Brain histamine H 3 receptors are predominantly presynaptic and serve an important autoregulatory function for the release of histamine and other neurotransmitters. They have been implicated in a variety of brain functions, including arousal, locomotor activity, thermoregulation, food intake, and memory. The recent cloning of the H 3 receptor in our laboratory has made it possible to create a transgenic line of mice devoid of H 3 receptors. This paper provides the first description of the H 3 receptor-deficient mouse (H 3 Ϫ/Ϫ ), including molecular and pharmacologic verification of the receptor deletion as well as phenotypic screens. The H 3 Ϫ/Ϫ mice showed a decrease in overall locomotion, wheel-running behavior, and body temperature during the dark phase but maintained normal circadian rhythmicity. H 3 Ϫ/Ϫ mice were insensitive to the wake-promoting effects of the H 3 receptor antagonist thioperamide. We also observed a slightly decreased stereotypic response to the dopamine releaser, methamphetamine, and an insensitivity to the amnesic effects of the cholinergic receptor antagonist, scopolamine. These data indicate that the H 3 receptor-deficient mouse represents a valuable model for studying histaminergic regulation of a variety of behaviors and neurotransmitter systems, including dopamine and acetylcholine.The neurotransmitter histamine, which originates from tuberomamillary nuclei in the posterior hypothalamus, projects diffusely throughout the central nervous system (CNS) and has been implicated in the regulation of many functions, including sleep/wake, food and water intake, thermoregulation, memory, and other homeostatic processes (Wada et al., 1991;Brown et al., 2001). Four subtypes (H 1 , H 2 , H 3 , and H 4 ) of histamine receptors are currently recognized (Hill et al., 1997;Hough, 2001). The H 3 subtype is predominantly located presynaptically and serves as an autoreceptor to regulate the synthesis and release of histamine (Hill et al., 1997). The H 3 subtype also has heteroreceptor functions and influences CNS dopamine, ␥-aminobutyric acid, noradrenaline, acetylcholine, and serotonin levels (Arrang et al., 1983(Arrang et al., , 1987bSchlicker et al., 1988;Clapham and Kilpatrick, 1992;Hill et al., 1997). Behavioral correlates of H 3 receptor function have primarily been studied in the context of pharmacologically blocking the receptor using the specific H 3 receptor antagonist, thioperamide. For instance, thioperamide has been used to increase the amount of wakefulness (Monti et al., 1991), to prevent scopolamine-induced amnesia (Giovannini et al., 1999), and to decrease food intake (Itoh et al., 1999;Attoub et al., 2001) in rats. The recent cloning of the H 3 receptor in our laboratory (Lovenberg et al., 1999) has made it possible to create a transgenic line of mice devoid of H 3 receptors and to explore at a molecular level the importance of this receptor in a variety of behaviors. This paper provides the first description of 1) generating the H 3 receptor knockout mice, 2) verifying the d...
1 The reversible fatty acid amide hydrolase (FAAH) inhibitor OL135 reverses mechanical allodynia in the spinal nerve ligation (SNL) and mild thermal injury (MTI) models in the rat. The purpose of this study was to investigate the role of the cannabinoid and opioid systems in mediating this analgesic effect. À/À mice. 5 OL135 given i.p. resulted in a dose-responsive reversal of mechanical allodynia in both MTI and SNL models in the rat with an ED 50 between 6 and 9 mg kg À1 . The plasma concentration at the ED 50 in both models was 0.7 mM (240 ng ml À1 ). 6 In the rat SNL model, coadministration of the selective CB 2 receptor antagonist SR144528 (5 mg kg À1 i.p.), with 20 mg kg À1 OL135 blocked the OL135-induced reversal of mechanical allodynia, but the selective CB 1 antagonist SR141716A (5 mg kg À1 i.p.) was without effect. 7 In the rat MTI model neither SR141716A or SR144528 (both at 5 mg kg À1 i.p.), or a combination of both antagonists coadministered with OL135 (20 mg kg À1) blocked reversal of mechanical allodynia assessed 30 min after dosing. 8 In both the MTI model and SNL models in rats, naloxone (1 mg kg À1 , i.p. 30 min after OL135) reversed the analgesia (to 15% of control levels in the MTI model, to zero in the SNL) produced by OL135.
Purpose: Approximately two-thirds of patients with the lysosomal storage disease mucopolysaccharidosis II have progressive cognitive impairment. Intravenous (i.v.) enzyme replacement therapy does not affect cognitive impairment because recombinant iduronate-2-sulfatase (idursulfase) does not penetrate the blood-brain barrier at therapeutic concentrations. We examined the safety of idursulfase formulated for intrathecal administration (idursulfase-IT) via intrathecal drug delivery device (IDDD). A secondary endpoint was change in concentration of glycosaminoglycans in cerebrospinal fluid. Methods:Sixteen cognitively impaired males with mucopolysaccharidosis II who were previously treated with weekly i.v. idursulfase 0.5 mg/ kg for ≥6 months were enrolled. Patients were randomized to no treatment or 10-mg, 30-mg, or 1-mg idursulfase-IT monthly for 6 months (four patients per group) while continuing i.v. idursulfase weekly. Results:No serious adverse events related to idursulfase-IT were observed. Surgical revision/removal of the IDDD was required in 6 of 12 patients. Twelve total doses were administrated by lumbar puncture. Mean cerebrospinal fluid glycosaminoglycan concentration was reduced by approximately 90% in the 10-mg and 30-mg groups and approximately 80% in the 1-mg group after 6 months. Conclusions:These preliminary data support further development of investigational idursulfase-IT in MPS II patients with the severe phenotype who have progressed only to a mild-to-moderate level of cognitive impairment.
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