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


OBJECTIVE
To better characterize the role of histamine and serotonin receptors in the modulation of PPI in rats, we studied the effects of the H(1) 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-HT(2) 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 H(1) receptors seems to contribute to the therapeutic effect of the antipsychotic clozapine. Serotonin 5-HT(2)-receptor blockade, though, does not appear to contribute to this effect, and may in fact detract from it.
Larrauri
José A
JA
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box #3412, Durham, NC 27710, USA.
Levin
Edward D
ED
D000161:Acoustic Stimulation; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D005260:Female; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D007266:Inhibition, Psychological; D007650:Ketanserin / Q000494:pharmacology*; D010812:Physical Stimulation; D011738:Pyrilamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects*; D055139:Sensory Gating / Q000187:drug effects; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology*
D000697:Central Nervous System Stimulants; D006634:Histamine H1 Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D007650:Ketanserin; D000661:Amphetamine; D011738:Pyrilamine
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