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PubMed1996

Does haloperidol block methylphenidate? Motivation or attention?

The effect of methylphenidate preceded by a moderate dose of haloperidol on reaction times over the duration of a continuous performance test (CPT), was investigated in ten male children, with a DSM-III diagnosis of attention deficit disorder with hyperactivity disorder (ADDH). Using a within-subject double-blind design, the effects of methylphenidate preceded by haloperidol on reaction time during the first and second blocks of CPT test were compared. Methylphenidate maintained a significantly improved reaction time in the second block of the CPT test. When methylphenidate, preceded by placebo, was preceded by haloperidol this effect was not observed, suggesting opposing effects on attentional systems by methylphenidate versus haloperidol. The study is the first to examine the "blocking" effect of haloperidol over the course of a CPT. The results suggest that dopamine systems are involved in the maintenance of the CPT response, and support an "incentive motivation" theory of sustained attention.

Analysis of Variance↗

PubMed1993

Clozapine's functional mesolimbic selectivity is not duplicated by the addition of anticholinergic action to haloperidol: a brain stimulation study in the rat.

This study examined whether the anticholinergic potency of the clinically superior antipsychotic drug clozapine contributes to clozapine's anatomically-selective functional inhibition of the mesolimbic dopamine (DA) system, using an electrical brain-stimulation reward (BSR) paradigm in rats that has been previously shown to be highly sensitive to clozapine's mesolimbic functional selectivity. Rats were chronically administered saline, clozapine, haloperidol, or haloperidol plus the anticholinergic compound trihexyphenidyl, and threshold sensitivity of the mesolimbic and nigrostriatal DA systems was assessed using the BSR paradigm, to infer degree of functional DA blockade produced by the chronic drug regimens. Chronic saline produced no change in either DA system. Congruent with previous findings, chronic clozapine powerfully inhibited the mesolimbic DA system but spared the nigrostriatal DA system. Also congruent with previous findings, chronic haloperidol powerfully inhibited both DA systems. Compared to chronic haloperidol alone, chronic haloperidol plus chronic trihexyphenidyl exerted diminished anti-DA action in both the mesolimbic and nigrostriatal DA systems. These results suggest that clozapine's anticholinergic potency is not an adequate explanation for its functional mesolimbic selectivity.

Animals↗

PubMed1996

Formation of pyridinium species of haloperidol in human liver and brain.

Recent interest in the neurotoxicity of haloperidol is based on its oxidation in rodents to the pyridinium derivative, HPP+, a structural analog of the neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). Recently, we reported that HPP+ and a newly identified reduced pyridinium, RHPP+, were present in blood and urine of haloperidol-treated schizophrenics and that the concentrations of RHPP+ exceeded those of HPP+. In this study, we examined pathways for formation of RHPP+ in subcellular fractions of human liver (n = 5) and brain (basal ganglia; n = 5). The major pathway was reduction of HPP+ (20 microM) to RHPP+ in cytosol (0.17-0.39 and 0.03-0.07 microM RHPP+/g cytosolic protein per h in liver and brain, respectively). The reactions were inhibited significantly by menadione and in brain also by daunorubicin. The inhibition profile, cytosolic location and strict NADPH dependence suggest that the enzymes involved are ketone reductases. A second pathway was oxidation of reduced haloperidol (50 microM), a major metabolite of haloperidol in blood and brain, to RHPP+. In liver microsomes, 0.17-0.63 mumol RHPP+ was formed /g microsomal protein per h. A potent inhibitor of the pathway was ketoconazole (IC50, 0.8 microM), which suggests that P-450 3A isozymes could be involved. In brain mitochondria but not microsomes, reduced haloperidol (120 microM) was oxidised to RHPP+ at a small but significant rate (0.005-0.020 mumol RHPP+/g mitochondrial protein per h) which was not attenuated by SKF 525A, quinidine, ketoconazole, or monoamine oxidase inhibitors. Further studies are warranted to establish the biological importance of these metabolites in vivo.

