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H3 receptor blockade by thioperamide enhances cognition in rats without inducing locomotor sensitization

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Abstract

Rationale

Attention deficit hyperactivity disorder (ADHD) is currently treated with psychomotor stimulants, including methylphenidate and amphetamine. Several adverse effects are associated with these drugs, however, such as agitation and abuse. H3 receptor antagonists are under clinical investigation for ADHD.

Objectives

To investigate the potential of thioperamide, a prototypical H3 receptor antagonist, to enhance learning and attention while inducing no effects on locomotor stimulation and sensitization, or alterations in ACTH levels.

Methods

Thioperamide (1, 3, 10, 30 mg/kg) was administered prior to testing in a multi-trial, inhibitory avoidance response in rat pups (five trials separated by 1 min) to evaluate attention/cognition. Locomotor sensitization and cross-sensitization was assessed following administration of methylphenidate (3 mg/kg), cocaine (10 mg/kg), or thioperamide (1, 3, 10 mg/kg).

Results

Thioperamide significantly enhanced performance of the five-trial inhibitory avoidance response with efficacy similar to that previously reported for methylphenidate. Administration of amphetamine, methylphenidate and cocaine produced significant locomotor sensitization, however. In contrast, thioperamide did not induce locomotor stimulation or sensitization, nor did it cross-sensitize to the stimulant effects of amphetamine or cocaine. The repeated administration of methylphenidate significantly elevated ACTH levels, while thioperamide did not affect this neuroendocrine endpoint.

Conclusions

H3 receptor blockade may offer a safer alternative to psychomotor stimulants for the treatment of ADHD.

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Authors and Affiliations

  1. Neuroscience Research, Abbott Laboratories, AP9A, D4N5, Abbott Park, IL 60064, USA

    Victoria A. Komater, Kaitlin E. Browman, Peter Curzon, Arthur A. Hancock, Michael W. Decker & Gerard B. Fox

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  1. Victoria A. Komater
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  2. Kaitlin E. Browman
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  3. Peter Curzon
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  4. Arthur A. Hancock
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  5. Michael W. Decker
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  6. Gerard B. Fox
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Correspondence to Gerard B. Fox.

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Komater, V.A., Browman, K.E., Curzon, P. et al. H3 receptor blockade by thioperamide enhances cognition in rats without inducing locomotor sensitization. Psychopharmacology 167, 363–372 (2003). https://doi.org/10.1007/s00213-003-1431-0

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  • DOI: https://doi.org/10.1007/s00213-003-1431-0

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