Chronic Neuroleptics Research Articles

Chronic treatment with atypical neuroleptics induces striosomal FosB/ΔFosB expression in rats

BackgroundStudies have shown that neuroleptics regulate expression of the transcription factor FosB/ΔFosB in the striatum, including the accumbens and caudate-putamen; however, the striatum is also divided into another structural dimension, the striosome and matrix compartments. The precise distribution of FosB/ΔFosB induced by chronic neuroleptics in these striatal compartments is poorly understood. MethodsRats received either single acute injections or chronic injections of clozapine (0 or 20 mg/kg, intraperitoneally [IP]), olanzapine (0 or 5 mg/kg, IP), or haloperidol (0 or 1.5 mg/kg, IP) for 25 days. The levels and compartmental distribution of FosB/ΔFosB were examined. ResultsChronic clozapine induced clustered FosB/ΔFosB expression within striosomes of the caudate-putamen. This pattern was due to increased levels of FosB/ΔFosB in striosomes within the ventrolateral caudate-putamen and reduced levels of basal FosB/ΔFosB in the matrix in the entire caudate-putamen. In contrast, chronic haloperidol increased FosB/ΔFosB equally within the matrix and striosomes throughout the entire caudate-putamen. Chronic olanzapine induced an intermediate pattern. ConclusionsThe relative absence of FosB/ΔFosB expression in the matrix correlates with the lack of parkinsonism of atypical neuroleptics. Expression of FosB/ΔFosB in the matrix may contribute to parkinsonism of typical neuroleptics.

Chronic treatment with atypical neuroleptics induces striosomal FosB/ΔFosB expression in rats

<h2>Abstract</h2><h3>Background</h3> Studies have shown that neuroleptics regulate expression of the transcription factor FosB/ΔFosB in the striatum, including the accumbens and caudate-putamen; however, the striatum is also divided into another structural dimension, the striosome and matrix compartments. The precise distribution of FosB/ΔFosB induced by chronic neuroleptics in these striatal compartments is poorly understood. <h3>Methods</h3> Rats received either single acute injections or chronic injections of clozapine (0 or 20 mg/kg, intraperitoneally [IP]), olanzapine (0 or 5 mg/kg, IP), or haloperidol (0 or 1.5 mg/kg, IP) for 25 days. The levels and compartmental distribution of FosB/ΔFosB were examined. <h3>Results</h3> Chronic clozapine induced clustered FosB/ΔFosB expression within striosomes of the caudate-putamen. This pattern was due to increased levels of FosB/ΔFosB in striosomes within the ventrolateral caudate-putamen and reduced levels of basal FosB/ΔFosB in the matrix in the entire caudate-putamen. In contrast, chronic haloperidol increased FosB/ΔFosB equally within the matrix and striosomes throughout the entire caudate-putamen. Chronic olanzapine induced an intermediate pattern. <h3>Conclusions</h3> The relative absence of FosB/ΔFosB expression in the matrix correlates with the lack of parkinsonism of atypical neuroleptics. Expression of FosB/ΔFosB in the matrix may contribute to parkinsonism of typical neuroleptics.

Conversation with Conan Kornetsky.

Conversation with Conan Kornetsky.

Central administration of the neurotensin receptor antagonist sr48692 attenuates vacuous chewing movements in a rodent model of tardive dyskinesia

