Effects of short- and long-term haloperidol administration and withdrawal on regional brain cholecystokinin and neurotensin concentrations in the rat

The effects of oral administration of the neuroleptic, haloperidol, on regional brain concentrations of cholecystokinin (CCK) and neurotensin were examined in the rat. Both short-term (3 weeks) and long-term (8 months) haloperidol administration increased the concentration of CCK inthe substantia nigra. While short-term administration significantly increased the concentration of CCK in the ventral tegmental area and decreased the concentration of CCK in the cortex, including the medial prefrontal cortex, these effects were not observed following long-term drug administration. In contrast, long-term, but not short-term, haloperidol administration decreased the concentration of CCK in the olfactory tubercle. Withdrawal from long-term haloperidol did not alter CCK concentrations in any of the brain regions examined. Short-term haloperidol administration significantly increased the concentration of neurotensin in the caudate-putamen. Both short- and long-term administration increased the concentration of neurotensin in the nucleus accumbens, but only the increase following long-term administration reached statistical significance. Withdrawal from long-term haloperidol administration slightly decreased the concentrations of neurotensin in the caudate-putamen and nucleus accumbens. These results indicate that dopamine receptor blockade can affect both CCK- and neurotensin-containing neural systems. Furthermore, these two neuropeptides are affected differently depending upon the duration of haloperidol administration and withdrawal from this drug. The results raise the possibility that chronic administration of haloperidol may be toxic to some neurotensin-containing neurons in the basal ganglia.     

Decreased choline acetyltransferase immunoreactivity in discrete striatal subregions following chronic haloperidol in rats

Neuronal loss within the basal ganglia has been hypothesized to play a role in movement disorders (e.g., tardive dyskinesia) that often occur following chronic neuroleptic treatment. Previous studies in animal models have provided some support to this possibility, but have not assessed regionally specific changes after chronic neuroleptic administration. The present study examined whether counts of neurons containing acetylcholine, described as large aspiny type II neurons, were altered in subregions of the corpus striatum and nucleus accumbens following chronic haloperidol administration in rats. Rats were administered haloperidol decanoate (21 mg/kg, i.m.) or vehicle every third week for 24 weeks. Following 4 weeks of withdrawal from the drug, predefined regions were examined for choline acetyltransferase (ChAT) immunoreactive (ir) cells. Compared to the vehicle group, the haloperidol group showed significant reductions in ChAT-ir cell counts in the ventrolateral striatum, nucleus accumbens core, and nucleus accumbens lateral shell. No significant differences were found in the other regions examined: dorsolateral striatum, dorsomedial striatum, ventromedial striatum, nucleus accumbens medial shell, and horizontal limb of the diagonal band. These findings indicate that there may be regionally specific alterations in ChAT-ir cells following chronic haloperidol treatment, supporting previous hypotheses of striatal cholinergic cell loss resulting from chronic neuroleptic treatment. More importantly, the regions affected (ventrolateral striatum and nucleus accumbens) are critical in the regulation of oral movements, thus suggesting that alterations in cholinergic cell activity, and perhaps actual loss of cholinergic cells in these regions, may be important in the manifestation of late-onset oral dyskinesia.     

Striatal tachykinin biosynthesis: regulation of mRNA and peptide levels by dopamine agonists and antagonists

The effects of dopamine agonists and antagonists on rat basal ganglia substance P, substance K, and preprotachykinin mRNA were examined. Chronic administration of the prototypical dopamine antagonist haloperidol decreased striatal preprotachykinin mRNA and nigral tachykinin peptides. Chronic treatment with the dopamine D2 receptor antagonist L-sulpiride (but not the inactive D-isomer) mimicked the effect of haloperidol. In contrast, the atypical neuroleptic clozapine did not decrease tachykinin mRNA or peptides. The potent indirect dopamine agonist methamphetamine rapidly increased preprotachykinin mRNA, substance P, and substance K although the direct agonist apomorphine was without effect. Methamphetamine-stimulated changes in preprotachykinin mRNA were prevented by prior haloperidol administration. These data demonstrate that alterations in dopaminergic transmission significantly alter striatonigral tachykinin biosynthesis in vivo.     

