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Rationale: Orexin-1 receptor antagonists have been shown to block the reinforcing effects of drugs of abuse and food. However, whether blockade of orexin-2 receptor has similar effects has not been determined. We have recently described the in vitro and in vivo effects of JNJ-10397049, a selective and brain penetrant orexin-2 receptor antagonist., Objective: The goal of these studies was to evaluate whether systemic administration of JNJ-10397049 blocks the rewarding effects of ethanol and reverses ethanol withdrawal in rodents. As a comparison, SB-408124, a selective orexin-1 receptor antagonist, was also evaluated., Methods: Rats were trained to orally self-administer ethanol (8% v/v) or saccharin (0.1% v/v) under a fixed-ratio 3 schedule of reinforcement. A separate group of rats received a liquid diet of ethanol (8% v/v) and withdrawal signs were evaluated 4 h after ethanol discontinuation. In addition, ethanol-induced increases in extracellular dopamine levels in the nucleus accumbens were tested. In separate experiments, the acquisition, expression, and reinstatement of conditioned place preference (CPP) were evaluated in mice., Results: Our results indicate that JNJ-10397049 (1, 3, and 10 mg/kg, sc) dose-dependently reduced ethanol self-administration without changing saccharin self-administration, dopamine levels, or withdrawal signs in rats. Treatment with JNJ-10397049 (10 mg/kg, sc) attenuated the acquisition, expression, and reinstatement of ethanol CPP and ethanol-induced hyperactivity in mice. Surprisingly, SB-408124 (3, 10 and 30 mg/kg, sc) did not have any effect in these procedures., Conclusions: Collectively, these results indicate, for the first time, that blockade of orexin-2 receptors is effective in reducing the reinforcing effects of ethanol.

Rationale: A few recent studies suggest that brain histamine levels and signaling via H(3) receptors play an important role in modulation of alcohol stimulation and reward in rodents., Objective: The present study characterized the effects of a novel, selective, and brain penetrant H(3) receptor antagonist (JNJ-39220675) on the reinforcing effects of alcohol in rats., Methods: The effect of JNJ-39220675 on alcohol intake and alcohol relapse-like behavior was evaluated in selectively bred alcohol-preferring (P) rats using the standard two-bottle choice method. The compound was also tested on operant alcohol self administration in non-dependent rats and on alcohol-induced ataxia using the rotarod apparatus. In addition, alcohol-induced dopamine release in the nucleus accumbens was tested in freely moving rats., Results: Subcutaneous administration of the selective H(3) receptor antagonist dose-dependently reduced both alcohol intake and preference in alcohol-preferring rats. JNJ-39220675 also reduced alcohol preference in the same strain of rats following a 3-day alcohol deprivation. The compound significantly and dose-dependently reduced alcohol self-administration without changing saccharin self-administration in alcohol non-dependent rats. Furthermore, the compound did not change the ataxic effects of alcohol, alcohol elimination rate, nor alcohol-induced dopamine release in nucleus accumbens., Conclusions: These results indicate that blockade of H(3) receptor should be considered as a new attractive mechanism for the treatment of alcoholism.