Tardive dyskinesia is a movement disorder that develops in 20–30% of patients treated with chronic neuroleptics. Whilst the pathogenesis of tardive dyskinesia remains unclear, altered expression of neuropeptides in the basal ganglia has been implicated in its emergence. The peptide neurotensin is expressed in both dopamine D1 receptor-bearing neurons of the direct striatonigral pathway and dopamine D2 receptor-bearing neurons of the indirect striatopallidal pathway. Increased levels of striatal neurotensin messenger RNA (mRNA) are reported following chronic neuroleptic therapy. Chronic treatment with the typical antipsychotic haloperidol elicits neurotensin immunoreactivity in a large number of striatopallidal and a modest number of striatonigral projection neurons, whilst treatment with the potent dopamine releaser, methamphetamine, induces intense neurotensin immunoreactivity in striatonigral projection neurons. In order to determine whether increased levels of striatal neurotensin mRNA in the direct striatonigral or the indirect striatopallidal pathway play a more influential role in the development of tardive dyskinesia, we explored the effects of a specific neurotensin antagonist in a rodent model (vacuous chewing movements [VCMs] induced by chronic neuroleptics). Three groups of animals received injections of fluphenazine decanoate (25 mg/kg) or its vehicle sesame oil every 3 weeks for at least 18 weeks. They were then surgically implanted with bilateral guide cannulae aimed at the striatum, the substantia nigra pars reticulata, or the globus pallidus respectively. After recovery, animals were infused with 2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-imethoxyphenyl)pyrazol-3-yl)carbonylamino]tricyclo(3.3.1.1. 3.7)decan-2-carboxylic acid (SR48692; 0.25, 0.50, and 1.0 nmol/μl), or its vehicle (10% dimethyl sulfoxide [DMSO] in saline) and observed for 60 min. Intra-striatal, intra-nigral or intra-pallidal infusion of SR48692 attenuated neuroleptic-induced VCMs. These findings lend further support to a role for neurotensin in the development of VCMs but do not clarify which pathway plays a more important role. Thus, treatments that reduce or prevent the effects of increased neurotensin expression and release may be useful in the management of tardive dyskinesia.

Metabolic changes in the basal ganglia of patients with Huntington's disease: an in situ hybridization study of cytochrome oxidase subunit I mRNA

On the basis of the functional model of the basal ganglia developed in the 1980s and the neuropathological findings in Huntington's disease (HD), changes in the neuronal activity of the basal ganglia have previously been proposed to explain the abnormal movements observed in this pathology. In particular, it has been stated that the neurodegenerative process affecting the basal ganglia in the disease should provoke a hypoactivity in the internal segment of the pallidum (GPi) that could explain choreic movements observed in the disease. To test this functional hypothesis, we performed an in situ hybridization study on control and HD brains postmortem, taking cytochrome oxidase subunit I (COI) mRNAs expression as index of neuronal activity. As most of the HD patients studied were under chronic neuroleptic (NL) treatment, we also studied the brains of non-HD patients under chronic NL treatment. Our results show that in HD brain the number of neurons expressing COI mRNA tends to be lower in the striatum, GPe and GPi, suggesting a severe involvement of these structures during the neurodegenerative process. Moreover, COI mRNA level of expression was markedly reduced within neurons of the putamen and GPe. Surprisingly, COI mRNA expression was not modified in the GPi in HD brains compared with controls. This paradoxical result in the GPi may be explained by the antagonistic effect of GPe hypoactivity and the degenerative process involving neurons of GPi. Our results indicate that the functional modifications, and consequently the pathophysiology of abnormal movements, observed in HD basal ganglia are more complex than expected from the currently accepted model of the basal ganglia organization.

The problem of antipsychotic treatment for functional imaging in Huntington's disease: receptor binding, gene expression and locomotor activity after sub-chronic administration and wash-out of haloperidol in the rat

It has been demonstrated that withdrawal from chronic treatment with haloperidol is associated with a long-lasting increase in the number of striatal dopamine D 2 receptors and variable changes in D 1 receptors. We have investigated the effect of withdrawal from sub-chronic administration of haloperidol on the density of dopamine receptors, dopamine receptor gene expression, and spontaneous locomotor activity. Following a 3-week treatment period with haloperidol (1.5 mg/kg, i.p.), spontaneous locomotor activity measurements, autoradiography of D 1 and D 2 receptors and in situ hybridisation histochemistry of D 1 and D 2 mRNA were performed. Using [ 3 H ]raclopride as the ligand, sub-chronic haloperidol administration produced a robust upregulation in D 2 binding in the striatum of rats which correlated with parallel increases in spontaneous locomotor activity from 24 h to 4 weeks. Using, [ 3 H ]SCH23390 as the ligand, D 1 binding was largely unaffected by the drug treatment. Non-significant changes were measured in the striatal expression of D 1 receptor mRNA or the nigral or striatal expression of D 2 receptor mRNA. Our findings have implications for the use of dopaminergic ligands in positron emission tomography (PET) imaging of patients under regimens of chronic neuroleptics in particular in the context of forthcoming trials of neural grafts in Huntington's disease (HD) striatum.

