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.     

Effect of chronic haloperidol and quinacrine coadministration on striatal HVA levels and stereotypic behaviors in response to apomorphine in the rat

The effects of chronic administration of quinacrine, a phospholipase A2 inhibitor, on striatal homovanillic acid (HVA) levels and behavioral sensitivity to challenge with a dopamine agonist were examined in rats. Moreover, the ability of chronic phospholipase A2 inhibition to modulate the behavioral supersensitivity and striatal HVA reduction induced by chronic haloperidol administration was also examined. Daily intraperitoneal injection of quinacrine resulted in a significant reduction of striatal HVA levels. Coadministration of haloperidol with quinacrine in this paradigm caused a more profound reduction of striatal HVA levels than either drug administered alone. That this effect of combined administration is not simply due to postsynaptic effects of quinacrine on dopamine receptor sensitivity is suggested by the fact that behavioral supersensitivity was not induced by quinacrine alone nor was the behavioral supersensitivity induced by the quinacrinehaloperidol combination greater than that induced by chronic haloperidol administration alone. There were no effects of any treatment condition on striatal levels of serotonin (5-HT) or 5-hydroxyindoleacetic acid (5-HIAA). These data implicate phospholipase A2 activity in the regulation of dopaminergic transmission.     

The effect of chronic levodopa on haloperidol induced behavioral supersensitivity in the guinea pig

The effect of chronic levodopa-carbidopa administration (200 mg/kg for 21 days) on guinea pigs rendered behaviorally supersensitive by the prior administration of haloperidol (.5 mg/kg for 21 days) was examined. Animals who showed an increased behavioral response to apomorphine after chronic haloperidol administration were treated with levodopa-carbidopa and then apomorphine - induced stereotypy was reexamined. Although the chronic levodopa control groups and the chronic haloperidol control remained supersensitive to the behavioral effect of apomorphine, the haloperidol-levodopa group's behavioral response to apomorphine returned to normal. Both chronic dopaminergic antagonist and agonist administration have been demonstrated to induce heightened apomorphine-induced stereotypy and this has been interpreted as a reflection of altered striatal dopamine receptor site sensitivity. The finding that the serial administration of a chronic dopaminergic antagonist followed by a chronic dopaminergic agonist results in a return to normal of a striatal dopamine receptor-dependent behavior suggests that these chronic treatments affect dopamine receptor sites by different mechanisms of action. Since neuroleptic induced dopaminergic supersensitivity in animals is an accepted model of tardive dyskinesia, levodopa may also reverse dopaminergic supersensitivity in patients and might be a potential therapeutic agent in tardive dyskinesia.     

Effects of cyclo (Leu-Gly) on neurochemical indices of striatal dopaminergic supersensitivity induced by prolonged haloperidol treatment

The effects of a prolonged treatment with cyclo (Leu-Gly) and/or haloperidol on biochemical parameters indicative of striatal dopamine target cell supersensitivity have been investigated in the rat. When given acutely, cyclo (Leu-Gly) (2 mg/kg sc) did not affect striatal homovanillic acid, dihydroxyphenylacetic acid and acetylcholine levels both under basal conditions or after acute haloperidol (1 mg/kg ip) treatment. When given concomitantly with haloperidol (infused by means of osmotic minipumps at a rate of 2.5 μg/h sc) for 14 days, cyclo (Leu-Gly) (2 mg/kg sc once daily) failed to prevent the fall of striatal dopamine metabolites observed 2 days following withdrawal and the tolerance to the elevation of dopamine metabolites which occurs in response to challenge with the neuroleptic during withdrawal. Prolonged treatment with cyclo (Leu-Gly) also failed to affect the tolerance to the decrease of striatal acetylcholine levels which occurs under chronic haloperidol treatment. These data suggest that the mechanism whereby cyclo (Leu-Gly) inhibits the development of neuroleptic-induced dopaminergic supersensitivity does not involve an action of the peptide on nigro-striatal dopaminergic and striatal cholinergic neurons and is probably exerted distally to both dopaminergic and cholinergic synapses.     