Rationale: The lack of potent, selective, brain penetrant Y(2) receptor antagonists has hampered in vivo functional studies of this receptor., Objective: Here, we report the in vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a novel Y(2) receptor antagonist., Methods: The affinity of JNJ-31020028 was determined by inhibition of the PYY binding to human Y(2) receptors in KAN-Ts cells and rat Y(2) receptors in rat hippocampus. The functional activity was determined by inhibition of PYY-stimulated calcium responses in KAN-Ts cells expressing a chimeric G protein Gqi5 and in the rat vas deferens (a prototypical Y(2) bioassay). Ex vivo receptor occupancy was revealed by receptor autoradiography. JNJ-31020028 was tested in vivo with microdialysis, in anxiety models, and on corticosterone release., Results: JNJ-31020028 bound with high affinity (pIC(50) = 8.07 +/- 0.05, human, and pIC(50) = 8.22 +/- 0.06, rat) and was >100-fold selective versus human Y(1), Y(4), and Y(5) receptors. JNJ-31020028 was demonstrated to be an antagonist (pK(B) = 8.04 +/- 0.13) in functional assays. JNJ-31020028 occupied Y(2) receptor binding sites (approximately 90% at 10 mg/kg) after subcutaneous administration in rats. JNJ-31020028 increased norepinephrine release in the hypothalamus, consistent with the colocalization of norepinephrine and neuropeptide Y. In a variety of anxiety models, JNJ-31020028 was found to be ineffective, although it did block stress-induced elevations in plasma corticosterone, without altering basal levels, and normalized food intake in stressed animals without affecting basal food intake., Conclusion: These results suggest that Y(2) receptors may not be critical for acute behaviors in rodents but may serve modulatory roles that can only be elucidated under specific situational conditions.

Rationale: Dependence can develop during chronic opioid use, and the emergence of withdrawal might promote drug taking., Objective: This study examined how chronic morphine administration or withdrawal modified self administration of heroin or cocaine., Methods: Four monkeys responded under a fixed ratio 10 schedule to receive i.v. infusions of heroin (0.56-560 microg/kg/infusion) or cocaine (1-100 microg/kg/infusion). Monkeys received morphine twice daily; the final dose was 10 mg/kg/12 h. Dose-effect curves for heroin or cocaine were determined in 150-min sessions throughout morphine administration and during temporary suspension when withdrawal signs were also monitored. Heroin dose-effect curves and withdrawal signs were determined daily following termination of morphine administration., Results: Before monkeys received morphine, heroin, and cocaine maintained responding with unit doses of 1.78 microg/kg of heroin and 10 microg/kg/injection of cocaine resulting in, on average, 13.4 and 20.8 infusions, respectively. When monkeys received morphine daily, self administration of heroin and cocaine decreased to, on average, 3.1 and 11.3 infusions, respectively. Responding for heroin or cocaine recovered following temporary (17-53 h) suspension of morphine administration. The number of heroin infusions and total withdrawal signs increased when morphine administration was terminated. Withdrawal signs peaked 3-4 days after morphine; however, the number of infusions remained elevated for 8 weeks., Conclusions: Changes in self administration responding did not precisely covary with signs of withdrawal and responding for small doses of heroin persisted long after discontinuation of morphine, suggesting that non-pharmacologic (e.g., conditioned reinforcing) effects might contribute to the maintenance of lever pressing under these conditions.

Rationale: Melanocortin and opioid systems regulate feeding as well as other behaviors; however, the relationship between the two systems is not yet defined. Since agonist-induced stimulation of melanocortin receptors blocks the behavioral effects of mu opioid receptor agonists, and melanocortin-4 (MC4) receptors and mu opioid receptors share a similar anatomical distribution in the central nervous system, MC4 receptor blockade may increase opioid responsiveness., Objectives: The goal of this study was to test the hypothesis that blockade of MC4 receptors increases the behavioral effects of morphine., Methods: The effects of HS014 (0.0032, 0.032, and 1 nmol, i.c.v.), a selective MC4 antagonist, on morphine-induced (3.2, 10, and 32 mg/kg, i.p.) locomotor activity (measured in the open field for 15 min) and antinociception (measured in the hot plate at 55 degrees C) were assessed in C57Bl/6 mice. In addition, the effects of morphine were evaluated in A(y) mice, a genetic model for MC4 receptor blockade., Results: The dose-effect curve of morphine for locomotor activity was shifted downwards in C57Bl/6 mice pretreated with HS014 and in A(y) mice. The dose-effect curve of morphine for antinociception was shifted two- and threefold to the left in C57Bl/6 mice pretreated with HS014 and in A(y) mice, respectively., Conclusions: These results indicate that blockade of MC4 receptors increases the antinociceptive effects of morphine without changing the potency of morphine for locomotor activity, suggesting that MC4 receptor antagonists may be candidate drugs that can be clinically used for the treatment of pain.