Differential effects of acute and chronic treatment with typical and atypical neuroleptics on c-fos mRNA expression in rat forebrain regions using non-radioactive in situ hybridization

The regional difference in the expression of c-fos mRNA in rat forebrain after either acute or chronic administration of typical (haloperidol and fluphenazine) and atypical neuroleptics (clozapine and (±)-sulpiride) was investigated. Rats were injected intraperitoneally with vehicle or neuroleptics daily for 14 days. Twenty-four hours after the last injection, the rats were challenged with vehicle or neuroleptics. C-fos mRNA expression was determined by non-radioactive in situ hybridization. Acute treatment with typical neuroleptics induced a remarkable induction of c-fos mRNA in the dorsolateral striatum, whereas this induction was greatly attenuated by chronic administration. All neuroleptics examined induced c-fos mRNA in the shell region of N. accumbens by acute administration and this expression was still elevated after chronic treatment. Since chronic neuroleptics do not induce tolerance to their antipsychotic activities, our study suggests that the shell region of N. accumbens is an important target site for antipsychotic effects of neuroleptics.

Effects of subthalamic nucleus lesions in a putative model of tardive dyskinesia in the rat.

The effects of bilateral excitotoxic lesions of the subthalamic nucleus on vacuous chewing movements induced by chronic neuroleptic therapy were examined in the rat. Fluphenazine decanoate (25 mg/kg i.m.q 3 weeks x 24 weeks) induced vacuous chewing movements, as previously described. This response was suppressed to control levels in animals tested 1-3 weeks following bilateral infusion of quinolinic acid (100 nmol/1 microliter per side) into the subthalamic nucleus. Subthalamic nucleus lesions resulted in increased locomotion and sniffing in neuroleptic-naive animals, but these responses were suppressed by concomitant neuroleptic treatment. As vacuous chewing movements induced by chronic neuroleptics are considered to be analogous to tardive dyskinesia in humans, our findings lend further support to the importance of the subthalamic nucleus in the regulation of orofacial movements and suggest that tardive dyskinesia may, in part, be related to altered activity in this structure. This, in turn, suggests that current models of basal ganglia function are inadequate to account for certain pathological states and require re-examination.

Supersensitivity of spinal dopaminergic receptors in rat after chronic haloperidol

In order to examine the effect of chronic neuroleptics on spinal dopaminergic system, rats were treated with haloperidol (0.5 mg/kg IP) for 21 days and the monosynaptic mass reflex (MMR) as well as dopamine (DA) metabolism were investigated. MMR, recorded from ventral root L6 following supramaximal stimulation to ipsilateral dorsal root L6 in spinalized rats, were found to be unaffected following chronic haloperidol treatment when compared to control. Apomorphine (0.1 mg/kg IV) caused 10–20% depression of MMR in control animals which was augmented to 40–50% in chronically haloperidol-treated animals suggesting an upregulation of DA receptors in the spinal cord. DA content of lumbar region of the spinal cord was unaffected whereas its major metabolite, homovanillic acid, was significantly reduced in chronic haloperidol-treated animals. This decreased utilization of DA may compensate the upregulation of DA receptors to maintain the physiological homeostasis of the spinal dopaminergic system.

Chronic administration of typical, but not atypical neuroleptics induce persisting alterations in rest-activity cycles in rats

The behavior of rats administered chronic neuroleptics was observed using an extremely sensitive, computerized device which detected any cage movements, thereby continuosly monitoring even very small levels of activity. In the first experiment, it was found that normal rats have a strong rest-activity rhythm with a cycle length of 60–70 min, whereas rats which have been chronically administered either haloperidol (HAL) or fluphenazine (FLU) decanoate for 20 months show a distinct lengthening of this cycle and that this effect persists long after cessation of drug injections. In a second experiment, it was further observed that these lengthened rest-activity cycles also occur when HAL is administered chronically either via osmotic minipumps or in the drinking water, but not following the chronic administration of two atypical neuroleptics (clozapine and raclopride). These findings suggest a useful new technique for the study of side-effects of neuroleptics in rats.