Adolescent↗

PubMed1996

Correlation of vacuous chewing movements with morphological changes in rats following 1-year treatment with haloperidol.

Long-term treatment with the typical antipsychotic drug, haloperidol, can lead to a sometimes irreversible motor disorder, tardive dyskinesia (TD). It has been hypothesized that increased release of glutamate due to prolonged neuroleptic drug treatment may result in an excitotoxic lesion in specific neuronal populations within the basal ganglia, leading to TD. We reported that treatment with haloperidol for 1 month results in an increase in the mean percentage of striatal asymmetric synapses containing a perforated postsynaptic density (PSD) and that these synapses are glutamatergic. Using quantitative immunocytochemistry, we found that depending on how long the animals had been off haloperidol following subchronic (30 d) treatment, there was either a decrease (1 day off) or increase (3-4 days off) in the density of glutamate immunolabeling within the presynaptic terminals of synapses with perforated PSDs. Using a rat model for TD, animals in the current study were treated for 1 year with haloperidol and spontaneous oral dyskinesias (i.e. vacuous chewing movements, VCMs) were recorded. In these long-term treated animals we wanted to determine if there was a correlation between glutamate function, as measured by changes in synapses with perforated PSDs and the density of nerve terminal glutamate immunoreactivity, and VCM behavior. In drug treated rats which demonstrated either a high or low rate of VCMs, there was a significant increase in the mean percentage of asymmetric synapses in the dorsolateral striatum with perforated PSDs in both haloperidol-treated groups compared to vehicle-treated rats. There was a small but significant increase in the density of glutamate immunolabeling within striatal nerve terminals of the high VCM group compared to the low VCM group. There was, however, no difference in the density of glutamate immunolabeling between the high VCM group compared to the vehicle-treated animals. One reason for this lack of difference was partially due to a significant increase in nerve terminal area within the high VCM group compared to either the low VCM- or vehicle-treated groups. The larger nerve terminal size in the high VCM group may be due to a small but sustained increase in glutamate neurotransmitter release with the ability of the terminal to maintain its supply of glutamate, while the terminals in the low VCM group showed evidence of glutamate depletion. This finding would be consistent with the hypothesis that increased glutamatergic activity may be associated with TD.

Animals↗

PubMed1997

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.

Aminopeptidases↗

PubMed1997

D2-dopamine-receptor occupancy during treatment with haloperidol decanoate.

We investigated in an open, explanatory study a total of 24 patients meeting DSM-III-R criteria for schizophrenia. Eighteen patients were treated for at least 4 weeks with a fixed dose of orally administered haloperidol for at least 4 weeks (mean daily dosage ranging from 0.07 to 0.35 mg/kg b.w.), and 6 patients received haloperidol decanoate with a fixed dose for at least 4 months (dosage range 50-150 mg/4 weeks; calculated mean daily dosage ranging from 0.02 to 0.09 mg/kg b.w.). One week after injection of haloperidol decanoate, the single photon emission computed tomography examination was performed. Our data suggest that D2-dopamine-receptor occupancy of 50 mg/4 weeks haloperidol decanoate 1 week after injection corresponds to an oral dose of 4.5 mg/day haloperidol.

Adult↗

PubMed2006

A feasibility study of [11C]SA4503-PET for evaluating sigmal receptor occupancy by neuroleptics: the binding of haloperidol to sigma1 and dopamine D2-like receptors.

We investigated feasibility of positron emission tomography (PET) with [11C]SA4503 for evaluating the sigma1 receptor occupancy rate by neuroleptics. Haloperidol, which is well known to bind dopamine D2-like receptor (D2R) as well as to be a representative non-selective antagonist for sigma1 receptor (sigma1R), was selected as a model drug. Three healthy male subjects underwent 60-min [11C]raclopride-PET and 90-min [11C]SA4503-PET scans successively at a 120-min interval twice in a day for baseline measurement and on another day for haloperidol-loading measurement 16 hours after peroral administration of 3 mg of haloperidol. Binding potential (BP) of [11C]raclopride and [11C]SA4503 was quantitatively evaluated and the sigma1R and D2R occupancy rates were determined. D2R occupancy rates by haloperidol were 64% and 62% in the caudate and putamen, respectively, 16 h after the administration, while sigma1R occupancy rates were approximately 80% in all seven regions investigated including the caudate, putamen and cerebellum 18 h after the administration, suggesting that the sigma1R receptor occupancy rate by haloperidol was slightly larger than the D2R receptor occupancy rate. We concluded that [11C]SA4503-PET can be used for evaluating the sigma1R occupancy rates by neuroleptics or other drugs.

