Catalepsy, Fos protein, and dopamine receptor occupancy after long-term haloperidol treatment

doi:10.1016/0091-3057(94)00397-2

Pharmacology Biochemistry and Behavior

Volume 51, Issues 2–3, June–July 1995, Pages 175-182

https://doi.org/10.1016/0091-3057(94)00397-2 Get rights and content

Abstract

During 12-week haloperidol treatment of rats, the cataleptic effect of an additional challenge dose becomes gradually weaker. We studied whether such a tolerance phenomenon is related to receptor supersensitivity—thus leaving more spare receptors—to a shift in affinity of the receptors towards agonist binding or to an attenuation of a postsynaptic response to dopamine (D₂-type) receptor blockade in the rat basal ganglia. Receptor occupancy was studied with the radioactive agonist [³H]N-propylapomorphine (NPA) and antagonist [³H]N-methylspiperone (MSPIP) to label free dopamine D₂ receptors in vivo. Fos protein served as an index of the postsynaptic response, which was histochemically quantified. This study does not support the concept that dopamine receptor supersensitivity may overcome neuroleptic receptor blockade, but there may be a shift towards higher agonist binding over time. The attenuation of Fos protein expression in the basal ganglia precedes the development of behavioral tolerance.

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Haloperidol is a typical antipsychotic agent belonging to a chemical class of butyrophenone. The neuroleptic and cataleptic effects of haloperidol are well ascribed to dopamine D2 receptor blockade (Coppens et al., 1995; Mizuki et al., 1996; Rehavi et al., 2002; Seeman, 1987; Umathe et al., 2009; Wang et al., 2006). An increasing body of evidence points towards the possible involvement of brain histaminergic system in the pathophysiology of schizophrenia as well as in the action of typical antipsychotic agents (Haas et al., 2008; Morisset et al., 2002; Pillot et al., 2002).
The antipsychotic properties of haloperidol are primarily attributed to its ability to block dopamine D₂ receptors. Histaminergic transmission modulates some of the behavioral effects of haloperidol. Hence, the present study investigated the contribution of central histaminergic transmission in the cataleptic and neuroleptic effect of haloperidol respectively, using bar test and conditioned avoidance response (CAR) in a two-way shuttle box. The studies revealed that haloperidol (0.50 or 1 mg/kg, i.p.) exhibited cataleptic behavior and inhibited conditioned avoidance response (CAR) in the doses 0.25 or 0.50 mg in rats. The rats, pretreated centrally (i.c.v.) with histamine precursor, l-histidine (1, 2.5 μg) or histamine neuronal inducer (H₃ receptor antagonist), thioperamide (20, 50 μg/rat), showed an enhanced cataleptic effect with sub-maximal dose of haloperidol (0.5 mg/kg, i.p.). Similarly, the neuroleptic effect of haloperidol (0.25 mg/kg, i.p.) in CAR was also potentiated in the rats pretreated with l-histidine (2.5 μg) or thioperamide (50 μg/rat). Further, the cataleptic effect of haloperidol (1 mg/kg, i.p.) was attenuated in rats pretreated with the H₁ receptor antagonist, chlorpheniramine (60, 80 μg/rat, i.c.v.) or H₂ receptor antagonist, ranitidine (60 μg/rat, i.c.v.). However, the neuroleptic effect of haloperidol (0.5 mg/kg, i.p.) was completely reversed by pretreatment with ranitidine (60 μg/rat, i.c.v.), and partially attenuated by chlorpheniramine (80 μg/rat, i.c.v.). These findings suggest the possible involvement of histaminergic transmission in the cataleptic and neuroleptic effects of haloperidol probably via H₁ or H₂ receptor stimulation.
Extracellular GABA in globus pallidus increases during the induction of oral tremor by haloperidol but not by muscarinic receptor stimulation
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Citation Excerpt :
Studies using c-Fos immunoreactivity as a marker of striatal neuron activation have shown that acute administration of DA D2 antagonists tends to produce greater increases in c-Fos expression compared to repeated administration. For example, while acute treatment with haloperidol induced a very substantial increase in the expression of c-Fos activity in the striatum [67–72], this induction was attenuated with repeated administration [72–75]. A recent paper also reported similar effects on c-Fos immunoreactivity using acute vs. repeated administration of the D2 antagonist pimozide [42].
Tremulous jaw movements in rats can be induced by several conditions associated with parkinsonism and tremorogenesis, including dopamine depletion, dopamine antagonism, and cholinomimetic drugs. Previous research indicates that neostriatal mechanisms are involved in the generation of tremulous jaw movements, but the striatal output pathways involved in these movements remain uncertain. One important pathway for striatal output is the GABAergic striatopallidal system. The present studies were undertaken to determine if extracellular levels of GABA in globus pallidus are associated with the induction of tremulous jaw movements by either a dopamine D2 antagonist (haloperidol) or a cholinomimetic (the muscarinic agonist pilocarpine). The first experiment studied the effects of both acute and repeated (i.e. 8 days) administration of the D2 antagonist haloperidol. In the second experiment, the effect of acute administration of the muscarinic agonist pilocarpine on GABA levels in the globus pallidus was examined. In both experiments, behavioral observations of tremulous jaw movements were conducted in parallel with the collection of microdialysis samples. Acute and repeated haloperidol treatment induced tremulous jaw movements, and significantly elevated extracellular GABA in globus pallidus. Pooling across all treatment groups, there was a significant positive correlation between pallidal GABA levels and the number of tremulous jaw movements induced during the first three samples collected after injection. However, injection of 4.0 mg/kg pilocarpine had no effect on pallidal GABA release, despite the robust induction of tremulous jaw movements. These results indicate that the tremulous jaw movements induced by dopamine D2 antagonism and those induced through muscarinic receptor stimulation may be generated via distinct mechanisms.
Neural basis of the potentiated inhibition of repeated haloperidol and clozapine treatment on the phencyclidine-induced hyperlocomotion
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Citation Excerpt :
Interestingly, the c-Fos expression in these areas underwent a time-dependent reduction from day 1 to day 5, consistent with the observed HAL and CLZ potentiated inhibition of PCP-induced hyperlocomotion from day 1 to day 5. This pattern of change in c-Fos expression over the repeated treatment period has been reported before in the studies of drugs of abuse (Hope et al., 1992; Persico et al., 1993; Rosen et al., 1994; Salminen et al., 1999), antipsychotic drugs (Atkins et al., 1999; Coppens et al., 1995; Hiroi and Graybiel, 1996; Sebens et al., 1995) and chronic stress (Melia et al., 1994; Stamp and Herbert, 1999; Umemoto et al., 1997). The exact mechanism responsible for this time-dependent c-Fos reduction is still not clear.
