide) and a 5-HT2 agonist [1-(4-bromophenyl-2,5-dimethoxy)-2-aminopropane (DOB)] had no significant effect. As most 5-HT receptors in the SNr are of the 5-HT1B subtype, these results suggest that the increased VCM frequency was mediated via nigral 5-HT1B receptors. The importance of 5-HTergic mechanisms in the development of drug-induced dyskinesias is discussed.

Intranigral stimulation of oral movements by [Pro9] substance P, a neurokinin-1 receptor agonist, is enhanced in chronically neuroleptic-treated rats.

Bilateral intranigral infusions of three different peptide agonists were made in rats exposed to fluphenazine decanoate, 30 mg/kg/month (FLU) or vehicle (CON) for seven months. Oral movements were monitored repeatedly during the neuroleptic pretreatment period, as well as before the intranigral infusion and during a 90-min period postinfusion. The FLU group had an increased frequency of vacuous chewing movements (VCM) during the pretreatment period in comparison to controls. Intranigral infusion of the neurokinin-1 (NK1) receptor agonist, [Pro9]Substance P (2.5 nmol on each side), 5-7 weeks after the last FLU injection, caused a significant increase of VCM in both pretreatment groups, lasting 7 min after the infusion. The VCM response to [Pro9]Substance P in the FLU group was significantly higher than in the CON group. A NK2 agonist [Lys5, MeLeu9, Nle10]Neurokinin A(4-10) (2.5 nmol) failed to produce significant changes in oral activity. A Leu-enkephalin analogue [D-Ala2,D-Leu5]enkephalin (3.8 nmol) induced a massive biting behavior in both FLU and CON rats. Using VCM as a behavioral assay, an increased nigral sensitivity to a NK1 agonist is demonstrated in rats chronically exposed to neuroleptics. No corresponding alterations could be ascribed for the NK2 receptor agonist or the Leu-enkephalin analogue.

An animal model for coexisting tardive dyskinesia and tardive parkinsonism: a glutamate hypothesis for tardive dyskinesia.

There is now ample evidence for long-term malfunctioning within five different brain GABAergic pathways in a monkey model for tardive dyskinesia (TD). Three of these GABA connections (GPe-STN, CP-SNr, and CP-GPi) are chronically downregulated during neuroleptic treatment and after some years they do not seem to regain their normal activity, even when the neuroleptics are discontinued. The persistent downregulation of these three GABA connections, evidenced by depressions of terminal GAD activity and GABA levels, appears to be a conceivable mechanism behind tardive parkinsonism (TP), often reported to coexist with TD in the clinic. The TD patients' well-known lack of awareness of their symptoms may be due to their parkinsonian "sensory neglect." Another two GABA malfunctioning connections were found in our monkey model: SNr-VA/VL and GPi-VA/VL. These pathways are upregulated during chronic neuroleptic treatment, partly due to an elevated glutamate release within subthalamofugal pathways. This chronic glutamatergic hyperactivity may have acted via an excitotoxic mechanism and consequently both GPi and VA/VL had a low synaptic activity in our dyskinetic monkeys, as measured by 2-deoxyglucose uptake, even 4 months after the last neuroleptic dose. It is hypothesized that TD may be due to an excitotoxic lesion of the inhibitory GABAergic VA/VL afferents, while TP has to do with persistent malfunctioning of downregulated SNr and GPi afferents.

Regional changes in 2-deoxyglucose uptake associated with neuroleptic-induced tardive dyskinesia in the Cebus monkey.

The neural mechanisms that mediate a primate model of tardive dyskinesia have been investigated using the 2-deoxyglucose (2-DG) uptake technique. Three groups of Cebus monkeys were used. Some of the animals received long-term neuroleptic treatment. These animals were allotted to one of two groups depending on whether they developed tardive dyskinesia or not. A third group of animals served as untreated controls. The neuroleptic-treated dyskinetic animals showed reduced uptake of 2-DG in the medial segment of the globus pallidus and in the ventral anterior (VA) and ventral lateral (VL) nuclei of the thalamus relative to that seen in the equivalent structures in the neuroleptic-treated nondyskinetic and untreated control animals. The data are interpreted as suggesting that tardive dyskinesia is mediated by underactivity of the pathways from the subthalamic nucleus to the medial pallidal segment and the substantia pars nigra pars reticulata, which in turn result in a loss of gamma-aminobutyric acid-ergic inhibition of the VA and VL thalamic nuclei. This suggests that tardive dyskinesia shares a common underlying neural mechanism with other hyperkinesias such as chorea and ballism.

Mortality in heroin addiction: impact of methadone treatment.

The mortality within a cohort of 115 street heroin addicts was studied for 5-8 years using the Kaplan-Meier survival estimate technique. This differed markedly from the relatively low mortality of 166 comparable heroin addicts given methadone maintenance treatment (MT). The street addicts' mortality rate was 63 times that expected, compared with official statistics for a group of this age and sex distribution. When 53 patients in MT were involuntarily expelled from treatment, due to violation of programme rules, they returned to the high mortality of street addicts (55 times that expected). A group of 34 rehabilitated patients who left MT with medical consent retained the low mortality of MT patients (their mortality rate was 4 times that expected). Despite this great improvement in survival, even patients in MT showed a moderately elevated mortality (8 times that expected), mainly due to diseases acquired before entering the treatment programme. It is concluded that MT exerts a major improvement in the survival of heroin addicts.

Rhythmic jaw movements induced by ethanol in rats.

