Chronic Administration Of Haloperidol Research Articles

Morphochemical changes in brain structures in the course of chronic haloperidol treatment and the correction of these changes with tuftsin.

The systemic injection of haloperidol (4 wk, 0.5 mg/kg/d) caused the increase of protein concentration and content, and the activity level of aminopeptidase in the cytoplasm of the neurons of associated type (layer III). The nucleus of these cells decreased both in sizes and in the content of proteins. In the neurons of efferent-projectory type (layer V), the decrease of studied peculiarities as compared with control level was observed. Tuftsin (300 micrograms/kg/d) injection after chronic haloperidol treatment causes the restoring action on changed parameters in sensomotor cortex. In caudate nucleus, tuftsin influence caused further reduction of neuron's cytoplasmic area and significant reduction in protein content. The received results testify to the morphobiochemical heterogenity of investigated brain structures, which is displayed both in the case of haloperidol treatment and in the case of its correction by neuropeptide tuftsin. Chronic haloperidol administration to animals can develop a model of certain symptoms and syndromes of parkinsonism. Its most pronounced manifestation is an imbalance in the neuromediator systems, especially the dopaminergic one (Mettler and Crandall, 1959; Colls, 1984; Funk et al., 1986). The research was performed in conjunction with the physiologists, whose experiments have shown that after chronic haloperidol administration, changes in animal behavior are developed that are typical for bradikinesia, and the motor regimen of integration is disturbed (Popova and Kachalova, 1991; Dovedova and Povova, 1993). Regulatory drugs, especially the tetrapeptide tuftsin, seem to correct such disturbances.

Aripiprazole, a novel antipsychotic drug, inhibits quinpriole-evoked GTPase activity but does not up-regulate dopamine D 2 receptor following repeated treatment in the rat striatum

Aripiprazole, a quinolinone derivative, is a new dopaminergic agent which has been recently developed and demonstrated to be clinically useful as an antipsychotic drug with reduced extrapyramidal motor side effects. Here, we found that aripiprazole competed [ 3H]spiperone binding with a 100-fold higher affinity than [ 3H]SCH23390 binding, and inhibited the quinpriole-induced facilitation of high-affinity GTPase activity in rat striatal membranes. The effects of chronic administration of aripiprazole and haloperidol on dopamine D 2 receptor binding and mRNA level in rat striata were examined by a [ 3H]spiperone binding assay and a ribonuclease protection assay. Haloperidol induced a significant rise in B max of [ 3H]spiperone binding at 1 mg/kg and in the level of dopamine D 2L receptor mRNA at 4 mg/kg. A high dose of aripiprazole (100 mg/kg) only tended to increase the B max of [ 3H]spiperone binding non-significantly, and had no effect on the level of dopamine D 2L receptor mRNA. These results indicated that aripiprazole had an antagonistic activity to dopamine D 2 receptors with a high affinity, but that the potency of aripiprazole to up-regulate dopamine D 2 receptors in the striatum was much smaller than that of haloperidol. This small up-regulation may be related to the ability of aripiprazole to act without side effects including tardive dyskinesia.

5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia

We have investigated 5-HT1A (serotonin1A) and 5-HT2A (serotonin2A) receptor mRNA abundance and binding site densities in various neocortical and hippocampal regions of schizophrenics and control subjects. Age, agonal state (brain pH), and post mortem interval were included where necessary as covariates in our analyses. In schizophrenics, 5-HT1A binding site densities, determined autoradiographically by [3H]8-hydroxy-2,3-(dipropylamino)-tetralin ([3H]8-OH-DPAT), were significantly increased (+23%) in the dorsolateral prefrontal cortex, with a similar trend in anterior cingulate gyrus. These increases were not accompanied by any change in 5-HT1A receptor mRNA. No differences between the groups in [3H]8-OH-DPAT binding or 5-HT1A receptor mRNA were seen in superior temporal gyrus, striate cortex, or hippocampus. 5-HT2A binding sites, determined by [3H]ketanserin, were decreased in the dorsolateral prefrontal cortex (-27%) and parahippocampal gyrus (-38%) of schizophrenics, with a similar trend in cingulate gyrus, but not in superior temporal gyrus or striate cortex. 5-HT2A receptor mRNA abundance was reduced in schizophrenics in the dorsolateral prefrontal (-49%), superior temporal (-48%), anterior cingulate (-63%) and striate (-63%) cortices, but not in parahippocampal gyrus. Parallel analyses of rat brain tissue showed no changes in 5-HT1A or 5-HT2A receptor mRNAs or binding site densities after chronic administration of haloperidol. These data show that schizophrenia is associated with alterations in the expression of central 5-HT1A and 5-HT2A receptors. They confirm reports of increased 5-HT1A and decreased 5-HT2A binding site densities in prefrontal cortex, and reveal more extensive decreases in 5-HT2A receptor gene expression at the mRNA level. The resulting imbalance in the 5-HT1A to 5-HT2A receptor ratio, when considered in terms of the chemoarchitectural distribution of these receptors, may contribute to an impairment of corticocortical association pathways. The apparent dissociation of the normal relationships between the abundance of each 5-HT receptor and its mRNA in schizophrenia introduces a separate complexity to the data, which may give clues to the underlying molecular mechanisms.

