Behavioral evidence for supersensitivity after chronic administration of haloperidol, clozapine, and thioridazine

doi:10.1016/0024-3205(76)90170-3

Life Sciences

Volume 19, Issue 5, 1 September 1976, Pages 725-731

https://doi.org/10.1016/0024-3205(76)90170-3 Get rights and content

Abstract

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.

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Cited by (95)

Rationale and neurobiological effects of treatment with antipsychotics in patients with chronic schizophrenia considering dopamine supersensitivity
2021, Behavioural Brain Research
Citation Excerpt :
A study reported that clozapine, like aripiprazole, did not cause DRD2 up-regulation at cell levels [154]. On the other hand, several animal models showed behavioral supersensitivity caused by clozapine [155,156]. Past studies have shown that clozapine greatly improved tardive dyskinesia which was caused by previous medications [157].
The long-term treatment of patients with schizophrenia often involves the management of relapses for most patients and the development of treatment resistance in some patients. To stabilize the clinical course and allow as many patients as possible to recover, clinicians need to recognize dopamine supersensitivity, which can be provoked by administration of high dosages of antipsychotics, and deal with it properly. However, no treatment guidelines have addressed this issue. The present review summarized the characteristics of long-acting injectable antipsychotics, dopamine partial agonists, and clozapine in relation to dopamine supersensitivity from the viewpoints of receptor profiles and pharmacokinetics. The potential merits and limitations of these medicines are discussed, as well as the risks of treating patients with established dopamine supersensitivity with these classes of drugs. Finally, the review discussed the biological influence of antipsychotic treatment on the human brain based on findings regarding the relationship between the hippocampus and antipsychotics.
Continuous versus extended antipsychotic dosing in schizophrenia: Less is more
2021, Behavioural Brain Research
Citation Excerpt :
This exaggerated response is the most commonly used index of antipsychotic-induced dopamine supersensitivity in laboratory rodents. In rats, antipsychotic-induced dopamine supersensitivity produces robust sensitization to the psychomotor-activating effects of dopamine agonists, but also to their reward-enhancing effects [39,40,43–49]. Antipsychotic-evoked dopamine supersensitivity is often studied in otherwise neurologically intact animals, but it can also be seen in well-established animal models of schizophrenia symptoms [45].
Antipsychotic drugs temper psychotic symptoms by interacting with dopamine D2 receptors to reduce dopamine neurotransmission. Currently, the standard of care involves antipsychotic treatment protocols that achieve steady-state levels of medication. Maintaining patients on continuous treatment is thought to be necessary to keep them stabilised. However, continuous antipsychotic exposure increases the risk of adverse effects over time. These effects include metabolic and cardiovascular disorders, extrapyramidal complications, and dopamine receptor supersensitivity, the latter of which could potentially promote both treatment tolerance and psychosis relapse. In the present review, we describe evidence showing that continuous exposure to antipsychotic drugs can not only worsen long-term outcome, but—past acute phase treatment—it is also unnecessary to effectively manage schizophrenia symptoms. We also describe evidence that regular but extended dosing, allowing predictable periods of lower antipsychotic levels/D2 occupancy, is both safe and effective in patients, and it greatly reduces drug exposure overall. Studies in laboratory animals show that compared to continuous antipsychotic exposure, regular but extended dosing actually has superior antipsychotic-like efficacy, and it also substantially reduces the likelihood of both motor side effects and dopamine receptor supersensitivity. We propose that regular, but extended dosing should be considered in the long-term treatment of people with schizophrenia, because the available evidence suggests it can be just as effective as continuous treatment, while decreasing overall drug exposure and potentially reducing harmful side effects.
5-HT<inf>2</inf> receptors modulate the expression of antipsychotic-induced dopamine supersensitivity
2015, European Neuropsychopharmacology
Citation Excerpt :