Behavioral evidence for dopaminergic supersensitivity after chronic haloperidol

Chronic administration for 16 days of haloperidol (in increasing doses up to 20 mg/kg/day) results in a supersensitivity of dopamine receptors. This supersensitivity is manifested by an enhanced stereotypy and aggression in response to small, otherwise ineffective, doses of apomorphine. Maximum aggression is observed 7 days after the last dose of haloperidol when 2.5 mg/Kg of apomorphine is administered. In addition, “wet shakes”, reminiscent of withdrawal from morphine, are observed in these animals after the cessation of the haloperidol administration. These shakes are blocked by morphine. These results may be interpreted to mean that “wet shakes” and drug induced aggression are the results of hyperactivity of the dopaminergic system.     

Differential effects of chronic clorgyline and amfonelic acid on desensitization of striatal dopamine receptors

Chronic treatment of rats with the MAOI clorgyline significantly reduced the density (Bmax) of cortical beta-adrenergic receptors but did not alter either the Bmax or dissociation constant (Kd) of 3H-spiperone binding to striatal DA receptors. Clorgyline co-treatment also did not significantly affect either behavioral supersensitivity to apomorphine or the increase in 3H-spiperone binding induced by chronic haloperidol. In contrast, repeated treatment with the DA uptake inhibitor amfonelic acid elicited behavioral subsensitivity and reduced striatal 3H-spiperone binding. Furthermore, amfonelic acid co-treatment prevented haloperidol-induced behavioral and receptor binding changes. The possible relevance of these findings in relation to drug choice in clinical trials of receptor sensitivity modification are discussed.     

L-prolyl-l-leucyl-glycinamide and its peptidomimetic analog 3(R)-[(2(S)-pyrrolidylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA) attenuate haloperidol-induced c-fos expression in the striatum

Acute treatment of rats with haloperidol results in a rapid and transient increase in striatal c-fos mRNA and Fos immunoreactivity. The induction of immediate early genes by haloperidol may be involved in the development of extrapyramidal side effects. L-Prolyl-L-leucyl-glycinamide (PLG, or MIF-1) has been observed to antagonize the development of haloperidol-induced D(2) receptor supersensitivity in rats. We investigated the modulatory effects of PLG on haloperidol-induced c-fos and Fos protein expression in the rat striatum. We report that coadministration of either PLG or the potent analog of PLG, 3(R)-[(2(S)-pyrrolidylcarbonyl)amino]-2-oxo-1-pyrrolidineacetam ide (PAOPA), attenuated haloperidol-induced c-fos and Fos expression. Haloperidol induced [2 mg/kg, intraperitoneally (i.p.)] c-fos and Fos expression by 500% and 100%, respectively. These responses were attenuated by 170% and 75%, respectively, when coadministered with PLG (20 mg/kg, i.p.) or by 79% by PAOPA (10 microg/kg, i.p.).     

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.     

Neuroprotective Effects of Alpha Lipoic Acid on Haloperidol-Induced Oxidative Stress in the Rat Brain

Haloperidol is an antipsychotic drug that exerts its' antipsychotic effects by inhibiting dopaminergic neurons. Although the exact pathophysiology of haloperidol extrapyramidal symptoms are not known, the role of reactive oxygen species in inducing oxidative stress has been proposed as one of the mechanisms of prolonged haloperidol-induced neurotoxicity. In the present study, we evaluate the protective effect of alpha lipoic acid against haloperidol-induced oxidative stress in the rat brain. Sprague Dawley rats were divided into control, alpha lipoic acid alone (100 mg/kg p.o for 21 days), haloperidol alone (2 mg/kg i.p for 21 days), and haloperidol with alpha lipoic acid groups (for 21 days). Haloperidol treatment significantly decreased levels of the brain antioxidant enzymes super oxide dismutase and glutathione peroxidase and concurrent treatment with alpha lipoic acid significantly reversed the oxidative effects of haloperidol. Histopathological changes revealed significant haloperidol-induced damage in the cerebral cortex, internal capsule, and substantia nigra. Alpha lipoic acid significantly reduced this damage and there were very little neuronal atrophy. Areas of angiogenesis were also seen in the alpha lipoic acid-treated group. In conclusion, the study proves that alpha lipoic acid treatment significantly reduces haloperidol-induced neuronal damage.     

