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.     

Increased amphetamine stereotypy and longer haloperidol catalepsy in spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) of both sexes and from two sources exhibited enhanced stereotyped behavior following amphetamine (AM) administration. Both the intensity and the duration of sniffing and licking were higher in SHR than in Wistar or Sprague Dawley controls. SHR exhibited longer catalepsy after haloperidol (HALO) than did controls. Rats made hypertensive by the Goldblatt one kidney method showed neither increased AM stereotypy nor longer HALO catalepsy. The increased effect of AM in SHR was not due to greater drug accumulation in the brain. These findings are discussed in terms of altered brain catecholamine metabolism in SHR, and are related to experiments of chronic stress and the sensitization of AM's effects.     

Effects of melatonin on behavioral dopaminergic supersensitivity

This study examines the effects of melatonin on dopaminergic supersensitivity induced by long-term treatment with haloperidol in rats. Enhancements of spontaneous general activity in an open-field and of stereotyped behavior induced by apomorphine after abrupt withdrawal from long-term treatment with haloperidol were used as experimental parameters for dopaminergic supersensitivity. Experiment 1 was conducted to investigate the effects of melatonin on the development of dopaminergic supersensitivity, and experiment 2 was conducted to investigate the effects of melatonin on the development as well as on expression of dopaminergic supersensitivity. Rats of both experiments were long-term treated with saline or haloperidol concomitant to saline or melatonin. In experiment 1 behavioral observations were performed after abrupt withdrawal from long-term treatment. In experiment 2 behavioral observations were performed 1 hour after an acute injection of saline or melatonin, administered after the abrupt withdrawal from long-term treatment. Both behavioral parameters used showed the development of central dopaminergic supersensitivity in rats treated with haloperidol since 24 hours after abrupt withdrawal. Concomitant treatment with melatonin intensified haloperidol-induced dopaminergic supersensitivity, observed 72 hours after withdrawal. Melatonin treatment per se also induced behavioral supersensitivity evaluated by both open-field and stereotyped behaviors, although it was more fugacious than that presented by haloperidol. Acute treatment with melatonin reverted the enhancement of the haloperidol-induced dopaminergic supersensitivity produced by concomitant long-term treatment with melatonin, as well as melatonin-induced dopaminergic supersensitivity per se. Our results support previous evidence of antidopaminergic effects of melatonin and demonstrate that repeated administration of this hormone modifies the plasticity of behaviors mediated by central dopaminergic systems.     

The effect of haloperidol on the performance of stereotyped behavior in sows

Environmentally induced stereotypies in gestating sows were inhibited by haloperidol. This inhibitory effect was stronger in sows that directed stereotyped activities toward objects in the environment than in sows performing self-directed stereotypies. The results indicate that dopamine is involved in the performance of stereotypies in pigs, and that haloperidol seem to impair motivational arousal primarily by reducing the rewarding impact of stereotyped self-stimulation.     

Chronic Administration of Lithium or Other Antidepressants Increases Levels of DARPP-32 in Rat Frontal Cortex

Abstract: We studied the chronic actions of lithium on rat brain by investigating its effects on cyclic AMP-dependent protein phos-phorylation by use of a back-phosphorylation procedure. We identified one heavily regulated phosphoprotein in frontal cortex as the 32-kDa dopamine- and cyclic AMP-regulated phosphoprotein (DARPP-32). Immunoblot experiments demonstrated that chronic lithium regulation of DARPP-32 back-phosphorylation is associated with equivalent increases in levels of DARPP-32 immunoreactivity. Lithium regulation of DARPP-32 immunoreactivity required chronic drug administration and was not observed in several other brain regions examined. Moreover, chronic administration of the antidepressant imipramine or tranylcypromine produced a similar increase in levels of DARPP-32 in frontal cortex, whereas other types of psychotropic drugs, including haloperidol. morphine, and cocaine, did not influence DARPP-32 levels. Increased levels of DARPP-32 could reflect a common functional effect on frontal cortex of long-term exposure to lithium and some other antidepressant medications, an effect possibly related to the clinical actions of these drugs.     