Different effects of chronic administration of haloperidol and pimozide on dopamine metabolism in the rat brain

We investigated the differences between the action of haloperidol and pimozide on dopamine metabolism and on catalepsy in periods up to 6 weeks after cessation of chronic administration of the neuroleptics to male Wistar rats. Dopamine and its metabolites (dihydroxyphenylacetic and homovanillic acids) were measured, using high-performance liquid chromatography (HPLC), in the frontal cortex, nucleus accumbens, and striatum. Both neuroleptics produced similar effects after a single dose: catalepsy and an increase of dopamine metabolism in the brain structures. However, haloperidol and pimozide differed after chronic treatment. In haloperidol-treated rats hypersensitivity of the dopaminergic system developed at the end of 2 weeks' administration, as evidenced by depression of dopamine metabolism. The biochemical changes were accompanied by behavioral hyperactivity that lasted up to 3 weeks. Dopamine metabolism in rats treated with pimozide was normal from 24 h after the end of the treatment, while catalepsy was maintained at the high level for up to 8 days and was observable up to 3 weeks after the last dose. Our results suggest that in contrast to haloperidol, pimozide is not able to produce adaptive changes leading to supersensitivity of the dopaminergic system. This may be the consequence of its potent Ca 2+ channel blocking action.

Morphochemical changes in brain structures and their correction by tuftsin in rats with hypofunction of the dopamine system

Chronic administration of haloperidol to Wistar rats induces specific changes in protein metabolism at the cortical-subcortical level (sensorimotor cortex—caudate nucleus), in associative and integrative triggering neurons, and in the cytoplasm and nucleus of the same neuron, judging from the state of structural proteins and aminopeptidase activity. Tuftsin reduces these changes only in the sensorimotor cortex.

Further evidence for the subsensitivity of striatal AMPA receptors, induced by chronic haloperidol administration: an autoradiographic study.

The aim of the present study was to investigate the influence of chronic treatment with haloperidol on the striatal N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxasole-propionic acid (AMPA) and dopamine D2 receptors using a quantitative autoradiography in rats. Haloperidol was given to animals in a dose of ca. 1 mg/kg/day in drinking water for 6 weeks or 3 months and was afterwards withdrawn for 5 days. Haloperidol increased by 20-50% the binding of [3H]spiperone in different regions of the caudate-putamen. Haloperidol decreased by ca. 30% the binding of [3H]AMPA in the ventrolateral region of intermediate part of the caudate-putamen, but did not influence the binding of [3H]MK-801. The present results suggest that, apart from supersensitivity to dopamine, chronic treatment with haloperidol also induces subsensitivity of striatal AMPA receptors.

The effect of chronic haloperidol treatment on glutamate receptor subunit (GluR1, GluR2, KA1, KA2, NR1) mRNAs and glutamate binding protein mRNA in rat forebrain

Antipsychotic (neuroleptic) drugs have effects on the glutamatergic system which include changes in the expression of glutamate receptor subunits. There are, however, no long-term studies. We have investigated the influence of 16 weeks' treatment with haloperidol on eight glutamate receptor mRNAs in dorsolateral striatum, frontoparietal cortex and hippocampus using in situ hybridization histochemistry. The mRNAs targetted were the flip and flop isoforms of GluR1 and GluR2, KA1 and KA2, NR1, and the glutamate binding protein (GBP). The flip isoform of GluR2 was elevated in striatum and cortex, leading to an increase in the GluR2 flip/flop ratio. KA2 mRNA was increased in hippocampus and cortex. GBP mRNA was increased in striatum. The other mRNAs were unaffected. The data show that the profile of glutamate receptor subunit mRNA expression is altered in a molecularly and anatomically selective way following chronic haloperidol administration. They provide another indication of glutamatergic involvement in the biochemical response to antipsychotic medication.