Adult↗

PubMed1981

On the distribution and elimination of haloperidol in cholecystectomized patients.

A single oral dose of haloperidol was given to 19 patients prior to cholecystectomy. The concentration of haloperidol was assessed in serum, urine, fatty tissue, liver tissue, choledochal bile and bile bladder contents. The biological half-life of the drug in the serum was 25.1 +/- 12.9 hours, which is comparable to that in healthy volunteers. Only minute amounts of the drug were excreted with the urine. The drug concentration was only slightly elevated in choledochal bile but in the bile bladder contents it was about 11 times higher than that in the serum. The low concentration of haloperidol in the bile indicated that there was no substantial enterohepatic recirculation of the drug in this patient material. The concentration of haloperidol in fatty tissue was about 20 times, and in liver tissue 900 times higher than that in the serum. The corresponding figures for intramuscular administration of haloperidol were 10 and 325, respectively. A possible relationship between the side-effects and the route of administration is discussed.

Adipose Tissue↗

PubMedDate not supplied

Hydrolysis of haloperidol decanoate in vitro by cultured cells.

[14C]Haloperidol decanoate was hydrolysed by partially purified carboxylesterase but not in plasma, blood, lymph and lymphatic liquid. These fluids inhibited the enzyme-mediated hydrolysis of the ester. Within the same incubation period as above, the ester was found hydrolysed to various extents in cell cultures of isolated rat liver cells, of human and rat lymphocytes and of established cell lines (BGM cells, WI-38 cells and L6 cells). Thus, the hydrolysis of the ester was demonstrated in vitro with use of viable cell cultures instead of enzyme preparation. From the time course study on the metabolism of haloperidol decanoate in cell cultures, it was concluded that haloperidol decanoate was first concentrated in the cells and hydrolysed to haloperidol. Based on these results, the metabolic sequences in vivo leading to the formation of active principle haloperidol after intramuscular administration of its decanoate were discussed.

Animals↗

PubMed1998

Chronic treatment with haloperidol diminishes the phencyclidine-induced sensorimotor gating deficit in rats.

Prepulse inhibition is a model in which a weak subthreshold stimulus (prepulse), presented to an individual before a strong stimulus (pulse), inhibits a startle response to the latter. A deficit of prepulse inhibition induced by dopaminomimetics and antagonists of NMDA receptors has been suggested as an animal model of the sensorimotor deficit in schizophrenia. The aim of the present study was to examine the effect of chronic treatment with the classic neuroleptic haloperidol on the disruption of prepulse inhibition induced by the uncompetitive antagonist of NMDA receptors phencyclidine (PCP, 5 mg/kg sc). Haloperidol in a dose of 1 mg/kg/day was given to rats in drinking water for 3 months. The PCP-induced reduction in prepulse inhibition was not reversed by short-term (4-day) haloperidol administration. In contrast, long-term treatment with haloperidol (6 weeks or 3 months) diminished the PCP-induced effect. The present study suggests that the improvement in sensorimotor gating in the PCP model in rats by prolonged treatment with haloperidol may reflect its antipsychotic action.

Animals↗

PubMed1999

Chronic haloperidol and clozapine administration increases the number of cortical NMDA receptors in rats.