Adaptive changes in sigma and phencyclidine receptors during the long-term use of haloperidol and raclopride in rats

The experiments on male albino rats have shown that 15 days haloperidol (0.5 mg/kg) and raclopride (1 mg/kg) treatment, but not acute administration, causes the increase of density of sigma receptors in the brain. The number of phencyclidine receptors was also elevated, but this increase was not statistically evident. The behavioral effects of ketamine (5 mg/kg) were evidently decreased after long-term haloperidol and raclopride treatment. The motor stimulation and stereotyped behavior induced by apomorphine (0.15 mg/kg) were increased only after treatment of haloperidol, but not raclopride. It seems probable that repeated neuroleptic (haloperidol and raclopride) treatment causes the hyposensitivity of sigma and phencyclidine receptors, despite the increase of their number. It is possible that this change is related to the depolarization inactivation of dopamine neurons caused by repeated neuroleptic administration.     

Phencyclidine-induced stereotyped behavior and serotonergic syndrome in rat

Phencyclidine (50 mg/kg, i.p.) induced in rats a biphasic response consisting of serotonergic syndrome followed by stereotyped behavior. The initial serotonergic syndrome was significantly reduced by cinanserin (20 mg/kg, i.p.) and cyproheptadine (2.0 mg/kg, i.p.) but not influenced by haloperidol (0.5 mg/kg, i.p.). The later stereotyped behavior was significantly reduced by haloperidol (0.5 mg/kg, i.p.) but not influenced by cinanserin (20 mg/kg, i.p.) or cyproheptadine (2.0 mg/kg, i.p.). A lower dose of phencyclidine (5.0 mg/kg, i.p.) elicited only haloperidol-sensitive stereotyped behavior. These results indicate that serotonergic and dopaminergic mechanisms may mediate the behavioral effects of phencyclidine in rats.     

The D2 autoreceptor agonists SND 919 and PD 128483 decrease stereotypy in developing rats

Although stereotyped behavior in adult rats is partly regulated by dopamine (DA) D2 autoreceptors, previous attempts to demonstrate D2 autoreceptor regulation of stereotypy in developing rats have been unsuccessful. In the present study, two highly selective D2 autoreceptor agonists were used to demonstrate D2 autoreceptor regulation of spontaneous stereotyped behavior in developing rats. Both SND 919 and PD 128483 produced significant dose-dependent decreases in the stereotypy counts of 21-day-old, 35-day-old, and adult rats. There was a 51% decrease in the stereotypy counts of 21-day-old rats injected with SND 919, 0.05 mg/kg, compared to a 36% decrease in the counts of rats pretreated with haloperidol. Similarly, PD 128483 significantly decreased the stereotypy counts of 21-, 35-day-old, and adult rats in a dose-dependent fashion. There was a 58% decrease in the stereotypy counts of 21-day-old rats injected with PD 128483, 0.1 mg/kg, compared to a 17% decrease in counts when the rats were first treated with haloperidol. The effect of haloperidol plus PD 128483 was significantly different from the effect of PD 128483 alone. Injection of SND 919 or PD 128483 had no significant effects on the stereotypy counts of 10-day-old rats. The results suggest that DA D2 autoreceptor-mediated regulation of spontaneous stereotyped behavior is functional at 21, but not 10, days of age.     

Effect of chronic haloperidol treatment on dopamine-induced inositol phosphate formation in rat brain slices

The effects of chronic haloperidol administration on the accumulation of inositol phosphates were examined in rat brain slices pre-labeled with [³H]myo-inositol and incubated with various dopaminergic drugs. Rats were treated with haloperidol-decanoate or its vehicle (sesame oil) for two, four or six weeks. Dopamine and the selective D₁ agonist, SKF38393, induced a significant increase in lithium-dependent accumulation of [³H]inositol monophosphate (IP₁) in the frontal cortex, hippocampus and striatum of vehicle-treated animals, while the selective D₂ agonist quinpirole did not show any effect on IP₁ accumulation. The actions of dopamine and SKF38393 were blocked by the D₁ antagonist, SCH23390, but not by the D₂ antagonist, spiperone, in all three brain regions. Haloperidol treatment did not affect basal phosphoinositide turnover in the three brain regions. Four or six weeks of haloperidol treatment significantly decreased dopamine-induced IP₁ accumulation in the striatum (by 30% and 25%, respectively), but not in the frontal cortex and the hippocampus. Four weeks of treatment with haloperidol significantly decreased IP₁ levels in the striatal slices when measured in the presence of quinpirole. However, the accumulation of IP₁ measured in the presence of SKF38393 was not significantly altered after haloperidol treatment. The loss of dopamine-sensitive IP accumulation was not observed in the presence of spiperone after haloperidol treatment. The number, but not the affinity, of [³H]sulpiride binding sites in the striatum was significantly increased (by 34–46%) after chronic haloperidol treatment. A timecourse study suggests that the inhibition by chronic haloperidol treatment of dopamine-induced phosphoinositide hydrolysis may involve an effect secondary to an increase in the number of dopamine D₂ receptors in the striatum.     