Induction of c-fos mRNA in Rat Medial Prefrontal Cortex by Antipsychotic Drugs: Role of Dopamine D2 and D3 Receptors

The present studies compared the effects of acute and chronic administration of haloperidol or clozapine on c-fos mRNA expression in the rat medial prefrontal cortex. Acute administration of clozapine, but not haloperidol robustly increased c-fos mRNA expression in the infralimbic and prelimbic cortex of the rat. Even though most c-fos mRNA-expressing neurons in the clozapine- treated animals were localized in deep cortical layers, labeled neurons were found organized into several cell bridges connecting the superficial and deep layers of the cortex. After chronic treatment with clozapine, c-fos mRNA was reduced by approximately 60% of that seen acutely; however, the columns of c-fos mRNA expressing neurons did not show the same magnitude of tolerance. Haloperidol had no significant effect even after chronic treatment. We examined further the role of dopamine D2 versus D3 receptors in c-fos gene induction in the infralimbic cortex by studying the acute effects of remoxipride and U-99194A. Remoxipride, a selective D2 antagonist in vitro, induced c-fos mRNA at very low doses and lost its ability to alter c-fos mRNA at higher doses. Interestingly, U-99194A, an antagonist with 20-fold selectivity for D3 over D2 receptors, also produced greater induction of c-fos mRNA at lower doses. We hypothesize that blockade of D3 receptors may enhance c-fos gene expression in the medial prefrontal cortex but that of D2 receptors may prevent the same.

Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments

The influence of chronic electroconvulsive seizure (ECS) or antidepressant drug treatments on expression of brain-derived neurotrophic factor (BDNF) and its receptor, trkB, was examined by in situ hybridization and Northern blot. In frontal cortex, acute ECS increased BDNF mRNA approximately twofold, an effect significantly augmented by a prior course of chronic ECS treatment (10 d). In the hippocampus, the influence of chronic ECS varied between the major subfields. In the dentate gyrus granule cell layer, chronic ECS decreased the acute induction of BDNF and trkB mRNA by approximately 50%, but prolonged their expression: levels remained elevated two- to threefold 18 hr later after the last chronic ECS treatment, but returned to control 18 hr after acute ECS. In CA3 and CA1 pyramidal cell layers, chronic ECS significantly elevated the acute induction of BDNF, and tended to prolong the expression of BDNF and trkB mRNA. A similar effect was observed in layer 2 of the piriform cortex, where chronic ECS significantly increased the acute induction and prolonged the expression of BDNF and trkB mRNA. Chronic (21 d), but not acute (1 d), administration of several different antidepressant drugs, including tranylcypromine, sertraline, desipramine, or mianserin, significantly increased BDNF mRNA and all but mianserin increased trkB mRNA in hippocampus. In contrast, chronic administration of nonantidepressant psychotropic drugs, including morphine, cocaine, or haloperidol, did not increase levels of BDNF mRNA. Furthermore, chronic administration of ECS or antidepressant drugs completely blocked the down-regulation of BDNF mRNA in the hippocampus in response to restraint stress. The enhanced induction and prolonged expression of BDNF in response to chronic ECS and antidepressant drug treatments could promote neuronal survival, and protect neurons from the damaging effects of stress.

Stimulus-evoked dopamine overflow in the rat nucleus accumbens is decreased following chronic haloperidol administration: an in vivo voltammetric study

Fast cyclic voltammetry was used to investigate the effects of chronic haloperidol (HAL) treatment on electrically evoked dopamine (DA) overflow in the nucleus accumbens of the anaesthetized rat in vivo. Evoked DA efflux was significantly reduced in rats treated with 1.0 mg/kg per day HAL for 21 days. In rats treated with 0.5 mg/kg per day, evoked DA overflow was reduced, but did not differ significantly from control values. In untreated animals, injection of a single dose of HAL resulted in a significant increase in the DA overflow evoked by subsequent stimulus trains. In contrast, this HAL challenge did not produce a significant enhancement in evoked DA overflow in any of the. HAL-treated groups. These results are consistent with the previous reports that basal DA release is reduced after chronic HAL treatment, and show for the first time that chronic HAL administration decreases stimulus-evoked DA overflow in the rat nucleus accumbens in vivo.

