Differential enhancement of behavioral sensitivity to apomorphine following chronic treatment of rats with (−)-sulpiride and haloperidol

Motola, Domenico; Dall’Olio, Rossella; Gandolfi, Ottavio; Vaccheri, Alberto

doi:10.1016/0014-2999(82)90595-7

Cited by 26 publications

(11 citation statements)

References 14 publications

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“…Previous work has shown that withdrawal from chronic antipsychotic treatment leads to a supersensitive psychomotor response to dopamine agonists (Gianutsos et al, 1974;Sayers et al, 1975;Davis, 1975, 1976;Clow et al, 1979;Montanaro et al, 1982;Rebec et al, 1982;Meng et al, 1998). We show here that behavioral dopamine supersensitivity is not just evident on withdrawal, but develops early during antipsychotic exposure and significantly undermines the efficacy of ongoing treatment.…”

Section: Discussionsupporting

confidence: 46%

“…In humans, this has been termed "neuroleptic-induced supersensitivity psychosis" (Chouinard et al, 1978;Chouinard and Jones, 1980), and has been observed after withdrawal from antipsychotic drugs such as quetiapine (Margolese et al, 2002), clozapine (Ekblom et al, 1984;Tollefson et al, 1999), olanzapine (Llorca et al, 2001), haloperidol (Kahne, 1989), and fluphenazine enanthate (Chouinard and Jones, 1980). In keeping with the clinical observations, animal studies show that withdrawal from antipsychotic treatment reveals an increased psychomotor response to apomorphine (Asper et al, 1973;Gianutsos et al, 1974;Sayers et al, 1975;Davis, 1975, 1976;Clow et al, 1979;Montanaro et al, 1982), amphetamine (Smith and Davis, 1975;Rebec et al, 1982;Meng et al, 1998), and dopamine injected into the caudate-putamen or nucleus accumbens (Halperin et al, 1983). Although such studies have conclusively demonstrated dopamine supersensitivity after withdrawal from an antipsychotic, much less is known about what happens during ongoing treatment.…”

Section: Introductionmentioning

confidence: 88%

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“Breakthrough” Dopamine Supersensitivity during Ongoing Antipsychotic Treatment Leads to Treatment Failure over Time

Samaha¹,

Seeman²,

Stewart³

et al. 2007

J. Neurosci.

237

276

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Antipsychotics often lose efficacy in patients despite chronic continuous treatment. Why this occurs is not known. It is known, however, that withdrawal from chronic antipsychotic treatment induces behavioral dopaminergic supersensitivity in animals. How this emerging supersensitivity might interact with ongoing treatment has never been assessed. Therefore, we asked whether dopamine supersensitivity could overcome the behavioral and neurochemical effects of antipsychotics while they are still in use. Using two models of antipsychoticlike effects in rats, we show that during ongoing treatment with clinically relevant doses, haloperidol and olanzapine progressively lose their efficacy in suppressing amphetamine-induced locomotion and conditioned avoidance responding. Treatment failure occurred despite high levels of dopamine D 2 receptor occupancy by the antipsychotic and was at least temporarily reversible by an additional increase in antipsychotic dose. To explore potential mechanisms, we studied presynaptic and postsynaptic elements of the dopamine system and observed that antipsychotic failure was accompanied by opposing changes across the synapse: tolerance to the ability of haloperidol to increase basal dopamine and dopamine turnover on one side, and 20 -40% increases in D 2 receptor number and 100 -160% increases in the proportion of D 2 receptors in the high-affinity state for dopamine (D 2 High ) on the other. Thus, the loss of antipsychotic efficacy is linked to an increase in D 2 receptor number and sensitivity. These results are the first to demonstrate that "breakthrough" supersensitivity during ongoing antipsychotic treatment undermines treatment efficacy. These findings provide a model and a mechanism for antipsychotic treatment failure and suggest new directions for the development of more effective antipsychotics.

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Section: Discussionsupporting

confidence: 46%

Section: Introductionmentioning

confidence: 88%

“Breakthrough” Dopamine Supersensitivity during Ongoing Antipsychotic Treatment Leads to Treatment Failure over Time

Samaha¹,

Seeman²,

Stewart³

et al. 2007

J. Neurosci.

237

276

View full text Add to dashboard Cite

show abstract

“…This work shows that when using the same achieved dose, peak level of D 2 receptor occupancy, route, and duration of treatment, continuous antipsychotic treatment/D 2 receptor blockade (as achieved via subcutaneous osmotic minipump) favors dopamine supersensitivity, while intermittent treatment/D 2 receptor blockade (via daily subcutaneous injection) does not [9,11,154]. There are reports that intermittent antipsychotic administration via daily subcutaneous injection can produce dopamine supersensitivity [155,156,157,158]. However, the antipsychotic doses used are quite large and would produce excessively high and clinically unrepresentative levels of striatal D 2 receptor blockade [159].…”