Lithium administration affects gene expression of thyroid hormone receptors in rat brain.

Even though lithium has received wide attention in the treatment of manic depressive illness, the mechanisms underlying its mood stabilizing effects are not understood. Lithium is known to interact with the thyroid axis and causes hypothyroidism in a subgroup of patients, which compromises its mood stabilizing effects. Since lithium was recently reported to alter thyroid hormone metabolism in the rat brain, the present study investigated whether these effects were mediated through regulation of thyroid hormone receptor (THR) gene expression. Adult male euthyroid rats were either given a diet containing 0.25% lithium or one without lithium for 14 days. Rats were sacrificed in the evening and RNA was isolated from different brain regions to quantitate the isoform specific mRNAs of THRs. Following 14 days of lithium treatment, THR alpha1 mRNA levels were increased in the cortex and decreased in hypothalamus; THR alpha2 mRNA levels were increased in the cortex and THR beta mRNA levels were decreased in the hypothalamus. No significant difference in the expression of these THR isoforms was observed in the hippocampus or cerebellum. Thus, chronic lithium treatment appeared to regulate THR gene expression in a subtype and region specific manner in the rat brain. It remains to be determined whether the observed effects of lithium on THR gene expression are related to its therapeutic efficacy in the treatment of bipolar disorder.     

Phencyclidine-induced stereotyped behavior in rats: dose response effects and antagonism by neuroleptics.

Phencyclidine hydrochloride produced a very characteristic and reproducible stereotyped behavioral syndrome in rats. Both the intensity and the duration of the phencyclidine-induced stereotyped behavior are elicited in a dose-dependent manner in the 2–16 mg/kg dose range. The predominant behavior elicited by low doses was repetitive lateral head swaying, while with higher doses circling and backward walking were observed in addition to the head swaying. This behavior was antagonized by the neuroleptic agents chlorpromazine, haloperidol, and pimozide, but not by α- or β-adrenergic blockers. These results indicate that the phencyclidine-induced stereotyped behavior may be mediated by central dopaminergic mechanisms.     

Dopamine-mediated behaviour and 3H-spiperone binding to striatal membranes in rats after nine months haloperidol administration

Rats were treated with haloperidol (1.5mg/kg/day) in their drinking water for 9 months, with or without a subsequent withdrawal period of 7–10 days. Compared with controls, spontaneous locomotion and apomorphine-induced stereotypy were reduced in rats maintained on haloperidol whereas both behaviours were increased after the withdrawal period. Maximum specific ³H-spiperone binding to striatal membrane preparations was increased (about 65%) in drug-treated rats with or without a withdrawal period. The dissociation constant for ³H-spiperone binding was significantly increased only in those rats maintained on haloperidol with no withdrawal period. The increase in maximum binding of ³H-spiperone was larger than that reported after less prolonged administration of neuroleptics. The size of the change should be taken into account in assessing the increased ligand binding reported in post-mortem brains of schizophrenics.     