Primate model of Parkinson''s disease: alterations in multiple opioid systems in the basal ganglia

A motor disorder similar to idiopathic Parkinson's Disease develops in rhesus monkeys after several daily repeated doses of N-methyl-4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP). The concentrations of peptides derived from proenkephalin A, proenkephalin B, substance P and somatostatin were measured by specific radioimmunoassays in the basal ganglia of MPTP-treated monkeys. In MPTP-treated monkeys, dynorphin B concentration was reduced in the caudate. In the putamen, the concentrations of peptides derived from both proenkephalin A and proenkephalin B were decreased. In the globus pallidus, the concentrations of all opioid peptides tend to be increased, reaching significance only for alpha-neo-endorphin. In the substantia nigra, only Met-enkephalin concentration was reduced, while other peptides derived from either proenkephalin A or proenkephalin B were not changed. Substance P and somatostatin were not changed in any brain area examined. Some of the symptoms associated with Parkinson's Disease may be related to altered activity of endogenous opiates in basal ganglia.     

Effects of the σ receptor ligand SR 31742A on neurotensin biosynthesis in rat basal ganglia

The effects of SR 31742A, a specific σ ligand, were investigated on neurotensin (NT) biosynthesis in the basal ganglia of the rat. Both single and repeated treatments with either SR 31742A (20 mg/kg i.p.) or haloperidol (1 mg/kg i.p.) increased the concentration of NT-like immunoreactivity (NT-1i) in the nucleus accumbens. In contrast to haloperidol, the administration of SR 31742A failed to increase the concentration of NT-li in the caudate-putamen. We have further investigated drug-induced variations in NT biosynthesis by studying NT/neuromedin N (NT/NN) mRNA levels in the nucleus accumbens and the ventral tegmental area of the rat following SR 31742A administration. The NT/NN mRNA levels in the ventral tegmental area were increased by a maximum of fifteen fold (7 h at 20 mg/kg i.p.). A lower increase in NTINN mRNA levels was elicited in the nucleus accumbens. These results suggest that the increase in NT-li observed after SR 31742A treatment, like that produced by haloperidol, may result from an increase of NT biosynthesis. Furthermore, the effects of SR 31742A on NT metabolism are similar to those of atypical antipsychotics, since they appear to be selective for the limbic system. © 1995 Wiley-Lies, Inc.     

Somatostatin is increased in the nucleus accumbens in Huntington's disease

Concentrations of somatostatin-like immunoreactivity (SLI) are elevated in the basal ganglia in Huntington's disease. The present study confirms these findings and, in addition, shows that concentrations of SLI are significantly elevated in the nucleus accumbens (4.04 +/- 0.66 versus 1.69 +/- 0.21 ng/mg protein in controls). This area is relatively spared pathologically and shows little atrophy in Huntington's disease. Since many patients with Huntington's disease are treated with haloperidol, we studied the effects of this drug in rats. There was a dose-dependent reduction of SLI in striatum, parietal cortex, and hippocampus. The elevated concentrations of SLI in the basal ganglia in Huntington's disease, therefore, do not appear to result from haloperidol therapy.     

Alterations in striatal neuropeptide Y system activity of rats with haloperidol-induced behavioral supersensitivity

