1. ¹Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, NIDA, NIH, Department of Health and Human Services, Baltimore, MD, USA
2. ²Psychobiology Section, Medications Discovery Research Branch, Intramural Research Program, NIDA, NIH, Department of Health and Human Services, Baltimore, MD, USA

Correspondence: Dr SR Goldberg, Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. Tel: 410 550 1522; Fax: 410 550 1648; E-mail: sgoldber@intra.nida.nih.gov

³Present address: ALEXZA Molecular Delivery Corporation, Palo Alto, CA 94303, USA.

⁴These authors contributed equally to this work.

Received 23 July 2003; Revised 4 December 2003; Accepted 7 December 2003; Published online 21 January 2004.

Abstract

Methamphetamine administration increases brain levels of histamine and neuronal histamine attenuates several of methamphetamine's behavioral effects. The role of different subtypes of histamine receptors in this negative feedback, however, remains unclear. There is some evidence on possible involvement of histamine H3 receptors in these actions of methamphetamine. The aim of the present study was to evaluate the effects of two histamine H3 receptor antagonists, clobenpropit and thioperamide, on rewarding and neurochemical effects of methamphetamine utilizing three in vivo methodologies, drug self-administration, drug discrimination, and microdialysis in Sprague–Dawley rats. In rats self-administering methamphetamine intravenously under a fixed-ratio schedule, presession treatment with thioperamide (1.0–3.0 mg/kg, subcutaneous, s.c.) or clobenpropit (1.0–3.0 mg/kg, s.c.) potentiated the reinforcing effects of methamphetamine, as indicated by a dose-dependent increase in responding for a low 0.03 mg/kg dose of methamphetamine, that by itself failed to maintain responding above saline substitution levels, and a decrease in responding for a higher 0.06 mg/kg training dose of methamphetamine. In contrast, neither thioperamide nor clobenpropit treatment increased responding during saline substitution. In other rats trained to discriminate intraperitoneal (i.p.) injection of 1.0 mg/kg methamphetamine from i.p. injection of saline, both thioperamide and clobenpropit (0.3–3.0 mg/kg, s.c.) dose dependently increased methamphetamine-appropriate responding when administered with a low 0.3 mg/kg i.p. dose of methamphetamine, which by itself produced predominantly saline-appropriate responding. However, thioperamide and clobenpropit produced only saline-appropriate responding when administered with saline vehicle. Finally, thioperamide and clobenpropit potentiated methamphetamine-induced elevations in extracellular dopamine levels in the shell of the nucleus accumbens, but did not increase brain dopamine levels when given alone. These findings point to histamine H3 receptors as a new and important receptor system modulating the reinforcing, subjective, and neurochemical actions of methamphetamine.