Intraperitoneal administration of an anaesthetic dose of ethanol, 3.0 mg/kg, produced rapid rhythmic jaw movements (RJM) in rats. The peak effect (90 RJM/min.) occurred after 5 min., and all movements ceased after about 15 min. Clozapine, (4.4 mg/kg intraperitoneally) completely abolished this RJM phenomenon, whereas halopridol (0.5 mg/kg intraperitoneally), apomorphine (1.0 mg/kg subcutaneously) and atropine (10 mg/kg intraperitoneally) reduced it. It is suggested that the postulated brain stem masticatory pattern generator is activated or released from inhibition during induction of ethanol anaesthesia. Apparently this masticatory movement pacemaker is amenable to pharmacological manipulation, as shown by the present experiments.

Chronic melperone administration does not enhance oral movements in rats.

Melperone and haloperidol were compared in a rat model for tardive dyskinesia. Drugs were given chronically for 12 months with the drinking water and the frequency of oral movements was measured at monthly intervals. Haloperidol (0.2 and 0.4 mg/kg/d) produced an increase in vacuous chewing movements, whereas melperone (2.4, 5.1 and 11.0 mg/kg/d) did not differ from untreated controls.

Chronic neuroleptic effects on spatial reversal learning in monkeys.

Cebus apella monkeys were chronically administered the antipsychotic drug fluphenazine decanoate for periods ranging from 3.5 to 5.5 years. In the present study, four of these monkeys and two controls were tested for cognitive abilities on a spatial learning task, which consisted of an original discrimination and four reversals of that discrimination. No effect of fluphenazine administration was seen in the rate of learning the original discrimination, but the carryover of learning across discrimination reversals was significantly reduced by fluphenazine. After overtraining on the original discrimination, the controls showed the normal difficulty in learning the first reversal. The fluphenazine-treated monkeys showed no such disruption. On subsequent reversals, the controls showed continually improving performance, so that on the third and fourth reversals they had near-perfect scores. On the other hand, the fluphenazine-treated monkeys showed no change over the four reversals. Unlike normal monkeys, their learning did not improve with practice. Although simple forms of learning seem to be relatively unaffected by chronic fluphenazine administration, more complex learning is disrupted.

Intranigral infusion of enkephalins elicits dyskinetic biting in rats.

Leu- and Metenkephalin (Lenk and Menk) and their more stable analogues D-Ala-Leu- and D-Ala-Metenkephalin (DALenk and DAMenk) as well as D-Ala-D-Leu- and D-Ala-D-Metenkephalin (DADLenk and DADMenk) were infused bilaterally into substantia nigra in awake rats and oral movements were recorded for 90 min. DADLenk and DADMenk elicited dose-dependent biting dyskinesias with a chewing rate of about 90 jaw movements/min. DALenk produced a similar but weaker effect, whereas DAMenk, Lenk and Menk were ineffective in the doses given. These findings suggest a possible enkephalinergic mechanism underlying neuroleptic-induced tardive dyskinesias.

Reduced glutamate decarboxylase activity in the subthalamic nucleus in patients with tardive dyskinesia.

Glutamate decarboxylase (GAD) activity was measured in the nuclei of the basal ganglia in patients with neuroleptic-induced tardive dyskinesia (TD) and controls matched for age and premortem state. In five TD patients, who all had a sudden death, a significant decrease in GAD activity was found in the subthalamic nucleus (STN). The lowered GAD activity in the STN may represent a biochemical substrate for neuroleptic-induced TD.

Neurobiochemical changes in tardive dyskinesia.

There is evidence for the view that both up- and downregulation of nigral GABA may give rise to dyskinetic movements. Intranigral infusion of GABA agonists causes stereotyped licking and gnawing in rats, while intranigral GABA antagonists produce vacuous chewing movements. It is hypothesized that during long-term neuroleptic treatment there may be a succession of changes within striatonigral GABA neurons: down-regulation caused by neuroleptic drugs may increase receptor sensitivity, and this may lead to overcompensation and withdrawal dyskinesia during periods of cessation of drug treatment. Reduced nigral GAD activity may be a marker of irreversible brain damage and has not been observed in all chronic experiments, but only in individuals with long-standing or irreversible dyskinesia. Changes within the GABA system seem to be accompanied by changes in the striatal and nigral levels of substance P.

Oral movements induced by interference with nigral GABA neurotransmission: relationship to tardive dyskinesias.

Previous studies have shown that the emergence of spontaneous dyskinetic behaviors, such as vacuous chewing movements, following several months of neuroleptic treatment in the rat, is correlated with depletion of nigral GABA. To explore the specificity of this relationship, we acutely interfered with nigral GABA transmission pharmacologically, by microinfusing either the GABA receptor antagonist, bicuculline, or the GABA-depleting agent, isoniazid, bilaterally into substantia nigra. We found that both acute treatments induced vacuous chewing movements in rats. Moreover, the time to onset of action of each of these drugs corresponded to the onsets of their respective effects on GABA transmission. In addition, we found that the application of muscimol into the target field of the nigrotegmental projection, which has been shown to block gnawing elicited by nigral GABA receptor stimulation, completely abolished elicitation of vacuous chewing movements by intranigral isoniazid. In contrast, bilateral microinfusions of muscimol into the nigrocollicular target region, in the deep layers of superior colliculus, blocked elicitation of gnawing by intranigral muscimol, but completely spared elicitation of vacuous chewing movements by intranigral isoniazid. We conclude that qualitatively different dyskinetic syndromes can be produced by bidirectional perturbations of nigral GABA function and are differentially mediated by nigrotegmental and nigrotectal projections. These syndromes may represent animal models of distinct components of extrapyramidal side effects of chronic neuroleptic administration.