The effect of thioridazine on haloperidol induced behavioral hypersensitivity

Behavioral Hypersensitivity (BH) to dopamine agonists occurs following chronic treatment with most neuroleptics including haloperidol. In the present study we observed that the concurrent administration of thioridazine and haloperidol prevented the development of BH. In contrast, another neuroleptic, fluphenazine, coadministered with haloperidol, potentiated the degree of BH relative to animals treated with haloperidol only. In rats already made hypersensitive by chronic treatment with haloperidol, a 4 week subsequent treatment with normal saline, thioridazine alone of thioridazine in combination with haloperidol, produced normal behavioral responsiveness. These results suggest that thioridazine prevents the development of BH and can reverse the expression of haloperidol-induced BH.     

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.     

Effects of haloperidol on rat behavior and density of dopaminergic D2-like receptors

The present work shows the effects of a typical neuroleptic drug (haloperidol, HAL) on rat behavior (catalepsy and locomotor activity) and dopaminergic D2-like receptor densities in the hippocampus and striatum. Male Wistar rats (2-3 months old) were treated daily for 30 days with HAL (0.2 or 1mg/kg, intraperitoneally (i.p.)). At the end of treatment and 1h or 1, 3, 7 and 15 days after drug withdrawal, animals were subjected to behavioral tests and sacrificed afterwards for binding assays. The results showed that behavioral effects with both doses were significant only 1h and 1 day after withdrawal, and similar to controls at the third day. An up-regulation of D2 receptors was observed in the striatum (28% increase) but not in the hippocampus after 24h HAL (1mg/kg) withdrawal. However, an up-regulation was seen in both areas (1mg/kg) 3 days after drug withdrawal (58 and 42% increases in the hippocampus and striatum, respectively), and continued after 7 days of withdrawal only in the striatum (43 and 49% for the doses of 0.2 and 1mg/kg, respectively), suggesting the influence of dose, age, and time of drug withdrawal on these parameters. The up-regulation disappeared after 15 days of haloperidol withdrawal. Increases (72 and 140%) in constant dissociation values (K(d)) values were also observed 7 days after withdrawal. Results show differences on a time-basis between behavioral alterations and dopaminergic D2 receptors up-regulation.     

No change in dopamine D1 receptor in vivo binding in rats after sub-chronic haloperidol treatment

A frequent side effect in the long-term treatment of schizophrenia with the dopamine D2 antagonist haloperidol (HAL) is the appearance of tardive dyskinesia or, in animals, of repetitive involuntary vacuous chewing movements (VCMs). In rats, chronic HAL-induced or D1 receptor-stimulated VCMs are suppressed by D1 antagonists, suggesting that this behavioral supersensitivity is mediated by D1 receptors. The goal of this study was to investigate in vivo the possible relationship between D1 receptor binding and D1-mediated behavioral supersensitivity, after subchronic HAL treatments. D1 agonist R-SKF 82957 and antagonist SCH 23390, both labeled with carbon-11, were used to assess in vivo D1 receptor binding. Rats were treated with HAL (1.5 mg/kg, i.p.) or vehicle for 21 days, followed by a 4 day washout period. No significant difference was found in the regional brain binding of either radioligand. D1 receptor-mediated behaviors including VCMs, grooming, and rearing were measured in control or HAL-treated rats. VCMs were significantly increased in HAL-treated rats, suggesting D1 receptor stimulation and possibly receptor supersensitivity. This study failed to link the purported D1 receptor-mediated behaviors with in vivo receptor binding measures of R-[11C]SKF 82957 or [11C]SCH 23390 in rat brain regions.     

