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PPI deficit induced by amphetamine is attenuated by the histamine H1 antagonist pyrilamine, but is exacerbated by the serotonin 5-HT2 antagonist ketanserin

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Abstract

Rationale

Prepulse inhibition (PPI) of the startle response is a classic model of sensorimotor gating. Robust PPI impairments can be induced by dopamine agonists such as the indirect agonist amphetamine. The antipsychotic clozapine can attenuate PPI impairment induced by dopamine agonists. Clozapine is a complex drug with antagonistic effects on a variety of receptors, including serotonin and histamine. The relative contribution of its component actions to its efficacy is still unclear.

Objectives

To better characterize the role of histamine and serotonin receptors in the modulation of PPI in rats, we studied the effects of the H1 histamine antagonist pyrilamine (10, 20, and 40 mg/kg) on amphetamine-induced (1 mg/kg) PPI deficits (Experiment 1); and the interaction of pyrilamine (20 mg/kg) with the 5-HT2 antagonist ketanserin (1 and 2 mg/kg) on the amphetamine-induced PPI disruption (Experiment 2).

Methods

Tactile startle stimuli consisted of 30 PSI air-puffs. Three acoustic prepulse intensity levels were used: 68, 71, and 77 dB, presented on a 65-dB background noise. In both experiments, all animals received all drug doses and combinations with different counterbalanced orders.

Results

Pyrilamine (20 mg/kg) was effective in counteracting the PPI impairment caused by amphetamine administration, whereas ketanserin exacerbated the amphetamine-induced PPI deficit.

Conclusions

Based on its ability to reverse amphetamine-induced PPI deficits, blockade of histamine H1 receptors seems to contribute to the therapeutic effect of the antipsychotic clozapine. Serotonin 5-HT2-receptor blockade, though, does not appear to contribute to this effect, and may in fact detract from it.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box #3412, Durham, NC, 27710, USA

    José A. Larrauri & Edward D. Levin

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  1. José A. Larrauri
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  2. Edward D. Levin
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Correspondence to Edward D. Levin.

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Larrauri, J.A., Levin, E.D. PPI deficit induced by amphetamine is attenuated by the histamine H1 antagonist pyrilamine, but is exacerbated by the serotonin 5-HT2 antagonist ketanserin. Psychopharmacology 212, 551–558 (2010). https://doi.org/10.1007/s00213-010-2005-6

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  • DOI: https://doi.org/10.1007/s00213-010-2005-6

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