The study was conducted to determine whether the expression of behavioral supersensitivity induced by haloperidol (HAL) administered once daily (2 mg/kg i.p.) for 14 days is associated with the alterations in activity of neuropeptide Y (NPY) system in the striatum (caudate-putamen) and nucleus accumbens. Dopamine supersensitivity was tested by measurement of locomotor activity and stereotyped behavior after administration of the dopamine D2/D3 receptor agonist quinpirole (1 mg/kg i.p.) on day 1, 3 and 7 after HAL withdrawal. Neuropeptide Y-like immunoreactivity (NPY-LI) was determined in the striatum and nucleus accumbens isolated 6 h after quinpirole injection on day 1, 3 and 7 after the end of HAL treatment. NPY mRNA was quantified in these structures on day 7 after HAL withdrawal. HAL increased spontaneous locomotor activity and prevalence of rearing, grooming and head-down sniffing. At the same time, striatal NPY-LI increased progressively from the reduced level found on day 1 of haloperidol withdrawal. NPY mRNA remained unchanged. In saline-treated rats, quinpirole enhanced locomotion, rearing, and induced intense head-down sniffing and oral activity. These behavioral effects were accompanied by a decrease in striatal NPY-LI. NPY mRNA was slightly increased. HAL treatment altered response to quinpirole, namely it increased locomotion, intensified oral activity and reduced rearing and head-down sniffing. The second and the third quinpirole injection decreased NPY-LI levels. NPY mRNA was unchanged. In the nucleus accumbens, apart from a decrease in NPY-LI on day 1 after the last haloperidol dose, the level of NPY-LI and NPY mRNA in any experimental group did not differ from the control value. The presented results suggest that the alterations in the activity of the striatal but not nucleus accumbens NPY system contribute to adaptive changes induced by long-term haloperidol treatment and may be of significance to the motor hyperactivity induced by intermittent stimulation of postsynaptic dopamine D2 receptors.     

Effects of CI-943, a potential antipsychotic drug, and haloperidol on regional brain neurotensin concentrations.

Treatment with efficacious antipsychotic drugs such as haloperidol increases the concentrations of neurotensin (NT) in the nucleus accumbens and caudate nucleus of the rat. These increases in NT concentrations may be associated with the therapeutic and/or side effects of these drugs. CI-943, a novel compound without appreciable affinity for dopamine-binding sites, produces behavioral effects in animals, which suggest that it may possess antipsychotic activity. This study evaluated the effects of subchronic treatment (3 weeks) with CI-943 or haloperidol on regional brain NT concentrations in rats. Haloperidol treatment (1 mg/kg) produced significant increases in the concentrations of NT in the nucleus accumbens and caudate nucleus but not in the other brain regions studied. Like haloperidol, CI-943 (40 mg/kg) increased NT concentrations in the nucleus accumbens and caudate but differed in that CI-943 produced significantly greater increases in NT concentration in the caudate than haloperidol and also increased NT content in the substantia nigra/ventral tegmental area and hypothalamus. The regional specificity of the NT alterations produced by chronic treatment with CI-943, a nondopamine receptor ligand, was similar to that previously reported after treatment with multiple doses of methamphetamine.     

D1 and D2 receptor modulation in rat striatum and nucleus accumbens after subchronic and chronic haloperidol treatment

The antipsychotic effects of neuroleptic drugs are believed to be achieved by chronic blockade of dopaminergic transmission in the limbic system. Nevertheless, the effects of chronic (3-12 months) haloperidol administration on the dopaminergic transmission in the nucleus accumbens of rodents remains poorly understood. Studies of spontaneous locomotor activity (SLA), a behavioral measure related to limbic dopamine transmission, and of dopamine D2 receptor density in the nucleus accumbens after chronic oral haloperidol treatment have yielded conflicting results. We evaluated these indices after 8 months of parenteral administration of haloperidol decanoate. We report here that, after 8 months of parenteral treatment, SLA stays significantly decreased and D2 receptors in the nucleus accumbens exhibit the same up-regulation as in the striatum (about 50%). These results fail to support the notion of a different pattern of D2 receptor adaptation to neuroleptic treatment between the nucleus accumbens and the striatum. In contrast, dopamine D1 receptors were found to be unaffected in the nucleus accumbens but decreased in the striatum by 22% after 8 months of treatment. This observation could be relevant to the pathogenesis of tardive dyskinesia.     

The C-terminal fragment of substance P enhances dopamine release in nucleus accumbens but not in neostriatum in freely moving rats.

The in vivo microdialysis technique was used to study the effects of carboxyl or amino terminal sequences of substance P on the extracellular concentrations of dopamine, its metabolites dihydroxyphenylacetic acid and homovanillic acid, as well as on 5-hydroxyindoleacetic acid, in neostriatum and nucleus accumbens of freely moving rats. The i.p. administration of 37 nmol/kg of the substance P C-terminal heptapeptide analog [pGlu5, MePhe8, Sar9]SP5-11 (DiMe-C7) caused an increase in extracellular dopamine concentrations in nucleus accumbens but not in neostriatum. The administration of the equimolar dose of the heptapeptide N-terminal fragment substance P 1-7 (SP1-7) did not have an effect in either structure. No changes were observed in the extracellular concentrations of the metabolites after the administration of either substance. These results are discussed with respect to the reinforcing effects of substance P and its C-terminal sequence, which may be mediated via dopamine release in the nucleus accumbens.     