Increases in rat striatal preproenkephalin mRNA levels following chronic treatment with the depot neuroleptic, haloperidol decanoate

Studies of the effects of chronic neuroleptic drug treatment have consistently demonstrated enhanced transcription and translation of the preproenkephalin gene in the rat striatum. However, all of these studies have used daily ip drug treatments and none have evaluated the effects of chronic depot neuroleptics. With these drug treatments, dopamine receptor blockade undergoes less variability as a result of sustained steady-state blood levels of the neuroleptic. Therefore, as a result of the increasing utilization of depot neuroleptics therapeutically, we examined the effects of haloperidol decanoate on striatal preproenkephalin mRNA levels. As with daily ip drug injections, the depot preparation was found to increase the levels of this mRNA to an apparent new steady-state level twice that of controls, by 3 days and sustaining this steady-state for the 14 day observation period. These data indicate that both continuous and fluctuating patterns of dopamine receptor blockade result in activation of the preproenkephalin gene.

Rats administered chronic neuroleptics develop oral movements which are similar in form to those in humans with tardive dyskinesia

Oral movements (OMs) in rats chronically administered haloperidol (HAL), fluphenazine (FLU), or no drug were recorded using a computerized video analysis system which measured the distance between two fluorescent dots painted above and below the rat's mouth. The resulting data was analyzed using fast-fourier analysis. Following an initial period of sedation (decreased energy at all frequencies), the drugged animals (and especially the FLU animals) began to show increased oral movements of 1-2 Hz, an effect which increased substantially upon drug withdrawal. This is precisely the altered energy spectrum observed in humans with tardive dyskinesia.

Computerized studies of mouth movement abnormalities which gradually develop in rats following chronic neuroleptics: implications for tardive dyskinesia

Computerized studies of mouth movement abnormalities which gradually develop in rats following chronic neuroleptics: implications for tardive dyskinesia

Chronic neuroleptics alter the effects of the D1 agonist SK&F 38393 and the D2 agonist LY171555 on oral movements in rats.

Vacuous oral movements (OMs) in rats chronically administered haloperidol (HAL), fluphenazine (FLU), or no drug were studied following injections of one of three doses of either a D1 agonist (SK&F 38393) or a D2 agonist (LY171555). Oral movements were observed via closed-circuit television and simultaneously recorded using a computerized video analysis system which measured the distance between two fluorescent dots painted above and below the rat's mouth. SK&F 38393 induced a dose-dependent increase in tremorous oral movements and repetitive chewing movements in the controls; this effect was more pronounced in rats treated with chronic HAL or FLU, both during chronic neuroleptic treatment and even more so when they were tested after drug withdrawal following 5 or 14 months of chronic neuroleptic administration. Conversely, LY171555 produced an inhibition of oral activity at all dose levels in controls. This inhibition was attenuated during chronic administration of HAL or FLU, but returned to control levels (without any signs of supersensitivity) when the animals were retested shortly after discontinuation of neuroleptics. These results indicate that heightened oral movements in rodents following chronic neuroleptic administration can be more clearly induced by D1 than by D2 receptor activation.

Characteristics of oral movements in rats during and after chronic haloperidol and fluphenazine administration.

Rats were chronically administered either haloperidol (HAL) or fluphenazine (FLU) via depot injections for 8 months, given these same drugs in their drinking water for the next 2 months, and then withdrawn from the drugs. Throughout the experiment the animals were tested repeatedly in an enclosed tube using a computerized device which measured computer-scored movelets (CSMs) and, in the latter half of the experiment, were also scored by a human observer in the tube, as well as in an open cage, for observed oral movements (OMs). In the tube, the animals in both neuroleptic-treated groups showed initial decreases in the number of CSMs and made sluggish CSMs; these effects were generally larger in the FLU animals. After 6 months of chronic neuroleptics, the HAL-treated animals showed increased oral movements, both as reported by the human observer and in CSMs of all amplitudes, and this effect increased upon drug withdrawal. FLU-treated animals showed a more persistent depression of both OMs and CSMs of large amplitudes. However, the behavior most characteristic of both neuroleptic-treated groups was the gradual development of increases in CSMs of the smallest amplitudes measurable. A different pattern was observed in the open cage test, where both neuroleptic groups showed significant increases in vacuous OMs during drug administration which rapidly became attenuated upon drug withdrawal. These results indicate a complex syndrome of oral activity in the drugged animals which changed over time. The measure of oral activity which most clearly showed the time-course for late-onset changes in oral activity was CSMs of the smallest amplitudes.

