Journal of Neurochemist,y Lippincott—Raven Publishers, Philadelphia © 1998 International Society for Neurochemistry Histamine H 1 Receptor Antagonists Produce Increases in Extracellular Acetyicholine in Rat Frontal Cortex and Hippocampus Hans C. Dringenberg, M. Angelica De Souza-Silva, Jens Roßmüller, Joseph P. Huston, and Rainer K. W. Schwarting Institute of Physiological Psychology I and Center for Biological and Medical Research, Heinrich-Heine University Düsseldorf Düsseldoif Germany Abstract: Lesions of the neuronal histaminergic system or pharmacological blockade of histamine receptors, e.g., with histamine H1 receptor antagonists, can enhance the performance of rats in several tests of learning and mem- ory. The underlying neuronal systems that mediate these behavioral effects are not known. Here, we examined the effects of treatment with histamine H1 antagonists on ex- tracellular levels of acetylcholine (ACh) in adult rats anes- thetized with urethane (1.25 g/kg). ACh was quantified using in vivo microdialysis and HPLC with electrochemi- cal detection. Basal levels of ACh in the frontal cortex and hippocampus were in the range of 0.54 ±0.13 and 0.96 ± 0.17 pmol/20 mm, respectively. Injection (intraper- itoneally) of saline did not produce significant increases in ACh levels, even though there was a slight and gradual increase in cortical ACh levels throughout the course of the experiments (up to 4h after an injection). Administra- tion of the H1 receptor antagonist chlorpheniramine (intra- peritoneally) produced a dose-dependent increase of cor- tical ACh levels to a maximum of 260, 280, and 570% of baseline values after doses of 5, 10, and 20 mg/kg, respectively. In the hippocampus, ACh content increased to a maximum of —.600% of baseline levels after chlor- pheniramine administration (20 mg/kg, i.p.). Administra- tion of the H1 antagonist pyrilamine (intraperitoneally) in- creased 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 nonanesthetized, freely moving rats, cortical ACh content showed a moderate increase (to 190%) after saline injections (intraperitone- ally) and a much higher increase (to 370%) after chlorphe- niramine treatment (20 mg/kg, i.p.). These data suggest that cortical and hippocampal levels of ACh can be effec- tively modulated by systemic treatment with histamine H1 antagonists. The increases in ACh levels produced by H1 antagonists may suggest that some histaminergic recep- tors exert an inhibitory influence over central ACh levels. The enhanced availability of ACh in the forebrain may contribute to the behavioral effects observed with H1 an- tagonist treatment. Key Words: Acetylcholine—Histamine —H1 antagonists—Neocortex—Hippocampus— Microdialysis. J. Neurochem. 70, 1750—1758 (1998). The cholinergic innervation of the cortical mantle arises predominantly from cholinergic cell groups in the basal forebrain that include the substantia innomi- nata, ventral pallidum, globus pallidus, nucleus basalis magnocellularis, and horizontal limb of the diagonal band of Broca, whereas the medial septum and vertical diagonal band of Broca provide the cholinergic in- nervation of the hippocampal formation (Divac, 1975; Big! et a!., 1982; Mesulam et a!., 1983; Saper, 1984; Luiten et a!., 1987; Semba and Fibiger, 1989; Woolf, 1991). Numerous hypotheses exist with regard to the behavioral functions controlled by these cholinergic projection systems. In rats and monkeys, cholinergic deficits related to lesions, pharmacological blockade, or aging can produce severe impairments in both spe- cies-specific behaviors, e.g., general activity, sexual behavior, and food hoarding, and in tests of learning and memory, such as avoidance or discrimination learning, or spatial navigation (Singer, 1968; Dubois et al., 1985; Whishaw et al., 1985; Collerton, 1986; Stroessner-Johnson et al., 1992; Quirion et al., 1995; Dornan et al., 1996). Thus, it appears that intact cholin- ergic transmission contributes importantly to various behavioral capacities, even though the underlying pro- cesses, e.g., ‘‘attention,‘‘ ‘‘storage,‘‘ and ‘‘retrieval,‘‘ involved remain controversial (Fibiger, 1991; Blok- land, 1996; Thiel et al., 1998). The importance of cholinergic transmission in be- havioral performance is widely recognized, but the role of complex interactions between cholinergic and other transmitter systems is less well understood. Several transmitter-specific cell populations (serotonergic, nor- Received July 11, 1997; revised manuscript received October 28, 1997; accepted November 24, 1997. Address correspondence and reprint requests to Dr. R. K. W. Schwarting at Institute of Physiological Psychology I, Heinrich- Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düssel- dorf, Germany. Abbreviations used: ACh, acetylcholine; TM, tuberomammillary nucleus. 1750