Down-regulation of haloperidol-induced striatal dopamine receptor supersensitivity by active analogues of L-prolyl-L-leucyl-glycinamide (PLG)

Tardive dyskinesia, a clinical syndrome, is one of the major side effects of protracted treatment with neuroleptics in schizophrenic patients. Functional supersensitivity of striatal dopamine receptors is believed to contribute to the pathogenesis of schizophrenia and tardive dyskinesia. In a rodent model of neuroleptic-induced dopamine receptor supersensitivity, we investigated the efficacy of structurally modified analogues of PLG to down-regulate the striatal dopamine receptor supersensitivity as determined by alterations in [³H]spiroperidol binding to striatal membranes in vitro. The PLG analogue, L-prolyl-L-leucyl-(+)-thiazolidine-2-carboxamide-HCl, when given at the dose of 10 mg/kg IP for 5 days prior to haloperidol (3 mg/kg IP 21 days) significantly prevented the up-regulation of striatal dopamine receptor supersensitivity, thus demonstrating a prophylactic effect. Two other analogues, L-prolyl-L-leucyl-5-aminomethyltetrazole and L-prolyl-L-leucyl-glycine-dimethylamide at a dose of 10 mg/kg IP when given concurrently with haloperidol for 21 days, suppressed the development of dopamine receptor supersensitivity. None of the analogues tested in the post-haloperidol session reversed the haloperidol-induced increase in the density of striatal dopamine receptors. Active PLG analogues hold promise as potential therapeutic agents for the amelioration of tardive dyskinesia.     

Behavioral and cross sensitization after repeated exposure to modafinil and apomorphine in rats

Repeated exposure to psychostimulant drugs has been known to produce behavioral sensitization, a phenomenon explicitly indexed by locomotion (LM) and stereotyped movements (SM). So far, no evidence has demonstrated that this phenomenon can be displayed following the administration of modafinil (MOD) in animal study. We, therefore, assessed the possibility of behavioral sensitization of MOD and a direct dopamine agonist, apomorphine (APO), and cross-sensitization of these two drugs with one other. Pretreatment with MOD (64 mg/kg) or APO (0.5 mg/kg or 1.0 mg/kg) for 10 consecutive days was followed by a short-term (3 days) or long-term (21 days) withdrawal. Rats were then challenged with the drug and reciprocally re-challenged with the counterpart drug. The results showed that following short-term and long-term washout periods, both MOD and APO successfully induced sensitization in LM and SM. There was no cross-sensitization; an even lesser magnitude in LM when MOD-sensitized rats were challenged with APO was observed. However, after both the short-term and long-term withdrawal periods, APO (1.0 mg/kg)-sensitized rats showed cross-sensitization in LM and SM to MOD (64 mg/kg) challenge. The magnitude of APO-MOD cross-sensitization was lesser than the behavioral sensitization induced by APO alone. Our results indicated behavioral sensitization could be induced in rats exposed to MOD. In addition, changes in dopaminergic receptor activities could be involved in cross-sensitization of APO to MOD but not vice versa.     

Mesolimbic and striatal dopamine receptor supersensitivity: prophylactic and reversal effects of L-prolyl-L-leucyl-glycinamide (PLG)

Functional supersensitivity of mesolimbic and striatal dopamine receptors has been suggested to contribute to the pathogenesis of schizophrenia and tardive dyskinesia. Using the rodent model of chronic administration of the neuroleptic haloperidol, we investigated the possible desensitizing effects of a tripeptide structurally unrelated to dopamine agonists, L-prolyl-L-leucyl-glycinamide (PLG) on mesolimbic and striatal dopaminergic receptor supersensitivity. Administration of PLG either prior to or after chronic haloperidol, inhibited the supersensitivity of dopamine receptors. The results have implications for pharmacological intervention in preventing tardive dyskinesia and relapse psychosis of schizophrenia.     

