Increased levels of extracellular dopamine in neostriatum and nucleus accumbens after histamine H1 receptor blockade

Abstract

The dopaminergic system plays a central role in the processing of reward or reinforcement since drugs that have reinforcing properties all share the ability to elevate dopamine (DA) levels in the nucleus accumbens or neostriatum. Histamine H1 receptor antagonists are known to have reinforcing effects in humans and laboratory rats. Here, we examined the effect of systemic (i.p.) treatment with two H1 antagonists, chlorpheniramine and pyrilamine, on the extracellular levels of DA and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the neostriatum and nucleus accumbens of urethane-anesthetized rats. Dopamine and metabolites were measured using in vivo microdialysis and HPLC with electrochemical detection. Saline injections did not produce significant effects on DA, DOPAC, or HVA levels in the neostriatum or nucleus accumbens. In the neostriatum, chlorpheniramine administration (5 and 20 mg/kg) produced a sustained increase in DA to approximately 140 and 180% of pre-injection baseline levels, respectively. In the nucleus accumbens, chlorpheniramine (20 mg/kg) produced a transient increase in DA levels to about 300% of baseline. In both the neostriatum and nucleus accumbens, DOPAC and HVA decreased after chlorpheniramine treatment. Pyrilamine administration (10 and 20 mg/kg) produced a sustained increase in neostriatal DA levels to 140 and 165%, respectively, and accumbens DA increased transiently to 230% after a dose of 20 mg/kg. Levels of neostriatal and accumbens DOPAC and HVA decreased after pyrilamine treatment. These results show that H1 antagonists can potently enhance DA levels in the neostriatum and nucleus accumbens of urethane-anesthetized rats. The neurochemical effects on DA and its metabolites seen here (increased DA, decreased DOPAC and HVA) are similar to those commonly observed with drugs of abuse (e.g. psychostimulants). The interaction of H1 antagonists with dopaminergic transmission may explain the reinforcing effects and abuse potential associated with these compounds.

Acute administration of amitriptyline and mianserin increases dopamine release in the rat nucleus accumbens: possible involvement of serotonin 2C receptors

“…F 1,9 =23.67, *P<0.05, **P<0.01; RO 60-0175 versus mianserin + RO 60-0175; two-way ANOVA followed by Tukey's test With regard to amitriptyline, it is well known that it blocks α 1 adrenergic, H 1 histaminergic, and muscarinic acetylcholine receptors (Richelson 1996;Frazer 1997). Although high doses of H 1 antagonists were found to cause a transient increase in DA release in the nucleus accumbens (Dringenberg et al 1998), neither α 1 nor muscarinic antagonists affected DA release (Meltzer et al 1994;Mathe et al 1996). Therefore, considering that amitriptyline causes a sustained increase in DA outflow in the nucleus accumbens, it is unlikely that this effect is mediated by blockade of H 1 histaminergic receptors.…”

Effects of the histamine H1 receptor blocker, pyrilamine, on spontaneous locomotor activity of rats with long-term portacaval anastomosis

“…43 It enhances dopaminergic activity through H 1 receptor blockade at the level of dopaminecontaining somata. 44 The multifactorial nature of PSE involves changes in the brain monoaminergic mechanisms, particularly those of serotonin and dopamine, that may partly account for the disturbed locomotion and feeding. 3,45 Thus, it is likely that pyrilamine has exerted its beneficial effects on PCA-operated rats by adjusting histaminergic neurotransmission and modulating serotonergic and dopaminergic mechanisms.…”

Chlorpheniramine exerts anxiolytic-like effects and activates prefrontal 5-HT systems in mice

“…When administered by local injection, drugs were dissolved in Ringer's solution (147 mM NaCl, 4 mM KCl, 1.2 mM CaCl 2 ) and infused in a volume of 0.5 μl/mouse. The maximum doses of chlorpheniramine for intraperitoneal (5 mg/kg) and local (100 ng) injections were based on previous reports (Dringenberg et al 1998;Privou et al 1998). Methiothepin was used at the 0.01-mg/kg dose since a higher dose produced an obvious hypolocomotor effect in mice (data not shown).…”