Basal ganglia organization in amphibians: Chemoarchitecture

Recent studies dealing with the investigation of the afferent and efferent connections of the basal ganglia of amphibians have revealed many similarities with basal ganglia structures of amniotes. In a further step, the chemoarchitecture of basal ganglia of the frog Rana perezi has been investigated. For use as main markers of amphibian basal ganglia structures, antibodies against tyrosine hydroxylase, substance P, and enkephalin were selected. Moreover, the distributions of nitric oxide synthase (nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry), calretinin, dopamine-β-hydroxylase, choline acetyltransferase, mesotocin, vasotocin, somatostatin, neuropeptide Y, neuropeptide FF, and serotonin were studied to corroborate a comparison with both basal ganglia and amygdaloid structures of amniotes. On the basis of connections and chemoarchitecture, a striatum proper, nucleus accumbens, dorsal and ventral pallidum, bed nucleus of the stria terminalis, and amygdaloid complex have been identified. Accordingly, a new terminology is proposed that is in line with our current understanding of basal ganglia organization in amphibians. J. Comp. Neurol. 392:285–312, 1998. © 1998 Wiley-Liss, Inc.     

Long-term haloperidol treatment decreases somatostatin binding in rat brain

The effects of short and long-term haloperidol treatment on somatostatin concentration and specific binding in rat cerebral cortex and hippocampus were examined using the binding ligand 125I-Tyr1-somatostatin. Haloperidol treatment did not affect the concentration of somatostatin-like immunoreactivity in the two brain areas. Nevertheless, long-term, and not short-term, haloperidol treatment decreased the number of somatostatin receptors in the cerebral cortex and hippocampus. No significant differences in the apparent binding affinity values were seen after haloperidol treatment. When added at the time of the binding assay haloperidol 34.2 microM produced a 42% and 27% decrease in cerebrocortical and hippocampal membrane somatostatin receptors respectively.     

Effects of haloperidol,quinelorane, and lithium on regional neurotensin/neuromedin N concentrations: Further evidence for neurotensin/neuromedin N-Dopamine interactions

In order to further characterize the pharmacologic mechanisms that mediate the antipsychotic drug-induced increase in neurotensin (NT) in nucleus accumbens and striatum, the effects of three weeks treatment with psychotherapeutic levels of lithium alone or in conjunction with haloperidol were compared to the ability of haloperidol alone to alter NT and neuromedin N (NMN) regional brain concentrations in rats. A separate experiment examined the ability of a selective dopamine D2 receptor agonist, quinelorane, to alter NT/NMN regional concentrations after three weeks of treatment as compared to haloperidol, a D₂ receptor antagonist. Haloperidol (1 mg/kg) increased both NT and NMN concentrations in several brain regions and these parallel peptide increases were highly correlated. Lithium chloride (0.4 mM) had no effect, either alone or with haloperidol, on NT/NMN concentrations. Quinelorane (1 mg/kg), however, effectively increased both NT and NMN concentrations in the caudate nucleus and nucleus accumbens, as did haloperidol (2 mg/kg). These data indicate that the induction of NT and NMN, whose adjacent sequences are contained in a pro-hormone product of a single gene, occurs in tandem and remains proportional, as well as demonstrating that putative D₂ receptor agonists can produce effects on NT/NMN systems that are similar to D₂ receptor antagonists. © 1994 Wiley-Liss, Inc.     