Effects of chronic haloperidol and intermittent cocaine administration on behavior elicited by apomorphine.

Effects of chronic haloperidol and intermittent cocaine administration on behavior elicited by apomorphine.

The Effects of Haloperidol on Dopamine Receptor Gene Expression

Haloperidol is a widely prescribed antipsychotic that acts as a dopamine D2 receptor antagonist. Chronic administration of haloperidol leads to an increase in striatal D2 receptor binding; however, studies examining striatal D2 receptor mRNA after haloperidol treatment report inconsistent results. This study examines the effects of haloperidol on dopaminoceptive striatal neurons, as well as dopamine D2 containing striatal inputs. Rats were injected subcutaneously with 2 mg/kg haloperidol twice daily for 7 days. A significant (36%) increase in D2 mRNA was observed in the anterior cingulate cortex. However, no changes were observed in the amounts of D1, D2, D3 mRNA, or D2 heteronuclear RNA (hnRNA) in the striatum or in the levels of D2 mRNA and hnRNA in the substantia nigra and ventral tegmental area. Thus, increased striatal D2 binding after haloperidol treatment may not be the result of altered D2 gene activity in the striatum or midbrain, but could result from an increase in D2 mRNA in cingulate corticostriatal neurons and/or a longer half-life for the D2 receptor protein in striatal neurons. Striatal proenkephalin mRNA increased significantly in the caudate-putamen (45%), nucleus accumbens (36%), and the olfactory tubercle (27%) while prodynorphin mRNA remained unaltered after haloperidol treatment. Since D2 receptor mRNA is generally colocalized with proenkephalin mRNA in striatal neurons, these results demonstrate what is likely a selective cellular increase in proenkephalin mRNA without a parallel increase in D2 mRNA.

Failure of chronic haloperidol to induce depolarization inactivation of dopamine neurons in unanesthetized rats

Chronic treatment with neuroleptics has been reported to induce a status of depolarization inactivation of the majority of midbrain dopamine neurons. The present study was aimed at determining whether general anesthesia might be a contributory cause of depolarization inactivation of substantia nigra dopamine neurons. In agreement with previous studies, where neuronal sampling was carried out in animals under chloral hydrate anesthesia, chronic treatment with haloperidol (0.5 mg/kg daily for 21-28 days) produced a marked reduction (about 80%) in the number of spontaneously active dopamine neurons. However, when neuronal sampling was performed in unanesthetized rats, chronic administration of haloperidol (daily for 21-28 days) failed to reduce the incidence of active dopaminergic neurons. The results suggest that depolarization inactivation of dopamine neurons is not present in the intact animal but is probably produced during the neuronal sampling procedure as a consequence of neuroleptic-induced hyperexcitability of dopamine neurons combined with their stimulation by general anesthetics.

The effects of chronic haloperidol administration on GABA‐immunoreactive. Axon terminals in rat medial prefrontal cortex

Several reports have suggested that chronic haloperidol (HAL) treatment induces ultrastructural changes in synapses of substantia nigra, corpus striatum, and medial prefrontal cortex (mPFC) of rat brain. The effects of HAL on specific cortical transmitter systems, however, are not well characterized. Recent studies have indicated that there may be a loss of gamma-aminobutyric acid (GABA)ergic cells in anterior cingulate cortex of schizophrenic subjects and this hypothesis has prompted interest in the question of whether dopamine receptor antagonists, such as HAL, may influence the activity of this transmitter system. This current report describes a quantitative light microscopic analysis of GABA-immunolabeled axosomatic terminals in mPFC of rats treated with HAL decanoate (0.5 mg/kg/day, i.m.) for a period of 4 months. GABA-containing terminals were visualized with an avidin-biotin immunoperoxidase method for localizing anti-GABA antibodies. Computer-assisted image processing was employed to determine the total number of pixels representing GABA-immunoreaction product in axon terminals that were in direct apposition to pyramidal cell bodies. Drug-treated animals showed a significant increase in the number of pixels representing GABA-immunoreaction product in axosomatic terminals of layers II, III, VI, and VI (93%, 63%, 31%, and 43%, respectively). These data are consistent with the idea that chronic HAL administration may be associated with a significant increase in the amount of GABA present in terminals surrounding pyramidal neurons of rat mPFC. The fact that GABA-containing terminals showed the greatest increase in layer II is not consistent with the known distribution of dopamine afferents to this region which is lowest in superficial laminae. Based on the laminar distribution of non-dopaminergic receptor types that have a high affinity for HAL, the effect of this drug on GABAergic transmission could potentially involve changes that are mediated through mechanisms in which 5-HT2 or sigma opiate receptors play a role.

