Behavioral evidence for dopaminergic supersensitivity after chronic haloperidol

Gianutsos, Gerald; Drawbaugh, Richard B.; Hynes, Martin D.; Lal, Harbans

doi:10.1016/0024-3205(74)90078-2

Cited by 187 publications

(19 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: 45%

“…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: 87%

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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: 45%

Section: Introductionmentioning

confidence: 87%

“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

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“…In 7 of our patients, preceding treatments with neuroactive drugs, e.g., neuroleptics, had been discontinued for at least 1 month, and 7 patients had never been treated, a fact which argues against the possibility that supersensi tive DA receptors had been generated for drug-induced chemical denervation [Gianutsos et al, 1974;Klawans and Rubovits, 1972].…”

Section: Discussionmentioning

confidence: 87%

Growth Hormone Hyperresponsiveness to Dopaminergic Stimulation in Huntington’s Chorea

Müller¹,

Parati

Panerai

et al. 1979

Neuroendocrinology

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The effect of 3 dopamine (DA) mimetic drugs, i.e. bromocriptine (Bro), apomorphine (Apo) and L-3,4-Dihydroxyphenylalanine (L-dopa), was evaluated on plasma growth hormone (GH) levels in 18 patients with Huntington’s chorea (HC). 27 nonobese hospitalized patients were used as controls. Mean baseline GH levels were not altered in patients with HC. Oral administration of Bro (2.5 mg po) or L-dopa (500 mg), or subcutaneous administration of Apo (1.0 mg) resulted in a significantly greater and more prompt (Bro, L-dopa) increase in plasma GH in patients than in controls. These results suggest the presence of an altered dopaminergic regulation of GH secretion inHC.

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“…Whatsoever, as opposed to continuous treatments, and according to our initial hypothesis on the regulation of receptor synthesis through glucose utilization, a daily treatment during 15 days, a period corresponding with the known half-life of receptors [6,19], followed by a single injection every other week was sufficient to clearly improve TD symptomatology. This time course makes it unlikely that such an effect could be linked to a direct effect of insulin on DA neurones but rather suggests a relation with a blockade of receptor synthesis due to a reduction in energy supply.…”

Section: Discussionmentioning

confidence: 99%

Low Doses of Insulin as a Treatment of Tardive Dyskinesia: Conjuncture or Conjecture?

et al. 1991

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Tardive dyskinesia (TD) induced by antipsychotic drugs represents a great concern for patients and psychiatrists. Considering its pathophysiological mechanisms, there exists a convergence towards the development of postsynaptic dopaminergic hypersensitivity as a possible cause of TD. Hypersensitivity following receptor blockade is the consequence of an increased number of receptors and such a synthesis is energy-dependent. In the brain, under normal conditions, energy is almost exclusively provided by glucose utilization. We thus hypothesized that, if glucose availability were reduced, the metabolically hyperactive structures should represent the best functional target of a reduction in fuel availability. Twenty chronic schizophrenic outpatients (13 males, 7 females), aged 20–67 (mean: 38.3), accepted to practicipate in this double-blind, placebo-controlled study. They were randomly assigned to either the insulin treatment group (10 patients) or to the insulin-placebo group (10 patients). They received a subcutaneous injection of 10 units of standard insulin or placebo at 10 a.m. From day 1 to day 15, injections were performed daily and, thereafter, every other week for 5 weeks totalizing 20 injections in 90 days. At day 7, the insulin treatment group showed a sharp decrease in the intensity of TD symptoms which persisted throughout the duration of the study. By contrast, no change in TD symptomatology was observed in the insulin-placebo-treated group. Although a direct effect on DA neurones, or at least the participation of such an effect, cannot be excluded, our data favor a role of decreased glucose availability in reversing receptor hypersensitivity.

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Behavioral evidence for dopaminergic supersensitivity after chronic haloperidol

Cited by 187 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

Growth Hormone Hyperresponsiveness to Dopaminergic Stimulation in Huntington’s Chorea

Low Doses of Insulin as a Treatment of Tardive Dyskinesia: Conjuncture or Conjecture?

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