Induction of dopaminergic mesolimbic receptor supersensitivity by haloperidol

Prior exposure to neuroleptics augments the severity of apomorphine-induced stereotypy. This is regarded as a manifestation of increased sensitivity of striatal dopaminergic receptors and has been offered as a model of tardive dyskinesia. The purpose of this study was to determine if neuroleptics modify the sensitivity of mesolimbic dopaminergic receptors. Haloperidol or saline was administered to rats for four weeks. There followed a one week withdrawal period in which cannulae were placed bilaterally in the nucleus accumbens. Histological examination confirmed cannulae placement. Animals received 0, 1.0, 2.5, 5.0 or 10 μg of dopamine through both cannulae beginning eight days after the discontinuation of haloperidol or saline. Locomotor activity was measured in photocell-equipped cages. Animals with a prior exposure to haloperidol had significantly more locomotor activity than control animals. These results indicate that, in the rat, haloperidol can produce a supersensitive dopaminergic mesolimbic receptor.     

Choline chloride in animal models of tardive dyskinesia

Rats treated chronically with haloperidol show evidence of supersensitive dopamine receptors by increased stereotypy when challenged with apomorphine. When such animals are treated acutely with choline chloride at the time of challenge, no changes in stereotypy were observed. Chronic treatment, either during or after induction of supersensitivity, mitigated stereotypy after challenge. This model of dopaminergic supersensitivity is pertinent to the development of tardive dyskinesia in man after treatment with neuroleptic drugs. Our results with choline chloride in the animal model are consistent with their therapeutic action in tardive dyskinesia.     

Neuroendocrine modulation of haloperidol-induced catalepsy

Evidence has been accumulated implicating sex hormones as possible modulators of extrapyramidal motor function. In the present study we have investigated the effects of estrogens, progesterone, testosterone, prolactin and calcitonin on behavioral parameters related to nigro-striatal dopaminergic system, such as haloperidol-induced catalepsy in male rats. It was found that 7-days estradiol benzoate treatment (5 micrograms/rat/day) significantly increases haloperidol-induced catalepsy, suggesting a possible antidopaminergic activity of estrogens. On the other hand, prolactin facilitates nigro-striatal dopaminergic transmission. Interestingly, 7 day treatment with medroxy-acetate progesterone (MAP, 5 mg/Kg, i.p.) brings about a trend to a decrease in haloperidol-induced catalepsy, while no significantly effect was observed following acute MAP administration at the same dose. So, it is tempting to speculate that chronic progestinic treatment may result in an increase in dopaminergic tonus. Testosterone, acutely administered (5mg/kg.s.c.) induces changes similar to those observed following progesterone administration. Finally, also calcitonin is able to influence haloperidol-induced catalepsy by markedly increasing it.     

Attenuation of the behavioral response to quisqualic acid and glutamic acid diethyl ester by chronic haloperidol administration

Long-term neuroleptic administration produces a behavioral supersensitivity to dopamine agonists. Tyrosine hydroxylase immunoreactive synapses in the striatum are closely associated with putative glutamate-mediated synapses, on dendrites and dendritic spines of the same neuronal population. The purpose of the present study was to determine whether chronic neuroleptic administration would alter the behavioral response to glutamatergic drugs. Mice were chronically administered haloperidol for 28 days. After four days of withdrawal, behavioral activity was measured following intraventricular administration of quisqualic acid or intraperitoneal injection of glutamic acid diethyl ester. Both agents decreased behavioral activity. This response to glutamatergic drugs at low dosages was attenuated by chronic haloperidol administration. It is concluded that chronic haloperidol administration alters the behavioral responsivity of animals to glutamatergic drugs.