Potentiation of the discriminative-stimulus effects of methamphetamine by the histamine H3 receptor antagonist thioperamide in rats

In order to assess the role of histamine H-3 receptors in the discriminative-stimulus effects of methamphetamine, rats were trained to discriminate 1.0 mg/kg methamphetamine, i.p., from saline under a fixed-ratio schedule of food presentation. The histamine H-3 receptor antagonist thioperamide (1.0 mg/kg s.c.), which facilitates histamine release, significantly shifted the methamphetamine dose-response curve to the left when tested together with different doses of methamphetamine and markedly extended the time-course of methamphetamine's discriminative-stimulus effects. The histamine H-3 receptor agonist R-alpha-methylhistamine (3.0 mg/kg i.p.), which blocks histamine release, did not produce any effects when given alone, but it attenuated the effects of thioperamide on the methamphetamine dose-response curve when both drugs were given together. Thus, methamphetamine's discriminative-stimulus effects are markedly potentiated by the blockade of histamine H-3 receptors by thioperamide. This is Likely due to thioperamide's actions at histamine H-3 autoreceptors on histaminergic neurons to facilitate release of histamine by methamphetamine or at histamine H-3 heteroreceptors on other monoaminergic neurons (e.g., dopaminergic, serotonergic or noradrenergic) to facilitate release of other neurotransmitters. (C) 1998 Elsevier Science B.V. All rights reserved.