title: Effects of the histamine H₁ receptor antagonist and benztropine analog diphenylpyraline on dopamine uptake, locomotion and reward.
abstract: Diphenylpyraline hydrochloride (DPP) is an internationally available antihistamine that produces therapeutic antiallergic effects by binding to histamine H₁ receptors. The complete neuropharmacological and behavioral profile of DPP, however, remains uncharacterized. Here we describe studies that suggest DPP may fit the profile of a potential agonist replacement medication for cocaine addiction. Aside from producing the desired histamine reducing effects, many antihistamines can also elicit psychomotor activation and reward, both of which are associated with increased dopamine concentrations in the nucleus accumbens (NAc). The primary aim of this study was to investigate the potential ability of DPP to inhibit the dopamine transporter, thereby leading to elevated dopamine concentrations in the NAc in a manner similar to cocaine and other psychostimulants. The psychomotor activating and rewarding effects of DPP were also investigated. For comparative purposes cocaine, a known dopamine transporter inhibitor, psychostimulant and drug of abuse, was used as a positive control. As predicted, both cocaine (15 mg/kg) and an equimolar dose of DPP (14 mg/kg) significantly inhibited dopamine uptake in the NAc in vivo and produced locomotor activation, although the time-course of pharmacological effects of the two drugs was different. In comparison to cocaine, DPP showed a prolonged effect on dopamine uptake and locomotion. Furthermore, cocaine, but not DPP, produced significant conditioned place preference, a measure of drug reward. The finding that DPP functions as a potent dopamine uptake inhibitor without producing significant rewarding effects suggests that DPP merits further study as a potential candidate as an agonist pharmacotherapy for cocaine addiction.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, North Carolina, USA.
authors.forename: Erik B
authors.initials: EB
authors.lastname: Oleson
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ferris
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: España
authors.forename: Jill
authors.initials: J
authors.lastname: Harp
authors.forename: Sara R
authors.initials: SR
authors.lastname: Jones
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001590:Benztropine / Q000031:analogs & derivatives*; D000697:Central Nervous System Stimulants / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D003042:Cocaine / Q000819:agonists / Q000494:pharmacology / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000503:physiopathology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005106:Exploratory Behavior / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D013287:Illicit Drugs / Q000494:pharmacology / Q000633:toxicity; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011595:Psychomotor Agitation / Q000209:etiology; D012201:Reward; D013037:Spatial Behavior / Q000187:drug effects
chemical_list: D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; D006634:Histamine H1 Antagonists; D013287:Illicit Drugs; D010880:Piperidines; D001590:Benztropine; C009871:diphenylpyraline; D003042:Cocaine