Clozapine and haloperidol block the induction of behavioral sensitization to amphetamine and associated genomic responses in rats

Meng, Zhi-Hong; Feldpaush, Dawna L.; Merchant, Kalpana

doi:10.1016/s0169-328x(98)00196-x

Cited by 61 publications

(31 citation statements)

References 35 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.

233

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.

233

276

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“…Nevertheless, an array of behavioral and molecular changes associated with this model suggest that early developmental insult of the ventral hippocampus may facilitate sensitization of the dopamine system, and thereby account for the adult onset of a maladaptive condition characterized by a vriety of dopamine-related abnormalities. Similar pathophysiological mechanisms have been hypothesized to underlie schizophrenia (Lieberman et al 1997;Meng et al 1998;Duncan et al 1999). Unlike psychostimulant sensitization models, however, the neonatal lesion model does not target the dopamine system directly and similar sensitization-like phenomena are not seen following an analogous hippocampal lesion in adult animals.…”

Section: Neonatal Brain Lesionsmentioning

confidence: 54%

To Model a Psychiatric Disorder in Animals Schizophrenia As a Reality Test

Lipska

Weinberger

2000

Neuropsychopharmacology

588

386

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Animal modeling has been instrumental in dissectingAnimal models are important developments in investigations of the mechanisms underlying a human disease and the design of new treatments. This is true for many diseases, but generally not for mental disorders, whose modeling in experimental animals has often been regarded as a highly controversial or outright heretic idea. An example of a particularly formidable challenge for animal modeling is schizophrenia, a complex disorder of unknown origin, characterized by abnormalities of uniquely human behaviors in the realms of perception, thinking and the experience of emotions, and whose onset is virtually restricted to young adulthood. Schizophrenia is such an inherently human disease that reproducing its most prominent symptoms-hallucinations, delusions and thought disorder-in a rodent or even in a non-human primate seems doomed. However, recent new evidence about the neurobiology of the condition has generated new avenues of animal research. In this perspective article, we highlight recent achievements in the efforts to model the neurobiology of schizophrenia in animals, consider limitations inherent in any heuristic animal model of this and probably other psychiatric disorders, and discuss the usefulness of a new generation of animal models for testing particular hypotheses about etiology and pathophysiology of schizophrenia.

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“…Lithium is not utilized clinically for the treatment of either schizophrenia or drug addiction. As would be expected from a putative model of schizophrenia, behavioral sensitization can be prevented by the administration of typical and atypical antipsychotics (Meng et al, 1998).…”

Section: The Effect Of Lithium On Behavioral Sensitizationmentioning

confidence: 89%

The behavioral actions of lithium in rodent models: Leads to develop novel therapeutics

O’Donnell

Gould

2007

Neuroscience & Biobehavioral Reviews

121

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For nearly as long as lithium has been in clinical use for the treatment of bipolar disorder, depression, and other conditions, investigators have attempted to characterize its effects on behaviors in rodents. Lithium consistently decreases exploratory activity, rearing, aggression, and amphetamine-induced hyperlocomotion; and it increases the sensitivity to pilocarpine-induced seizures, decreases immobility time in the forced swim test, and attenuates reserpine-induced hypolocomotion. Lithium also predictably induces conditioned taste aversion and alterations in circadian rhythms. The modulation of stereotypy, sensitization, and reward behavior are less consistent actions of the drug. These behavioral models may be relevant to human symptoms and to clinical endophenotypes. It is likely that the actions of lithium in a subset of these animal models are related to the therapeutic efficacy, as well the side effects, of the drug. We conclude with a brief discussion of various molecular mechanisms by which these lithium-sensitive behaviors may be mediated, and comment on the ways in which rat and mouse models can be used more effectively in the future to address persistent questions about the therapeutically relevant molecular actions of lithium.

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Clozapine and haloperidol block the induction of behavioral sensitization to amphetamine and associated genomic responses in rats

Cited by 61 publications

References 35 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

To Model a Psychiatric Disorder in Animals Schizophrenia As a Reality Test

The behavioral actions of lithium in rodent models: Leads to develop novel therapeutics

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