Acute wake-promoting actions of JNJ-5207852, a novel, diamine-based H3 antagonist.

1 1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidine (JNJ-5207852) is a novel, non-imidazole histamine H3 receptor antagonist, with high affinity at the rat (pKi=8.9) and human (pKi=9.24) H3 receptor. JNJ-5207852 is selective for the H3 receptor, with negligible binding to other receptors, transporters and ion channels at 1 microm. 2 JNJ-5207852 readily penetrates the brain tissue after subcutaneous (s.c.) administration, as determined by ex vivo autoradiography (ED50 of 0.13 mg kg(-1) in mice). In vitro autoradiography with 3H-JNJ-5207852 in mouse brain slices shows a binding pattern identical to that of 3H-R-alpha-methylhistamine, with high specific binding in the cortex, striatum and hypothalamus. No specific binding of 3H-JNJ-5207852 was observed in brains of H3 receptor knockout mice. 3 In mice and rats, JNJ-5207852 (1-10 mg kg(-1) s.c.) increases time spent awake and decreases REM sleep and slow-wave sleep, but fails to have an effect on wakefulness or sleep in H3 receptor knockout mice. No rebound hypersomnolence, as measured by slow-wave delta power, is observed. The wake-promoting effects of this H3 receptor antagonist are not associated with hypermotility. 4 A 4-week daily treatment of mice with JNJ-5207852 (10 mg kg(-1) i.p.) did not lead to a change in body weight, possibly due to the compound being a neutral antagonist at the H3 receptor. 5 JNJ-5207852 is extensively absorbed after oral administration and reaches high brain levels. 6 The data indicate that JNJ-5207852 is a novel, potent and selective H3 antagonist with good in vitro and in vivo efficacy, and confirm the wake-promoting effects of H3 receptor antagonists.

Effect of chronic nicotine on brain stimulation reward. I. Effect of daily injections.

Previous work has shown that nicotine facilitates brain stimulation reward (BSR) but that the maximum effect obtainable with nicotine is similar to that seen with nonaddictive compounds. This study examined whether repeated nicotine injections would enhance the facilitatory action of nicotine on BSR. Rats with lateral hypothalamic stimulating electrodes were tested using a threshold-tracking procedure. This procedure determined the minimum stimulation frequency (i.e. stimulation threshold) necessary to maintain 30 presses/min during 30-min test sessions. Rats were injected daily with nicotine bitartrate (0.5 mg/kg, s.c., dose expressed as free base weight) or physiological saline (1 ml/kg, s.c.) immediately before testing for 21 consecutive days. Nicotine lowered thresholds across the 21-day injection regimen. Neither tolerance nor sensitization to this effect was apparent. The magnitude of threshold lowering produced by nicotine was similar to that previously reported for acute nicotine and for mild stimulants with low addiction liabilities (i.e. caffeine and pseudoephedrine). This finding suggests that even under chronic administration, nicotine's profile in this animal model is that of a substance with a low addiction liability.

Effect of chronic nicotine on brain stimulation reward. II. An escalating dose regimen.

This study examined whether repeated nicotine injections, using an escalating dose regimen, would produce brain stimulation reward facilitation indicative of a strong rewarding action. Male, Long-Evans rats with lateral hypothalamic stimulating electrodes were injected daily with escalating doses of nicotine bitartrate across 5-day cycles: 0.5, 1, and 2 mg/kg/day (dose expressed as freebase weight) were administered subcutaneously (s.c.) in consecutive 5-day cycles. Nicotine lowered thresholds across the first two 5-day cycles (i.e. 0.5 and 1 mg/kg/day doses), but thresholds returned to baseline levels during the last 5-day cycle (i.e. 2 mg/kg/day). The maximum threshold lowering produced by nicotine was similar to that previously reported for acute and chronic nicotine and for mild stimulants with a low addiction liability (i.e. caffeine and pseudoephedrine). Forty-eight h after terminating the nicotine injection regimen, thresholds were elevated revealing a nicotine withdrawal reaction. However, the high nicotine dose used during the last 5-day cycle is probably not pharmacologically relevant, thus making the significance of the withdrawal effect unclear. Overall, this study suggests that even under chronic administration using escalating doses, nicotine's profile in this animal model is that of a substance with a low addiction liability.