However, amphetamine-induced locomotion permits an accessible and rapid assessment of dopamine function following antipsychotic treatment. In parallel, other studies have shown that antipsychotic-induced dopamine supersensitivity is also characterized by an enhanced ability of the direct dopamine receptor agonist apomorphine to stimulate both horizontal locomotor activity and stereotyped behaviour (Asper et al., 1973; Clow et al., 1979; Gianutsos et al., 1974; Montanaro et al., 1982; Sayers et al., 1975; Smith and Davis, 1975, 1976). Finally, a question raised by our findings is whether treatment with an atypical antipsychotic would induce similar alterations in 5-HT2 receptor density and function.
Antipsychotic treatment can produce supersensitivity to dopamine receptor stimulation. This compromises the efficacy of ongoing treatment and increases the risk of relapse to psychosis upon treatment cessation. Serotonin 5-HT₂ receptors modulate dopamine function and thereby influence dopamine-dependent responses. Here we evaluated the hypothesis that 5-HT₂ receptors modulate the behavioural expression of antipsychotic-induced dopamine supersensitivity. To this end, we first treated rats with the antipsychotic haloperidol using a clinically relevant treatment regimen. We then assessed the effects of a 5-HT₂ receptor antagonist (ritanserin; 0.01 and 0.1 mg/kg) and of a 5-HT_2A receptor antagonist (MDL100,907; 0.025–0.1 mg/kg) on amphetamine-induced psychomotor activity. Antipsychotic-treated rats showed increased amphetamine-induced locomotion relative to antipsychotic-naïve rats, indicating a dopamine supersensitive state. At the highest dose tested (0.1 mg/kg for both antagonists), both ritanserin and MDL100,907 suppressed amphetamine-induced locomotion in antipsychotic-treated rats, while having no effect on this behaviour in control rats. In parallel, antipsychotic treatment decreased 5-HT_2A receptor density in the prelimbic cortex and nucleus accumbens core and increased 5-HT_2A receptor density in the caudate-putamen. Thus, activation of either 5-HT₂ receptors or of 5-HT_2A receptors selectively is required for the full expression of antipsychotic-induced dopamine supersensitivity. In addition, antipsychotic-induced dopamine supersensitivity enhances the ability of 5-HT₂/5-HT_2A receptors to modulate dopamine-dependent behaviours. These effects are potentially linked to changes in 5-HT_2A receptor density in the prefrontal cortex and the striatum. These observations raise the possibility that blockade of 5-HT_2A receptors might overcome some of the behavioural manifestations of antipsychotic-induced dopamine supersensitivity.
Antipsychotic treatment leading to dopamine supersensitivity persistently alters nucleus accumbens function
2015, Neuropharmacology
Chronic exposure to some antipsychotic medications can induce supersensitivity to dopamine receptor stimulation. This is linked to a worsening of clinical outcome and to antipsychotic treatment failure. Here we investigated the role of striatal subregions [nucleus accumbens (NAc) and caudate-putamen (CPu)] in the expression of antipsychotic-induced dopamine supersensitivity. We treated rats with haloperidol (HAL) or olanzapine (OLZ), using regimens that achieve clinically relevant kinetics of striatal D2 receptor occupancy. Under these conditions, HAL produces dopamine supersensitivity whereas OLZ does not. We then assessed behaviors evoked by the dopamine agonist amphetamine (AMPH). We either injected AMPH into the striatum or inhibited striatal function with microinjections of GABA receptor agonists prior to injecting AMPH systemically. HAL-treated rats were dopamine supersensitive, as indicated by sensitization to systemic AMPH-induced potentiation of both locomotor activity and operant responding for a conditioned reward (CR). Intra-CPu injections of AMPH had no effect on these behaviors, in any group. Intra-NAc injections of AMPH enhanced operant responding for CR in OLZ-treated and control rats, but not in HAL-treated rats. In HAL-treated rats, inhibition of the NAc also failed to disrupt systemic AMPH-induced potentiation of operant responding for CR. Furthermore, while intra-NAc AMPH enhanced locomotion in both HAL-treated and control animals, inhibition of the NAc disrupted systemic AMPH-induced locomotion only in control rats. Thus, antipsychotic-induced dopamine supersensitivity persistently disrupts NAc function, such that some behaviors that normally depend upon NAc dopamine no longer do so. This has implications for understanding dysfunctions in dopamine-mediated behaviors in patients undergoing chronic antipsychotic treatment.
Parallels between behavioral and neurochemical variability in the rat vacuous chewing movement model of tardive dyskinesia
2012, Behavioural Brain Research
Citation Excerpt :