Chronic haloperidol increases voltage-gated Na currents in mouse cortical neurons

Typical antipsychotics are characterized by extrapyramidal syndrome (EPS). Previous studies demonstrated that typical antipsychotics could inhibit neuronal voltage-gated sodium channel (VGSC). However, EPS typically emerge only upon prolonged exposure. As a result, we examined effects of haloperidol, a prototype typical antipsychotic, on neuronal VGSC upon incubation for varying duration. Briefly, VGSC currents were activated and recorded using a whole-cell patch-clamp technique in primary culture of mouse cortical neurons. VGSC activity was inhibited by acute haloperidol exposure (for minutes), but enhanced in a time- and concentration-dependent manner by chronic haloperidol exposure (for hours). The effects of chronic haloperidol were associated with increased expression of VGSC subunits as well as corresponding electrophysiological channel properties. In summary, we found enhanced VGSC currents upon chronic haloperidol exposure in cortical neurons in contrast to inhibition by acute haloperidol exposure. Such a results may contribute to EPS of typical antipsychotics.     

Evidence that Phosphoinositide Metabolism in Rat Cerebral Cortex Stimulated by Pilocarpine, Physostigmine, and Pargyline In Vivo Is Not Changed by Chronic Lithium Treatment

The effect of chronic versus acute administration of lithium on receptor-linked phosphoinositide metabolism was assessed by comparing the change in the cerebral cortex levels of myo-inositol 1-phosphate in response to pilocarpine, physostigmine, or pargyline in rats. Rats were exposed to either 29 consecutive days of LiCl injections or 27 and 39 days of dietary Li2CO3, followed by injected LiCl at the end of the diet to insure a constant level of exposure to the drug. In each experiment, an acute group received a single injection of LiCl 20-24 h before they were killed. One hour before being killed, some of the animals acutely exposed to lithium and some of the animals chronically exposed to lithium each received pilocarpine, physostigmine, or pargyline. At the conclusion of the experiment, the rats were killed and brain levels of myo-inositol 1-phosphate and lithium were determined. A differential production of myo-inositol 1-phosphate in groups receiving acute versus chronic lithium would provide evidence of a change in receptor-linked phosphoinositide metabolism due to the chronic administration of lithium. Brain levels of myo-inositol 1-phosphate are dependent on tissue lithium concentrations; consequently, significant differences observed in brain lithium levels between the groups receiving acute versus chronic lithium prevented a meaningful assessment of the effect of the mode of lithium administration on the production of myo-inositol 1-phosphate in those groups. Stepwise multiple regression analysis and the measured brain lithium levels were used to assess the response of myo-inositol 1-phosphate levels to stimulation in animals receiving acute or chronic lithium treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation by GTP of Basal and Agonist-Stimulated Striatal Adenylate Cyclase Activity Following Chronic Blockade of D1 and D2 Dopamine Receptors: Involvement of G Proteins in the Development of Receptor Supersensitivity

Rats receiving injections of specific antagonists of dopamine receptors (SCH 23390 for D1, haloperidol for D2, and haloperidol+SCH 23390) once daily for 21 days develop a selective supersensitivity of the blocked receptors. To study the molecular correlates of these adaptive changes, we evaluated the involvement of GTP-binding proteins in the development of supersensitivity of dopamine receptors. By means of adenylate cyclase studies, we tested whether any of the treatments modified the functional response to GTP in striata dissected from control and treated rats. Our data show that the chronic blockade of D1 and/or D2 receptors potentiates both basal and dopamine receptor-stimulated adenylate cyclase activity in response to GTP. D1 receptor up-regulation correlates with an increased adenylate cyclase response to GTP, whereas D2 receptor up-regulation is accompanied by an enhanced GTP-induced inhibition of enzyme activity, in both basal and receptor-activated conditions. This potentiation does not seem to match the changes in mRNA content of Gs and Gi alpha subunits. Unexpectedly, however, a significant increase in Gi alpha subunit mRNA was found after the chronic blockade of D1 receptors; this result could be explained by cross-regulation between GTP-binding protein-mediated pathways. This cross-regulation could serve as a protective mechanism whereby cells exposing up-regulated receptors protect themselves from a condition of hyperactivity of the adenylate cyclase enzyme.     