Nitric oxide synthesis inhibition attenuates haloperidol-induced supersensitivity.

Increased responsiveness to psychomotor stimulants can be produced by either chronic stimulant administration or by chronic dopamine receptor blockade. This study examined the role of nitric oxide in the development of neuroleptic-induced supersensitivity. N omega-nitro-L-arginine methyl ester hydrochloride (L-NAME) administered during chronic intraperitoneal (i.p.) haloperidol treatment (0.2 mg/kg/d for 14 d) was used to inhibit nitric oxide synthesis. Locomotor activity following a cocaine(i.p.) challenge injection (10 mg/kg) administered at 3 and 10 d after cessation of haloperidol treatment demonstrated the development of supersensitivity. Haloperidol animals pretreated with L-NAME i.p. (30 mg/kg) showed significantly less cocaine-stimulated locomotor activity on both tests than saline-pretreated animals. This finding suggests that nitric oxide is involved in haloperidol-induced supersensitivity and that a common neural mechanism may underlie the development of supersensitivity and stimulant-induced sensitization. This study also suggests that treatment with a nitric oxide synthesis inhibitor may decrease the side effects accompanying long-term treatment with antipsychotic medications.

Nitric oxide synthesis inhibition does not affect brain stimulation reward.

The effect of nitric oxide synthesis inhibition on brain stimulation reward was examined. A wide range of doses of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 30-300 mg/kg IP) failed to affect frequency thresholds for brain stimulation reward. The effect of L-NAME on cocaine's facilitation of brain stimulation reward was also examined. Nitric oxide synthesis inhibition had no effect on cocaine's ability to lower reward thresholds for electrical brain stimulation. Despite reports that nitric oxide may modulate dopamine release, these data suggest that nitric oxide is not involved in the dopamine-dependent rewarding effect of electrical brain stimulation or the reward facilitation produced by cocaine's enhancement of dopaminergic activity. Because L-NAME potently decreases cerebral blood flow, its lack of effect on cocaine-enhanced brain stimulation reward has additional significance. The failure of a moderate dose of L-NAME (30 mg/kg IP) to attenuate cocaine's lowering of reward thresholds argues against pharmacokinetic explanations of L-NAME's effect on other cocaine-induced behaviors.

Cocaine fatalities increased by restraint stress.

Laboratory rats injected daily with a moderate dose of cocaine hydrochloride (30 mg/kg, i.p.) showed increased fatalities when cocaine injections were followed by 30 min of restraint stress. The 5-day mortality rate was 58% for the cocaine-plus-stress group, while 17% of the animals receiving cocaine without restraint stress died. This finding suggests that stress can augment the toxic effect of cocaine and that minimizing stress may be an important consideration in the clinical management of cocaine overdose.

L-NAME and MK-801 attenuate sensitization to the locomotor-stimulating effect of cocaine.

Locomotor activity was tested daily following cocaine injections across 21 consecutive days. Subjects were pretreated 30-min before testing with physiological saline, the nitric oxide synthase inhibitor N omega-nitro-L-arginine (L-NAME), or the NMDA-receptor antagonist MK-801. Other rats received daily injections of physiological saline instead of cocaine just prior to testing. Rats pretreated with saline and injected daily with cocaine showed increased locomotor activity across the 21-day test period. L-NAME pretreatment depressed cocaine-stimulated locomotor activity, while MK-801 pretreatment increased locomotor activity. To test for behavioral sensitization to cocaine, rats were injected with cocaine 72 hours after their last daily injections. Sensitization was seen in saline pretreated subjects injected daily with cocaine compared to subjects injected daily with saline only, but both L-NAME and MK-801 pretreatment strongly attenuated cocaine sensitization. This finding is consistent with the proposed roles of nitric oxide and NMDA-receptors in cellular adaptation and learning.