Typical and atypical antipsychotic occupancy of D2 and S2 receptors: An autoradiographic analysis in rat brain

In thin sections of rat brain, [3H]spiperone binds to D2 sites in the basal ganglia (caudate-putamen, nucleus accumbens, olfactory tubercle) and S2 sites in the claustrum and motor cortex. The in vitro displacement of [3H]spiperone from these regions was quantified autoradiographically with the "atypical" neuroleptics clozapine and thioridazine, which ameliorate psychosis, a "typical" neuroleptic, haloperidol, which also induces extrapyramidal side effects, or with metoclopramide, which induces extrapyramidal side effects but is an ineffective antipsychotic. Whereas metoclopramide was equipotent at D2 sites, haloperidol was less potent and clozapine and thioridazine more potent by 2- to 3-fold at competing for D2 sites in the nucleus accumbens or olfactory tubercle than in the caudate-putamen. As measured autoradiographically or with tissue homogenates, clozapine, thioridazine, and five other atypical neuroleptics were 4- to 800-times more potent at competing for S2 sites in the frontal cortex than for D2 sites in the basal ganglia. A preference of atypical antipsychotics for D2 receptors in the nucleus accumbens and olfactory tubercle and for the S2 receptor may explain the relative lack of extrapyramidal side effects produced by these compounds.     

Effects of long-term haloperidol treatment on the responsiveness of accumbens neurons to cholecystokinin and dopamine: electrophysiological and radioligand binding studies in the rat

Cholecystokinin (CCK) and dopamine (DA) coexist in a subpopulation of neurons of the ventral tegmental area projecting to the nucleus accumbens. The present experiments were undertaken to determine the effect of acute and long-term administration of haloperidol on the responsiveness of accumbens neurons to microiontophoretic applications of the sulfated cholecystokinin octapeptide (CCK-8S), kainate (KA), and DA and on the density of CCK, D1, and D2 receptors determined by radioautography. Acute administration of haloperidol (1 mg/kg, i.v.) did not modify the neuronal responsiveness to DA and KA but increased that to CCK-8S. Long-term treatment with haloperidol decanoate (4 mg/kg/week, i.m., for 3-5 weeks) induced a marked increase in the responsiveness to CCK-8S, without noticeable change of that to DA and KA. After a 5 week treatment, significant increases in the amounts of CCK and D2 binding were found in the nucleus accumbens, whereas D1 binding parameters remained unchanged. Since long-term haloperidol treatment results in a depolarization inactivation of A10 dopaminergic neurons, these results suggest that, despite the reduced firing activity of mesolimbic dopaminergic neurons induced by the long-term haloperidol treatment, dopamine is still released in an amount sufficient to maintain a normal neuronal responsiveness of postsynaptic accumbens neurons to DA, whereas the release of CCK is possibly decreased to a greater extent, resulting in an enhanced responsiveness of the neurons to this peptide.     

Ontogeny of the effect of antipsychotic drug treatment on neurotensin concentrations in the rat brain

It has been well documented that treatment with haloperidol and other typical antipsychotic drugs increase neurotensin (NT) concentrations in the nucleus accumbens and caudate nucleus in adult rats. The NT neuronal system has been found to undergo distinct age-related changes in the rat brain, and therefore, it is of interest to examine the ontogeny of the effects of antipsychotic drug treatment on NT concentrations. In order to determine when, or if, antipsychotic drug treatment has an effect on NT-containing neurons in the developing rat, rat pups received a single dose of haloperidol (2.0 mg/kg, s.c.) or vehicle at 9, 14, or 20 days after birth. Regional brain NT concentrations were then measured using a sensitive and specific radioimmunoassay. Treatment with haloperidol had no effect on NT concentrations in any brain region in 10-day-old rat pups. At 15 days of age, haloperidol significantly increased NT concentrations in the caudate nucleus (120% of control, P < 0.05). At 21 days of age, haloperidol increased NT concentrations in the caudate nucleus (193% of control, P < 0.001) and nucleus accumbens (126% of control, P < 0.005) similar to that seen in adult animals. There were no statistically significant gender-related differences found in any age or treatment group studied. These findings indicate that there is a specific time point during postnatal development when rat brain NT systems become responsive to antipsychotic drug administration. © 1995 Wiley-Liss, Inc.     

