HISTAMINE H-1 RECEPTOR ANTAGONISTS PRODUCE INCREASES IN EXTRACELLULARACETYLCHOLINE IN RAT FRONTAL-CORTEX AND HIPPOCAMPUS

Lesions of the neuronal histaminergic system or pharmacological blocka de of histamine receptors, e.g., with histamine H-1 receptor antagonis ts, can enhance the performance of rats in several tests of learning a nd memory, The underlying neuronal systems that mediate these behavior al effects are not known. Here, we examined the effects of treatment w ith histamine H-1, antagonists on extracellular levels of acetylcholin e (ACh) in adult rats anesthetized with urethane (1.25 g/kg). ACh was quantified using in vivo microdialysis and HPLC with electrochemical d etection. Basal levels of ACh in the frontal cortex and hippocampus we re in the range of 0.54 +/- 0.13 and 0.96 +/- 0.17 pmol/20 min, respec tively. Injection (intraperitoneally) of saline did not produce signif icant increases in ACh levels, even though there was a slight and grad ual increase in cortical ACh levels throughout the course of the exper iments (up to 4 h after an injection). Administration of the H-1 recep tor antagonist chlorpheniramine (intraperitoneally) produced a dose-de pendent increase of cortical ACh levels to a maximum of 260, 280, and 570% of baseline values after doses of 5, 10, and 20 mg/kg, respective ly. In the hippocampus, ACh content increased to a maximum of similar to 600% of baseline levels after chlorpheniramine administration (20 m g/kg, i.p.). Administration of the H-1 antagonist pyrilamine (intraper itoneally) increased cortical ACh content to a maximum of 300 and 500% , whereas hippocampal ACh levels increased to 215 and 280% after doses of 10 and 20 mg/kg, respectively. In an additional experiment using n onanesthetized, freely moving rats, cortical ACh content showed a mode rate increase (to 190%) after saline injections (intraperitoneally) an d a much higher increase (to 370%) after chlorpheniramine treatment (2 0 mg/kg, i.p.). These data suggest that cortical and hippocampal level s of ACh can be effectively modulated by systemic treatment with hista mine H-1 antagonists. The increases in ACh levels produced by H-1 anta gonists may suggest that some histaminergic receptors exert an inhibit ory influence over central ACh levels, The enhanced availability of AC h in the forebrain may contribute to the behavioral effects observed w ith H, antagonist treatment.