The aim of the present study was to examine the influence of 3-month administration of haloperidol (1 mg/kg per day) and clozapine (30 mg/kg per day) in drinking water on cortical NMDA (N-methyl-D-aspartate) receptors in rats. On day 5 of withdrawal, the animals were killed and their brains were removed. The binding of [3H]MK-801 ([3H](5R, 10S)-(+)-5-methyl-10,1 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) and [3H]CGP 39653([3H]D,L-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid) to NMDA receptors in different cortical areas, as well as the binding of [3H]spiperone to dopamine D2 receptors in the striatum, were analysed by quantitative autoradiography. Haloperidol increased the binding of [3H]CGP 39653 in frontal, insular and parietal cortices. Clozapine increased the binding of [3H]CGP 39653 in insular and parietal cortices. Haloperidol, but not clozapine, increased the binding of [3H]spiperone in the striatum. None of the neuroleptics influenced the binding of [3H]MK-801 to cortical NMDA receptors. An additional assay revealed an increase in the Bmax value, with no significant changes in the K(D) of [3H]CGP 39653 binding in parieto-insular cortical homo-genates as a result of haloperidol and clozapine administration. The present results suggest that long-term treatments with haloperidol and clozapine increase the number of NMDA receptors in different cortical regions.

2-Amino-5-phosphonovalerate↗

PubMed2003

Olanzapine vs haloperidol: treating delirium in a critical care setting.

OBJECTIVE: To compare the safety and estimate the response profile of olanzapine, a second-generation antipsychotic, to haloperidol in the treatment of delirium in the critical care setting. DESIGN: Prospective randomized trial. SETTING: Tertiary care university affiliated critical care unit. PATIENTS: All admissions to a medical and surgical intensive care unit with a diagnosis of delirium. INTERVENTIONS: Patients were randomized to receive either enteral olanzapine or haloperidol. MEASUREMENTS: Patient's delirium severity and benzodiazepine use were monitored over 5 days after the diagnosis of delirium. MAIN RESULTS: Delirium Index decreased over time in both groups, as did the administered dose of benzodiazepines. Clinical improvement was similar in both treatment arms. No side effects were noted in the olanzapine group, whereas the use of haloperidol was associated with extrapyramidal side effects. CONCLUSIONS: Olanzapine is a safe alternative to haloperidol in delirious critical care patients, and may be of particular interest in patients in whom haloperidol is contraindicated.

Adult↗

PubMed2002

Differential effects of chronic haloperidol and clozapine administration on glutamatergic transmission in the fronto-parietal cortex in rats: microdialysis and electrophysiological studies.

Glutamatergic neurotransmission has been suggested to be involved in the pathogenesis of schizophrenia. Hence the aim of the present study was to examine the influence of haloperidol, a typical neuroleptic, and clozapine, an atypical one, on glutamatergic transmission in the fronto-parietal cortex. Haloperidol (1 mg/kg per day), or clozapine (30 mg/kg per day), was administered in drinking water for 6 weeks and was afterwards withdrawn for 4 days. The basal and the veratridine (100 microM)-induced extracellular glutamate and aspartate levels were measured by a microdialysis in vivo; neuronal discharges which developed in a Mg(2+)-free medium were recorded extracellularly in cortical slices ex vivo. Haloperidol elevated the basal, but not the veratridine-stimulated, extracellular levels of glutamate and aspartate. Haloperidol enhanced the activity of cortical neurons, which resulted in a decrease in the inhibitory influence of CGP 37849 on their frequency. The increased frequency of discharges induced by NMDA was not affected by haloperidol. In contrast, clozapine lowered both the basal and the stimulated levels of glutamate and aspartate, but had no effect on the activity of cortical neurons. The present study suggests that the two representatives of typical and atypical neuroleptics affect differently glutamatergic neurotransmission in the fronto-parietal cortex, which may reflect their diverse efficacy as antipsychotic agents.

Animals↗

PubMed2003

Procedural learning in schizophrenia after 6 months of double-blind treatment with olanzapine, risperidone, and haloperidol.