Tremorous mouth movements in rats administered chronic neuroleptics.

Oral movements (OMs) in rats administered chronic haloperidol (HAL) were quantified simultaneously by a human observer and via a computerized video analysis system which monitored the distance between the upper and low lips using TV images. The human observer data indicated that during HAL administration the total duration of OMs was initially decreased, gradually returned to levels slightly above controls, and then increased substantially upon drug withdrawal. The computer records confirmed these findings and further indicated that after prolonged HAL administration a syndrome developed in which large-amplitude OMs remained suppressed but OMs of the smallest detectable amplitudes increased. Upon drug withdrawal, these small OMs increased in amplitude and rhythmicity, developing into repetitive tremors.

Chronic haloperidol effects on oral movements and radial-arm maze performance in rats

Rats were examined for were examined for the development of adverse motor and cognitive effects during and after 24 weeks of chronic haloperidol (HAL) administration using an 8-arm maze and a computerized apparatus for measuring spontaneous oral movements. In the maze, HAL caused a significant decline in choice accuracy only during the first week of administration, whereas it caused a significant decline in locomotor speed throughout drug administration. There were no effects of HAL on maze behavior after withdrawal. Haloperidol reduced the number of mouth movements during drug administration, but after withdrawal there was a significant increase. This replicated a previous finding from our lab. The oral movements which did occur in the HAL-treated rats were slower than normal. The timing of the HAL-induced cognitive dysfunction was similar to the Parkinson-like disorder shown by patients given chronic neuroleptics, whereas the timing of the increase in oral movements after the withdrawal of HAL was more related to the appearance of tardive dyskinesia. There was evidence in both tests of a persisting sedation during chronic neuroleptic administration.

Intermittent neuroleptic therapy and tardive dyskinesia: a literature review.

Many authorities advocate neuroleptic-free periods for patients on chronic neuroleptics as a means of reducing the incidence or severity of tardive dyskinesia. This practice continues, despite the absence of any controlled clinical studies showing that intermittent therapy reduces the incidence or progression of tardive dyskinesia. After reviewing the pertinent clinical and animal literature, the authors conclude that there are few data to support the use of intermittent therapy as a means of reducing tardive dyskinesia and, in fact, evidence suggests it may increase the risk of persistent tardive dyskinesia.

Chronic haloperidol treatment fails to alter the anorexic actions of dopaminergic agonists and cholinergic drugs

1. 1. Experimental rats were chronically treated with haloperidol and tested with dopaminergic and cholinergic drugs for their anorexic effects. 2. 2. All of the test drugs significantly reduced the compulsive eating that results from food deprivation. 3. 3. Chronic haloperidol failed to change sensitivity of the animals to dopaminergic or cholinergic drugs. There was a trend towards an increase in sensitivity to a peripheral effect of a cholinergic drug. 4. 4. In contrast to the present data, sensitivity to dopaminergic drugs in producing locomotor stimulation and stereotypy is increased after chronic haloperidol. These experiments suggest that alteration in neurotransmitter functioning after chronic neuroleptics markedly differs in different neurobehavioral systems.

Behavioral evidence for supersensitivity after chronic administration of haloperidol, clozapine, and thioridazine

Rats administered chronic neuroleptics for 6–7 weeks-- haloperidol (2.5 mg/rat or 1 mg/kg), clozapine (25 mg/kg), or thioridazine (20 mg/kg)--after termination of chronic drug treatment exhibited greater apomorphine-induced stereotyped behavior than their saline controls. Rats treated with thioridazine or clozapine, but not haloperidol, also showed increases in locomotor activity during withdrawal. These findings indicate that behavioral supersensitivity may develop after chronic clozapine treatment as well as after chronic haloperidol.