Rationale: Cinnamoylquinides are formed from the corresponding chlorogenic acids during coffee roasting. Instant coffee has been shown to displace binding of the mu opioid receptor antagonist, [3H]naloxone, but the putative active agent, feruloylquinide, has not been characterized., Objectives: The goal was to identify the active agent(s) in coffee by measuring the binding affinity of individual cinnamoyl-1,5-quinides to the human mu opioid receptor, and determine the effects of these compounds on morphine-induced anti-nociceptive behavior in mice., Methods: Cinnamoyl-1,5-quinides in extracts of decaffeinated instant coffee were quantified by reverse-phase HPLC comparisons with synthetic samples of 3-coumaroyl-1,5-quinide and 4-coumaroyl-1,5-quinide, 3-caffeoyl-1,5-quinide and 4-caffeoyl-1,5-quinide (4-CQL) 3-feruloyl-1,5-quinide and 4-feruloyl-1,5-quinides and 3,4-dicaffeoyl-1,5-quinide (DICAQ). Affinities of the cinnamoyl-1,5-quinides and decaffeinated instant coffee extract were determined by displacement of [3H]naloxone binding in cultured HEK-MOR cells. Inhibition of the anti-nociceptive activity of morphine (1 mg/kg IP) was determined in C57BL/6J mice using the hot plate test at 52 degrees C., Results: Extract of decaffeinated instant coffee produced a displacement K(i) of 42+/-16 mg/l, while the K(i) of a synthetic sample of 4-CQL was 4.4+/-0.4 microM. Compounds with a cinnamoyl substituent in the 4-position of the quinide, i.e. 4-CQL, DICAQ, 3,4-diferuloyl-1,5-quinide, and 3,4-dicoumaroyl-1,5-quinide, had affinities for the mu opioid receptor in the low micromolar range. In the hot plate test, coffee extract, containing 0.78% of 4-CQL, reversed the anti-nociceptive effect of morphine at 10 mg/kg IP. Two cinnamoyl-1,5-quinides found in roasted coffee, DICAQ, and 4-CQL, were active at 1 and 0.1 mg/kg IP, respectively., Conclusions: These results suggest that the previously reported anti-opioid activity of instant coffee is caused primarily by the presence of 4-CQL, and to lesser extent by other cinnamoyl-1,5-quinides.

Rationale: Buprenorphine is a low-efficacy mu opioid agonist that can reduce drug taking in opioid abusers; however, the mechanism by which buprenorphine modifies the actions of other drug taking and the consequences of repeated treatment with buprenorphine are not fully understood., Objective: The purposes of this study were to evaluate the time- and dose-dependence of discriminative stimulus effects in pigeons receiving buprenorphine repeatedly and to examine possible interactions between buprenorphine and heroin., Methods: Six pigeons discriminated between vehicle and 0.178 mg/kg buprenorphine while responding under an FR schedule for food. Substitution and drug combination studies characterized the potency and time course for buprenorphine, as well as interactions between buprenorphine and heroin., Results: Stimulus control by buprenorphine was maintained throughout the study and was not changed by repeated daily dosing or by an acute injection of large doses of buprenorphine. Mu opioid agonists substituted for buprenorphine with the following order of potency: heroin > or = butorphanol > nalbuphine > or = morphine. Ketamine, enadoline, spiradoline, amphetamine and cocaine failed to substitute completely for buprenorphine. The discriminative stimulus effects of buprenorphine lasted 2-72 h, depending on dose, and naltrexone prevented but did not reverse the effects of buprenorphine., Conclusion: Despite a very long duration of action and apparent irreversibility, under these conditions in pigeons, buprenorphine does not modulate the discriminative stimulus effects of itself or heroin. Thus, simple agonism might account for the therapeutic effectiveness of buprenorphine in opioid abusers.