RATIONALE: First generation antipsychotics induce extrapyramidal motor symptoms (EPS), presumably through dopamine D(2) receptor blockade at the dorsal striatum. This may also produce impairment of cognitive processes, such as procedural learning, that are dependent on this region. Haloperidol and, to a lesser extent, risperidone, are active in the dorsal striatum and may induce EPS and impairment of procedural learning. In contrast, the prototypical second-generation antipsychotic, clozapine, is less active in the dorsal striatum and does not induce EPS or impair procedural learning. Olanzapine is pharmacologically similar to clozapine and has a low incidence of EPS induction. OBJECTIVES: To assess the hypothesis that olanzapine would not have a deleterious effect on procedural learning. METHODS: Thirty-nine subjects with early phase schizophrenia were randomly assigned to double blind treatment with haloperidol, risperidone, or olanzapine. They were administered the Tower of Toronto test at an unmedicated baseline and again following 6 weeks and 6 months of treatment. RESULTS: Procedural learning, defined as the improvement observed between two blocks of five trials of the Tower of Toronto, was preserved after 6 weeks of all three treatments but showed a substantial decline after 6 months of treatment with haloperidol or risperidone. CONCLUSIONS: These data are consistent with the differential activity of the three medications in dorsal striatum structures and suggest that the advantages of olanzapine over haloperidol and risperidone in relation to extrapyramidal syndromes may also generalize to procedural learning. The results also suggest that the procedural learning disadvantages of haloperidol and risperidone accrue slowly but are apparent after 6 months of treatment.

Adolescent↗

PubMed2003

Differential region-specific regulation of central alpha 1-adrenoceptor binding following chronic haloperidol and clozapine administration in the rat.

RATIONALE: Many antipsychotics exhibit potent anti-alpha(1)-adrenergic receptor activity, which has been suggested to contribute to typical and atypical antipsychotic effects and to the production of centrally mediated side effects. OBJECTIVES: To assess the relative contribution of alpha(1)-adrenoceptors to the mechanism of action of haloperidol and clozapine and to identify possible sites of action. METHODS: We examined the effect of chronic haloperidol and clozapine treatment on alpha(1)-adrenoceptor characteristics in several rat brain regions. For comparison, D(2)-like dopamine receptor density in the striatum was also determined. RESULTS: Clozapine administration (25 mg/kg/day i.p., 21 days) significantly increased alpha(1)-adrenoceptor density in the frontal cortex (44%), remaining cortex (49%) and thalamus (93%) but binding levels in the hippocampus and spinal cord were unchanged relative to vehicle. Haloperidol treatment (1.5 mg/kg/day i.p., 21 days) also significantly increased the density of alpha(1)-adrenoceptor binding in the thalamus (73%), but had no effect on alpha(1)-adrenoceptor levels in any other region examined. alpha(1)-Adrenoceptor affinity in the cortex was not significantly altered by either antipsychotic treatment. Haloperidol, in contrast to clozapine, significantly upregulated dopamine D(2)-like binding in the striatum. CONCLUSIONS: Central alpha(1)-adrenoceptors are differentially regulated after chronic haloperidol and clozapine treatment. It is suggested that thalamic alpha(1)-adrenoceptors may represent a common anatomical locus contributing to the antipsychotic activity and/or alpha(1)-adrenoceptor centrally mediated side effects of both drugs, whereas the selective upregulation of cortical alpha(1)-adrenoceptor density by clozapine may contribute, in part, to its superior atypical properties.

Animals↗

PubMed2005

Clozapine increases cutaneous blood flow and reduces sympathetic cutaneous vasomotor alerting responses (SCVARs) in rats: comparison with effects of haloperidol.