5-HT 1C receptor-mediated phosphoinositide hydrolysis in the rat choroid plexus after chronic treatment with clozapine

Chronic treatment with clozapine (14 days; 10 and 25 mg/kg/day) decreases 5-HT 1C receptor density but not affinity in rat choroid plexus measured with [ 3H]mesulergine. We now report the effects of the same clozapine treatment regimens on the function of 5-HT 1C receptors (measured by maximal stimulation of 5-HT 1C receptor-mediated phosphoinositide hydrolysis) in relation to receptor changes in rat choroid plexus. Quantitative 5-HT 1C receptor autoradiography indicated that chronic clozapine treatment decreased, in a dose-related manner, 5-HT 1C receptor binding sites labeled by antagonist ([ 3H]mesulergine) and agonist ( [ 125 I](±)-1-(2,5- dimethoxy-4- iodophenyl)-2- aminopropane, [ 125 I] DOI ) radioligands. However, only the higher dose of clozapine decreased statistically significantly the maximal 5-HT 1C receptor-mediated phosphoinositide hydrolysis response. Chronic administration of haloperidol (0.5 mg/kg/day) did not change any of the 5-HT 1C receptor parameters. In conclusion, chronic clozapine treatment is able to modulate the function of 5-HT 1C receptors. This further strengthens the possibility that 5-HT 1C receptors may contribute to some of the atypical effects of clozapine.

Differential influence of haloperidol and sulpiride on dopamine receptors and peptide mRNA levels in the rat striatum and pituitary

We examined the effect of chronic administration (14 days) of haloperidol (2 mg/kg/day) or sulpiride (100 mg/kg/day), on the mRNA levels of various genes in the rat striatum and pituitary by quantitative in situ and Northern blot hybridizations. In the pituitary, haloperidol and sulpiride induced similar increases of mRNAs of pro-opiomelanocortin (POMC) (+65% and +73%), prolactin (PRL) (+821% and +840%) and growth hormone (GH) (+32% and +47%), but sulpiride induced a greater increase of D2R mRNA (+125%) than haloperidol (+92%). In the striatum, sulpiride and haloperidol had different effects: sulpiride induced a higher increase than haloperidol of both preproenkephalin A (PPA) mRNA (+67% versus +47%) and D 2 dopamine receptor (D 2R) mRNAs (+72% versus +40%). Moreover, haloperidol and sulpiride had opposite effects on substance P (SP) mRNA. Haloperidol decreased the amount of SP mRNA by 20% while sulpiride increased it by 20%. The D 1 dopamine receptor (D 1R) mRNA level was not significantly modified after either treatment. Our results demonstrate that the effect of a chronic haloperidol treatment on striatal dopamine receptors and neuropeptide mRNA levels is different to that of sulpiride, whereas it is similar on pituitary hormones mRNA levels.

Tiagabine inhibits haloperidol-induced oral dyskinesias in rats.

Chronic administration of haloperidol to male Sprague Dawley rats for 6 months at a dosage of 1.5 mg/kg/day produces oral dyskinesias in a significant percent of the treated group. This has been used as an animal model of tardive dyskinesia in several laboratories, because the rat movements display characteristics reminiscent of the human dyskinetic condition. Previously, we have reported a reduction in these haloperidol-induced oral dyskinesias with the coadministration of a direct acting GABA agonist progabide. Here, we have tested an indirect acting GABA agonist, tiagabine, coadministered with haloperidol, for its effect on the oral dyskinesias. At a dosage of 75 mg/kg/day tiagabine significantly inhibited the onset of vacuous chewing movements (VCMs), decreasing the average movement severity from 11.2 +/- 2.0 to 4.4 +/- 1.4, compared with a placebo rate of 1.3 +/- 0.5 (VCMs/5 min). These data support the proposition that an effective, potent GABAmimetic coadministered with haloperidol, will block the onset of rat oral dyskinesias. This conclusion has important implications for the treatment and prevention of tardive dyskinesia in humans.