Effects of Chronic Lithium Treatment on Agonist-Enhanced Extracellular Concentrations of Cyclic AMP in the Dorsal Hippocampus of Freely Moving Rats

Abstract: Studies on brain slices and homogenates suggest that chronic lithium treatment affects the activity of adenylate cyclases in the brain. To investigate whether chronic lithium administration influences the cyclic AMP (cAMP) synthesis in vivo, we have used microdialysis to assess lithium-induced alterations in extracellular concentrations of cAMP in the dorsal hippocampus of freely moving rats. Local infusion of noradrenaline or forskolin through the microdialysis probes produced rapid increases in the extracellular concentrations of cAMP in the dorsal hippocampus. Lithium administration for 4 weeks (serum lithium concentration of 0.8 ± 0.11 mmol/L) did not affect the baseline levels of cAMP. However, in rats fed a lithium-supplemented diet, noradrenaline- and forskolin-induced enhancement of cAMP levels was decreased in the dorsal hippocampus. The rats were videotaped 18 min before and 27 min after initiating the introduction of noradrenaline and forskolin into the dorsal hippocampus. The infusion of agonists induced a moderate behavioral excitation. Rats treated with lithium were less active compared with the control rats. Taken together, these data confirm that chronic lithium administration affects the cAMP signaling system in the brain of living animals, presumably by interfering with a site beyond the receptor level.     

Rebound cue state following a single dose of haloperidol

It has been reported that chronic administration of haloperidol produces an amphetamine-like rebound cue state. The experiments reported here were designed to assess whether a similar rebound phenomenon would result from a single dose of haloperidol. Rats were trained to discriminate .5 mg/kg amphetamine from distilled water. Five groups were formed to allow testing of haloperidol's effect at 12, 18, 24, 30, and 36 hr postinjection. Each animal was given 0, .5, 1.0, and 1.5 mg/kg haloperidol at its appropriate injection time in a counterbalanced fashion with one week between each test. A shift in the dose-response function of amphetamine that occurred during these weeks, however, precluded appropriate analysis of haloperidol's effects. Given this result, a second experiment was conducted using a between-subjects design. Half of the animals were injected with 1 mg/kg haloperidol 23 hr prior to testing, whereas the others were injected with distilled water. When tested, the haloperidol group responded 33% of the time on the amphetamine-correct lever, whereas the control group responded at 20%. The observation of posthaloperidol rebound in the between-subjects study and the failure to find significant temporal patterns of rebound phenomena using a within-subjects design have both theoretical and methodological importance.     

Tolerance develops to the haloperidol-induced increase in the efflux of dopamine metabolites from the brains of unanesthetized, freely-moving rats

The lateral cerebral ventricles of freely moving rats were perfused by means of chronically implanted push-pull cannulae every second day for 2 weeks. Perfusates were analyzed for metabolites of dopamine [dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] and of 5-hydroxytryptamine [5-hydroxyindoleacetic acid (5HIAA)] using high performance liquid chromatography and an amperometric detector. Rats received daily subcutaneous injections of haloperidol (1 mg/kg) or its vehicle. After the first injection of haloperidol the concentrations of DOPAC and HVA were markedly increased while that of 5HIAA was unchanged. Complete tolerance developed to the haloperidol-induced increased efflux of dopamine metabolites by day 9, although a higher dose of haloperidol (2 mgf/kg) on day 15 was still capable of eliciting a modest increase in the efflux of DOPAC and HVA.     

Chronically Administered Lithium Alters Neither myo-Inositol Monophosphatase Activity nor Phosphoinositide Levels in Rat Brain

Rats were exposed to either 29 consecutive days of LiCl injections or 27 and 39 days of dietary Li2CO3, followed by injected LiCl at the end of the diet to insure a constant level of exposure to the drug. At the end of the period of chronic exposure to lithium, the rats were sacrificed and brain myo-inositol-1-phosphate phosphohydrolase (myo-inositol monophosphatase) activity was measured. In none of the experiments was there any difference in the lithium-sensitive activity toward myo-inositol monophosphatase when comparing the control and chronic groups. These brains and those from another group of rats that had been given Li2CO3 in their diet for 41 days, followed by 7 additional days of LiCl injections, were also examined for changes in the levels of the phosphoinositides. No reproducible differences in the absolute tissue levels of those lipids were found when control and chronic lithium groups were compared. These results are contrary to published reports which suggest that myo-inositol monophosphatase activity increases and that the phosphatidylinositol level decreases in rat brain as a result of chronic administration of lithium.