RATIONALE: Clozapine inhibits sympathetic outflow to the cutaneous vascular bed. Clozapine reverses hyperthermia and cutaneous vasoconstriction induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) or by lipopolysaccharide (LPS). Clozapine also reverses cutaneous vasoconstriction elicited by exposure to cold. These actions distinguish clozapine from haloperidol. Clozapine could also inhibit sympathetic cutaneous vasomotor alerting responses (SCVARs), vasoconstrictor episodes that reflect emotional/psychological function, and this property might also distinguish clozapine from haloperidol. OBJECTIVES: Experiments in rats determined whether clozapine and haloperidol inhibit SCVARs, and whether SR46349B (a 5HT2A receptor antagonist), 8-OH-DPAT (a 5-HT1A agonist), L741,626 (a dopamine D2 antagonist) or SCH23390 (a dopamine D1 antagonist) have clozapine-like effects on SCVARs. METHODS: Mean level and pulse amplitude of the tail artery Doppler flow signal were recorded in conscious freely moving rats before and after alerting stimuli (e.g. tapping the cage), and expressed as a SCVAR index (fall to zero flow implies SCVAR index of 100%, no fall implies 0%). RESULTS: Clozapine (0.0625-1.0 mg/kg, s.c.) dose-dependently increased resting tail blood flow. After 1 mg/kg, the SCVAR index was 18+/-1%, compared with 83+/-2% after vehicle. SR46349B (0.01-1.0 mg/kg) and 8-OH-DPAT (0.25 mg/kg) had similar but less potent effects on cutaneous blood flow and on SCVARs. Haloperidol (0.005-0.5 mg/kg) and L741,626 (1 mg/kg) had no or little effect on these variables. SCH23390 mildly inhibited SCVARs. CONCLUSIONS: Clozapine, but not haloperidol, increases resting cutaneous blood flow and decreases SCVARs. Antagonism at 5-HT2A receptors and agonism at 5-HT1A receptors could contribute to these actions.

Animals↗

PubMed1997

Subchronic effects of clozapine and haloperidol on rats' forelimb force and duration during a press-while-licking task.

In order to compare and contrast the behavioral effects of the typical neuroleptic haloperidol with the atypical neuroleptic clozapine, ten daily doses of these drugs were administered to separate groups of rats trained to extend the forelimb through a rectangular hole and to exert downward pressure on a force transducer to gain access to water. Doses were individually titrated daily for each rat in an attempt to achieve a 50% reduction in time on task (analogous to response rate) during 8-min daily sessions. Clozapine-treated rats exhibited dramatic tolerance to the drug's suppressive effect on time on task. In contrast, haloperidol rats displayed little tolerance on this measure. Despite the tolerance reflected by time on task, no tolerance was seen in clozapine's marked slowing of the dominant frequency of oscillations in forelimb force as measured by Fourier analysis of the force-time recordings. Haloperidol did not slow the dominant frequency. No tolerance was seen for clozapine's effects on forelimb force or tremor measures. Haloperidol did not significantly affect forelimb force. Both haloperidol and clozapine produced increases in the duration of long-duration forelimb responses, and no tolerance was seen for either drug on this measure of behavior. For clozapine, the dissociation between the tendency to respond (time on task) and the observed slowing of the dominant frequency may reflect effects peculiar to atypical neuroleptics, while the lengthening of long-duration responses by both drugs may reflect a more general behavioral effect that is characteristic of both typical and atypical antipsychotic drugs.

Animals↗

PubMed1997

The effects of kainic acid lesions on dopaminergic responses to haloperidol and clozapine.

The antipsychotic drugs haloperidol and clozapine have the common action of increasing dopamine metabolism in the striatum (nucleus accumbens, caudate-putamen) of the rat. Intracerebroventricular administration of kainic acid (KA) produces neuronal loss in limbic-cortical brain regions which project directly or indirectly to the striatum. In the present study, dopamine metabolism in subregions of the striatum was examined in rats with KA lesions after acute and chronic haloperidol or clozapine administration. The main findings was that the elevating effect of acute haloperidol treatment on the dopamine metabolite, DOPAC, was blocked in the nucleus accumbens shell and diminished in medial and laterodorsal caudate-putamen of the KA-lesioned rats. In addition, the elevating effects of both acute and chronic haloperidol treatment on dopamine turnover were attenuated in the laterodorsal caudate-putamen of KA-lesioned rats. The levels of dopamine, DOPAC, and HVA after chronic clozapine treatment were greater in KA-lesioned than control rats. These results indicate that dopaminergic responses to haloperidol may be diminished by limbic-cortical neuropathology, while such pathology does not significantly alter dopaminergic responses to clozapine.

Animals↗