Section: Guidelines For Sp and Td Preventionmentioning

confidence: 99%

Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy

Chouinard

Samaha

Chouinard

et al. 2017

Psychother Psychosom

225

227

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The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D₂-like dopamine receptors. However, long-term administration of antipsychotics can upregulate D₂ receptors and produce receptor supersensitivity manifested by behavioral supersensitivity to dopamine stimulation in animals, and movement disorders and supersensitivity psychosis (SP) in patients. Antipsychotic-induced SP was first described as the emergence of psychotic symptoms with tardive dyskinesia (TD) and a fall in prolactin levels following drug discontinuation. In the era of first-generation antipsychotics, 4 clinical features characterized drug-induced SP: rapid relapse after drug discontinuation/dose reduction/switch of antipsychotics, tolerance to previously observed therapeutic effects, co-occurring TD, and psychotic exacerbation by life stressors. We review 3 recent studies on the prevalence rates of SP, and the link to treatment resistance and psychotic relapse in the era of second-generation antipsychotics (risperidone, paliperidone, perospirone, and long-acting injectable risperidone, olanzapine, quetiapine, and aripiprazole). These studies show that the prevalence rates of SP remain high in schizophrenia (30%) and higher (70%) in treatment-resistant schizophrenia. We then present neurobehavioral findings on antipsychotic-induced supersensitivity to dopamine from animal studies. Next, we propose criteria for SP, which describe psychotic symptoms and co-occurring movement disorders more precisely. Detection of mild/borderline drug-induced movement disorders permits early recognition of overblockade of D₂ receptors, responsible for SP and TD. Finally, we describe 3 antipsychotic withdrawal syndromes, similar to those seen with other CNS drugs, and we propose approaches to treat, potentially prevent, or temporarily manage SP.

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“…It has been proposed that DA supersensitivity underlies the relapse of psychotic symptoms following discontinuation of treatment or dose reduction, which may include the appearance of new or more severe psychotic symptoms [18,19]. In animal models, increased striatal D 2 receptor density is associated with an increased locomotor response to amphetamine and DA agonists following withdrawal from repeated APD administration [20][21][22][23]. Although numerous studies have associated the emergence of DA supersensitivity to increased D 2 receptor density, the nature of the relationship is not clearly understood.…”

mentioning

confidence: 99%

State-dependent effects of the D2 partial agonist aripiprazole on dopamine neuron activity in the MAM neurodevelopmental model of schizophrenia

Sonnenschein

Gill

Grace

2018

Neuropsychopharmacol

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Aripiprazole is an antipsychotic drug characterized by partial agonist activity at D receptors to normalize both hyperdopaminergic and hypodopaminergic states. Traditional D antagonist antipsychotic drugs have been shown previously to reduce dopamine neuron activity through action on D autoreceptors to produce an overexcitation-induced cessation of cell firing, referred to as depolarization block. It is unclear whether aripiprazole reduces dopamine neuron activity via inhibition or, as seen following D antagonist administration, depolarization block. The impact of acute and repeated aripiprazole treatment was examined in the methylazoxymethanol acetate (MAM) rodent model to observe its effects on a hyperdopaminergic system, compared to normal rats. We found that administration of aripiprazole acutely or after 1 or 7 days of withdrawal from 21-day repeated treatment led to a decrease in the number of spontaneously active dopamine neurons in MAM rats but not in controls. This reduction was not reversed by apomorphine (100-200 µg/kg i.p. or 20 µg/kg i.v.) administration, suggesting that it was not due to depolarization block. In contrast, 1 h after induction of depolarization block of dopamine neurons by acute haloperidol treatment (0.6 mg/kg i.p.), aripiprazole (1 mg/kg, i.p.) reversed the depolarization block state. Therefore, aripiprazole rapidly reduced the hyperdopaminergic activity selectively in MAM rats. The reduction is unlikely due to depolarization block and persists following 7-day withdrawal from repeated treatment. Aripiprazole also removes haloperidol-induced depolarization block in MAM rats, which may underlie the acute psychotic state often observed with switching to this treatment.

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Differential enhancement of behavioral sensitivity to apomorphine following chronic treatment of rats with (−)-sulpiride and haloperidol

Cited by 26 publications

References 14 publications

“Breakthrough” Dopamine Supersensitivity during Ongoing Antipsychotic Treatment Leads to Treatment Failure over Time

“Breakthrough” Dopamine Supersensitivity during Ongoing Antipsychotic Treatment Leads to Treatment Failure over Time

Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy

State-dependent effects of the D2 partial agonist aripiprazole on dopamine neuron activity in the MAM neurodevelopmental model of schizophrenia

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