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Cocaine‐like neurochemical effects of antihistaminic medications

The pattern of activation of dopamine (DA) neurotransmission in the nucleus accumbens (NAc) of rats produced by H1 histamine antagonists which have behavioral effects like those of psychostimulant drugs was examined. Diphenhydramine and (+)‐chlorpheniramine were compared with triprolidine, a potent and selective H1 antagonist and (−)‐chlorpheniramine which is less active than its enantiomer at H1 receptors. Affinities of the drugs to DA, serotonin, and norepinephrine transporters at H1 receptors and potencies for DA uptake inhibition in striatal synaptosomes were determined to assess mechanisms by which the compounds increased DA levels. Intravenous diphenhydramine (1.0–3.0 mg/kg) (+)‐ and (−)‐chlorpheniramine (1.0–5.6 mg/kg) but not triprolidine (1.0–3.0 mg/kg) elicited a cocaine‐like pattern of stimulation of DA transmission with larger effects in the NAc shell than core. The absence of stereospecific effects with chlorpheniramine enantiomers along with the lack of an effect with triprolidine suggest that the effects on DA transmission were not related to H1 receptor antagonism. Although in vivo potencies were not directly related to DA transporter affinities, it is hypothesized that actions at that site modulated by other actions, possibly those at the serotonin transporter, are primarily responsible for the neurochemical actions of the drugs on DA neurotransmission and might underlie the occasional misuse of these medications.