While variability is not explicitly discussed in those studies, the standard error reported by Burt et al. [87] for increased binding after 3 weeks of the low dose of haloperidol is 8% of the mean (i.e. the standard deviation would be 18% of the mean), and standard errors for stimulant behavioral sensitization appear to be similarly small [16,17], a far cry from the extreme variability observed in both tardive dyskinesia and vacuous chewing movements. Both behavioral sensitization to stimulants [90–92] and receptor upregulation [86] reverse within a few weeks after neuroleptic withdrawal. Moreover, D2 receptor supersensitivity and vacuous chewing movements have often been found to be dissociable.
The widely accepted rat vacuous chewing movement model for tardive dyskinesia could be more fully mined through greater focus on individual variability in vulnerability to this neuroleptic-induced behavior. We have examined parallels between behavioral and neurobiological variability within a cohort in order to evaluate the role that neurobiological factors might play in determining susceptibility to tardive dyskinesia. Inter-observer reliability and individual consistency across time, in both spontaneous and neuroleptic-induced vacuous chewing movements, were empirically demonstrated. While this behavior increased across 8 months of observation in both vehicle controls and haloperidol-treated rats, pre-treatment baselines were predictive of final levels across individuals only in the vehicle control group, not the haloperidol-treated group. Haloperidol-induced elevations in neostriatal D2 and GAD₆₇ mRNA were not correlated with individual variability in haloperidol-induced vacuous chewing movements. Ambient noise during the observations was found to exacerbate chronic haloperidol-induced, but not spontaneous vacuous chewing movements. Significant correlations were found among the haloperidol-treated rats between nigral and tegmental GAD₆₇ and tegmental α7 mRNA levels, measured by in situ hybridization histochemistry, and vacuous chewing movements, specifically in the noisy conditions. Variability in these secondary responses to primary striatal dopamine and GABA perturbations may play a role in determining vulnerability to vacuous chewing movements, and by analogy, tardive dyskinesia. Both the differential predictive value of baseline vacuous chewing movements and the differential effect of noise, between controls and haloperidol-treated rats, add to evidence that haloperidol-induced vacuous chewing movements are regulated, in part, by different mechanisms than those mediating spontaneous vacuous chewing movements.
T-type calcium channel antagonism produces antipsychotic-like effects and reduces stimulant-induced glutamate release in the nucleus accumbens of rats
2012, Neuropharmacology
Citation Excerpt :
On day 21 animals were given vehicle or TTA-A2 60 min prior to saline or amphetamine and locomotor activity was evaluated. These groups allowed us to determine whether 20 days pre-treatment with TTA-A2 resulted in desensitization of the ability of TTA-A2 to attenuate amphetamine-induced psychomotor activity, as well as whether prior treatment with TTA-A2 sensitized the amphetamine response, as has been observed with haloperidol and other clinically approved antipsychotics (Rebec et al., 1982; Samaha et al., 2007; Smith and Davis, 1975, 1976). As a positive control, a sixth group of animals was treated with haloperidol (0.2 mg/kg) for 20 consecutive days and on day 21 received amphetamine (without haloperidol) to confirm the sensitized amphetamine response.
T-type calcium channels are important in burst firing and expressed in brain regions implicated in schizophrenia. Therefore, we examined the effects of novel selective T-type calcium channel antagonists in preclinical assays predictive of antipsychotic-like activity. TTA-A2 blocked the psychostimulant effects of amphetamine and MK-801 and decreased conditioned avoidance responding. These effects appeared mechanism based, rather than compound specific, as two structurally dissimilar T-type antagonists also reduced amphetamine-induced psychomotor activity. Importantly, the ability to reduce amphetamine’s effects was maintained following 20 days pre-treatment with TTA-A2. To explore the neural substrates mediating the observed behavioral effects, we examined the influence of TTA-A2 on amphetamine-induced c-fos expression as well as basal and stimulant-evoked dopamine and glutamate release in the nucleus accumbens. TTA-A2 decreased amphetamine-induced c-fos expression as well as MK-801-induced, but not basal, glutamate levels in the nucleus accumbens. Basal, amphetamine- and MK-801-induced dopamine efflux was altered. These findings suggest that T-type calcium channel antagonism could represent a novel mechanism for treating schizophrenia.
This article is part of a Special Issue entitled ‘Schizophrenia’.

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Behavioral evidence for supersensitivity after chronic administration of haloperidol, clozapine, and thioridazine

Abstract

Psychopharm. Comm.

Neuropharmacology

Life Sci.

Arch. Gen. Psychiat.

Drugs

Psychopharmacologia

Curr. Ther. Res.