Clinical observations suggest that antipsychotic effect starts early and increases progressively over time. This time course of antipsychotic effect can be captured in a rat phencyclidine (PCP)-induced hyperlocomotion model, as repeated antipsychotic treatment progressively increases its inhibition of the repeated PCP-induced hyperlocomotion. Although the neural basis of acute antipsychotic action has been studied extensively, the system that mediates the potentiated effect of repeated antipsychotic treatment has not been elucidated. In the present study, we investigated the neuroanatomical basis of the potentiated action of haloperidol (HAL) and clozapine (CLZ) treatment in the repeated PCP-induced hyperlocomotion. Once daily for five consecutive days, adult Sprague–Dawley male rats were first injected with HAL (0.05 mg/kg, sc), CLZ (10.0 mg/kg, sc) or saline, followed by an injection of PCP (3.2 mg/kg, sc) or saline 30 min later, and motor activity was measured for 90 min after the PCP injection. C-Fos immunoreactivity was assessed either after the acute (day 1) or repeated (day 5) drug tests. Behaviorally, repeated HAL or CLZ treatment progressively increased the inhibition of PCP-induced hyperlocomotion throughout the five days of drug testing. Neuroanatomically, both acute and repeated treatment of HAL significantly increased PCP-induced c-Fos expression in the nucleus accumbens shell (NAs) and the ventral tegmental area (VTA), but reduced it in the central amygdaloid nucleus (CeA). Acute and repeated CLZ treatment significantly increased PCP-induced c-Fos expression in the ventral part of lateral septal nucleus (LSv) and VTA, but reduced it in the medial prefrontal cortex (mPFC). More importantly, the effects of HAL and CLZ in these brain areas underwent a time-dependent reduction from day 1 to day 5. These findings suggest that repeated HAL achieves its potentiated inhibition of the PCP-induced hyperlocomotion by acting on the NAs, CeA and VTA, while CLZ does so by acting on the mPFC, LSv and VTA.
Viral restoration of dopamine to the nucleus accumbens is sufficient to induce a locomotor response to amphetamine
2003, Brain Research
Citation Excerpt :
This supports the notion that the DA released is acting specifically on DA receptors, and this DA is responsible for the observed locomotor effect. High doses of DA receptor antagonists, especially haloperidol, can induce cataleptic behaviors, which could explain the lack of locomotion [4]. However, a basic catalepsy test confirmed that these mice were capable of initiating movement.
Administration of amphetamine to mice evokes hyperlocomotion. Dopamine deficient (DD) mice, in which tyrosine hydroxylase (TH) has been specifically inactivated in dopaminergic neurons, have a blunted response to amphetamine, indicating that the hyperlocomotive response requires dopamine. Dopamine production can be restored to specific brain regions by using adeno-associated viruses expressing TH and GTP cyclohydrolase 1 (GTPCH1). Restoration of dopamine specifically to the nucleus accumbens (NAc) of DD mice completely restores the ability of these mice to respond to amphetamine. This response is specific to the dopamine production in the NAc, as restoration of dopamine production to the caudate putamen (CPu) does not fully restore the hyperlocomotive response to amphetamine. These data support previous studies in which accumbal dopamine is required for producing a normal locomotor response to amphetamine and further show that release of dopamine restricted to the NAc is sufficient for this response
Role of nitric oxide in catalepsy and hyperthermia in morphine-dependent rats
2001, Pharmacological Research
The possible involvement of nitric oxide (NO) in morphine-induced catalepsy and hyperthermia was studied in morphine-dependent rats. Four days repeated injection regimen was used to induce morphine dependence, which was assessed by naloxone challenge (0.5 mg kg ⁻¹, s.c.). Pretreatment of rats with the NO synthase inhibitor, N^G-nitro- $l$ -arginine ( $l$ -NA, 8 mg kg ⁻¹twice daily, i.p.) potentiated the cataleptic response of morphine as shown by a rightward shift in the morphine-log dose–response curve. Prior treatment of rats with the NO precursor, $l$ -arginine (200 mg kg ⁻¹, twice daily, i.p.) abolished the potent effect of $l$ -NA and restored the cataleptic scores to levels similar to those of morphine-dependent rats. The same dose of $l$ -NA significantly blocked morphine-induced hyperthermia at the dose levels of morphine (15–105 mg kg ⁻¹) and this effect was reversed by $l$ -arginine. These data provide the first experimental evidence that NO is involved in morphine induced catalepsy and hyperthermia and demonstrated that blockade of NO synthesis may suggest a dangerous interaction with opioids in the control of motor function.
Enhancement of laminar FosB expression in frontal cortex of rats receiving long chronic clozapine administration
2001, Experimental Neurology
The frontal cortex (FrC) and cingulate cortex (CgC) are critical sites for normal cognitive function, as well as cognitive dysfunction in schizophrenia. Thus, modulation of synaptic transmission within these cortical areas may, in part, account for the therapeutic actions of antipsychotic drugs such as haloperidol and clozapine. FosB and ΔFosB are immediate–early gene (IEG) products sensitive to changes in response to chronic neuroleptic drug administration. We quantitatively examine whether there are light microscopic regional and/or laminar variations in FosB or ΔFosB in the FrC or CgC of normal adult rats, or animals receiving 6 months administration of either drinking water clozapine, or depot haloperidol. Only animals receiving chronic haloperidol developed vacuous chewing movements, the equivalent of tardive dyskinesia in humans. In control animals, the deep and superficial layers of the FrC showed a higher area density of FosB, but not ΔFosB immunoreactive cells than the medial layers of FrC or any of the CgC layers. In animals receiving clozapine, but not haloperidol there was increase in the area density of FosB immunoreactive neurons in all FrC layers, but the major increase occurs in medial layers. These findings suggest that FosB expression identifies those FrC neurons that are most active during normal waking behaviors and are further activated following chronic administration of atypical neuroleptics without motor side effects. The results also indicate that the actions of clozapine are attributed in large part to modulation of the output of frontal cortical pyramidal neurons residing in the medial layers.