Effect of haloperidol on immunoreactive neuropeptide Y in rat cerebral cortex and basal ganglia

To clarify the dopaminergic regulation of neuropeptide Y (NPY) neurons, the effect of haloperidol on NPY in basal ganglia and the cerebral cortex of the rat brain was investigated by sensitive radioimmunoassay and immunocytochemistry using antiserum against rat NPY. After repeated intraperitoneal injections of haloperidol (5 mg/kg) for 6 days, the content of immunoreactive NPY was significantly decreased in the caudate-putamen, but significantly increased in the lateral prefrontal cortex. After treatment for 21 days, the content of immunoreactive NPY in the caudate-putamen remained significantly low, but the extent of change in the lateral prefrontal cortex diminished. In the medial prefrontal cortex, piriform cortex, parietal cortex and nucleus accumbens, no significant changes were found after treatment for either 6 or 21 days. These findings were compatible with those obtained by immunocytochemistry using the same antiserum: an increase of immunoreactive fibers and terminals in the lateral prefrontal cortex and their decrease in the caudate-putamen. However, in the nucleus accumbens the density of immunoreactive fibers and terminals was decreased in the rostral portion, but not in the caudal portion after haloperidol treatment for 6 and 21 days. These findings suggest that dopaminergic afferents region-specifically regulate dopamine-sensitive NPY neurons in the rat brain.     

Enhancement of self-stimulation behavior in rats and monkeys after chronic neuroleptic treatment: Evidence for mesolimbic supersensitivity

The effect of chronic neuroleptic drug treatment on self-stimulation of the mesolimbic dopamine system was tested. Rats with electrodes implanted into the ventral tegmental nucleus (A10 cell body area) were treated with haloperidol for three weeks. Afterwards, the rats showed a 35% increase in self-stimulation rate, as compared to pre-drug control rates. This increase persisted for three weeks after drug withdrawal before returning to baseline rates. Rats treated for three weeks with the atypical neuroleptic, clozapine, also showed an increase, the duration and magnitude of which was similar to that seen in the haloperidol group. In addition, four rhesus monkeys with electrodes in the nucleus accumbens (one of the terminal projection areas of the A10 mesolimbic dopamine system) were given a three week treatment with haloperidol, after which all animals showed a significant, long-lasting decrease in self-stimulation threshold, as measured by a rate-independent reward paradigm. Taken together, these results suggest the induction of receptor supersensitivity in the mesolimbic dopamine system by long-term treatment with neuroleptic drugs.     

Lack of effect of chronic carbamazepine on brain somatostatin in the rat

Summary We investigated the effects of chronic carbamazepine treatment in rats on brain somatostatin. Following 12 days of carbamazepine treatment, no changes in somatostatin levels were found in any of the brain areas examined which included: amygdala, hippocampus, caudate-putamen, median eminence, arcuate nucleus, nucleus accumbens, nucleus interstitialis of the stria terminalis, nucleus periventricularis, parietal cortex, and occipital cortex. Thus, carbamazepine in low doses does not affect basal levels of brain somatostatin in the rat, in contrast to the previous reports of decreased somatostatin in the cerebrospinal fluid of affectively ill patients.     

Expression of Glutamic Acid Decarboxylase mRNA in Striatum and Pallidum in an Animal Model of Tardive Dyskinesia

Long-term administration of neuroleptics can induce tardive dyskinesia in humans. Oral movements with the same distinctive form observed in humans with tardive dyskinesia are observed in rats treated with haloperidol for 8 and 12 months but not 28 days. We have examined the effects of these long-term haloperidol treatments on the levels of mRNA encoding glutamic acid decarboxylase (GAD, M_r 67,000), the rate-limiting enzyme of GABA synthesis, in the striatum and pallidum of adult rats. Despite the differences in behavior, GAD67 mRNA was increased in the striatum and entopeduncular nucleus (internal pallidum) after both 28 days and 8 months of haloperidol administration. In contrast, only long-term haloperidol treatments (8 and 12 months) decreased GAD67 mRNA in globus pallidus (external pallidum). This effect contrasted with the increased level of GAD67 mRNA we have previously observed in the globus pallidus after short-term haloperidol treatment (3-14 days), a regimen that induces catalepsy. Together with data indicating a loss of GAD activity in target areas of the globus pallidus in humans with tardive dyskinesia, the results suggest that decreased GABAergic transmission in the projection neurons of the external pallidum may play a critical role in the motor side effects associated with long-term neuroleptic therapy.