Acute versus chronic haloperidol: relationship between tolerance to catalepsy and striatal and accumbens dopamine, GABA and acetylcholine release

Using in vivo microdialysis, changes in extracellular dorsolateral striatum and nucleus accumbens dopamine, GABA and acetylcholine following acute and chronic haloperidol (0.25 mg/kg, s.c.) were evaluated in rats concurrent with the measurement of catalepsy. When administered to drug-naive and chronically treated rats, haloperidol was associated with a consistent and prolonged (> 150 min) increase in dorsolateral striatum and nucleus accumbens DA release and a transient (60 min) increase in dorsolateral striatum GABA release. Haloperidol was also associated with a transient (30 min) increase in dorsolateral striatum acetylcholine release in the chronically treated rats. Basal dopamine and acetylcholine levels were similar in both brain regions; however, basal dorsolateral striatum GABA levels were two-fold higher in the chronically treated rats. Administration of haloperidol was associated with a prolonged (> 150 min) catalepsy in the drug-naive rats which was greatly diminished or absent in chronically treated rats. Additionally, serum haloperidol levels were shown to be similar 120 min following administration of haloperidol in both groups. These results indicate a marked behavioral difference in the effects of haloperidol in drug-naive and chronically treated rats which is not related to an altered bioavailability of the drug and which is dissociated from both basal and haloperidol induced effects on dopamine and acetylcholine release in both brain regions. However, the selective elevation of basal dorsolateral striatum GABA release following chronic administration of haloperidol may contribute to the development of tolerance to catalepsy as well as providing an in vivo neurochemical marker of the long-term effects of haloperidol.

Prevention and reversal of dopamine receptor supersensitivity by cyclo(leucyl-glycyl) (CLG): Biphasic dose-response curves

Chronic administration (21 days) of haloperidol (HAL) (IP, 1.0 mg/kg/day) induced a behavioral supersensitivity (stereotypic sniffing) to dopamine (DA) agonists (apomorphine) and upregulation (increased B max for sulpiride-inhibitable [ 3H]spiroperidol binding) of striatal and limbic D 2 DA receptors (DAr). Coadministration of cyclo(leucyl-glycyl) (CLG; 8mg/kg, SC; every third day, every other day, but not every day) with HAL attenuated the behavioral supersensitivity. D 2-DAr binding assays showed 1) that CLG-induced changes in B max parallel these behavioral changes and 2) that the biphasic CLG dose-response curve may involve CLG failure at high cumulative doses to lower B max. CLG also reversed an already established D 2 DAr supersensitivity/upregulation (i.e., when CLG was injected daily for four days after the withdrawal or HAL). CLG alone did not alter behavior or binding. CLG's ability to both prevent and reverse D 2 DAr upregulation/supersensitivity in animal models suggests that CLG may be useful, within a therapeutic window, in clinical disorders that are thought to involve upregulated DAr (e.g., tardive dyskinesia, L-DOPA-induced dyskinesias, and schizophrenia).

Assessment of striatal extracellular dopamine and dopamine metabolites by microdialysis in haloperidol-treated rats exhibiting oral dyskinesia.

Rats that had received continuous, chronic haloperidol (HAL) for 32 weeks were mentioned for changes in oral movements as determined by Fast Fourier analysis of jaw movements recorded with a computerized video analysis system. Beginning at 24 weeks of administration, HAL-treated animals exhibited a pattern of significant increases in oral movement activity in the 1 to 3 Hz range and decreases in the 5 to 8 Hz range when compared to control animals. The release and metabolism of dopamine (DA) in the striatum of these animals was then assessed using intracranial microdialysis during week 32 of HAL administration and 3 days after withdrawal of HAL. Basal extracellular concentrations of the DA metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid were significantly increased in the HAL-treated rats during continuous HAL administration. Three days after withdrawal from HAL, no difference was seen in basal extracellular concentrations of any of the analytes. No difference in the magnitude of DA release was seen between groups following local application of amphetamine (10 microM) through the dialysis probe during or after chronic HAL administration. These results confirm previous findings that long-term HAL administration produces increased DA turnover during HAL administration, but that this increase does not persist following HAL withdrawal. The increased striatal DA turnover seen during chronic HAL administration may have relevance to the development of late-onset neuroleptic-induced dyskinesia in rats.