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¹: Present address: Psychiatric Center “Brothers Alexians,” Provinciesteenweg 408, B 2530 Boechout, Belgium.

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ArticleCatalepsy, Fos protein, and dopamine receptor occupancy after long-term haloperidol treatment

Abstract

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

Neuroscience

Eur. J. Pharmacol.

Neuropharmacology

Eur. J. Pharmacol.

Neuroscience

Neuropharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

Effect of age on D2 dopamine receptors in normal human brain measured by positron emission tomography and 11C-raclopride

Arch. Neurol.

Antipsychotic agents, toxicology

Homovanillic acid in caudate and prefrontal cortex following acute and chronic neuroleptic administration

Psychopharmacology (Berlin)

Effects of maturation and aging on behavioral responses to haloperidol in the rat

Psychopharmacology (Berlin)

Decreasing sensitivity to neuroleptic agents in developing rats; evidence for a pharmacodynamic factor

Psychopharmacology (Berlin)

High central D2-dopamine receptor occupancy as assessed with positron emission tomography in medicated but therapy-resistant schizophrenic patients

Biol. Psychiatry

Dopamine receptor binding clinical and pharmacological potencies of antischizophrenic drugs

Science

Limbic/mesolimbic connections and the pathogenesis of schizophrenia

Biol. Psychiatry

Conditional tolerance to haloperidol-induced catalepsy is not caused by striatal dopamine receptor supersensitivity

Psychopharmacology (Berlin)

Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs

Arch. Gen. Psychiatry

Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects

Arch. Gen. Psychiatry

Tolerance to tyrosine hydroxylase activation in n. accumbens an c. striatum after repeated injections of “classical” and “atypical” antischizophrenic drugs

Life Sci.

Neuroimaging in schizophrenia research

Schizophr. Bull.

Article
Catalepsy, Fos protein, and dopamine receptor occupancy after long-term haloperidol treatment

High central D₂-dopamine receptor occupancy as assessed with positron emission tomography in medicated but therapy-resistant schizophrenic patients