Attenuation of hypoxia-induced increases in ventilation by adenosine antagonists in rhesus monkeys

The respiratory effects of caffeine and paraxanthine, two xanthine adenosine antagonists with phosphodiesterase (PDE) activity, CGS 15943, a non-xanthine adenosine antagonist lacking PDE inhibitory activity, and rolipram, a non-xanthine PDE inhibitor lacking adenosine antagonist activity, were characterized in unanesthetized, seated rhesus monkeys exposed to 10% O2 balanced in N2 (hypoxia). Ventilation was measured continuously by enclosing the monkey's head in a fitted helmet and using a pressure-displacement plethysmographic technique. Respiratory frequency (f) and minute volume (VE) increased during 15-minute periods of hypoxia, and intramuscular administration of caffeine (0.3 and 1.0 mg/kg), paraxanthine (0.3 and 1.0 mg/kg) and CGS 15943 (0.03 and 0.1 mg/kg) attenuated the ventilatory response to hypoxia. In contrast, rolipram (0.003-0.03 mg/kg) did not significantly alter the ventilatory response to hypoxia. Drug effects also were characterized in monkeys exposed to air (normoxia) or 3%, 4% and 5% CO2 balanced in air (hypercapnia). Doses of caffeine, paraxanthine or CGS 15943 that attenuated the ventilatory response to hypoxia had no significant effect on f or VE during conditions of normoxia or hypercapnia. The results indicate that adenosine may play a major role in the function of peripheral, O2-sensitive mechanisms during hypoxia.     

Discriminative effects of CGS 15943, a competitive adenosine receptor antagonist, in monkeys: comparison to methylxanthines

Caffeine and related methylxanthines are competitive antagonists at A1- and A2-adenosine receptors, but have other actions at the cellular level that contribute to their effects on behavior. As an approach toward determining the role of adenosine receptors in the behavioural effects of drugs, four squirrel monkeys were trained to discriminate between injections of CGS 15943 (1.0 mg/kg i.m.), a nonxanthine adenosine receptor antagonist that does not inhibit phosphodiesterase, and its vehicle. All monkeys generalized dose-dependently and completely to six of seven methylxanthines: 3-isobutyl-1-methylxanthine (0.1-1.75 mg/kg), theophylline (0.03-3.0 mg/kg), paraxanthine (0.3-30 mg/kg), 8-cyclopentyltheophylline (0.3-30 mg/kg), theobromine (0.3-30 mg/kg) and caffeine (1.0-30 mg/kg). Three of four monkeys did not generalize to 8-p-sulfophenyl-theophylline (1.0-30 mg/kg), which does not cross the blood-brain barrier. When the training dose of CGS 15943 was administered concurrently with adenosine-receptor agonists, its effects were blocked dose-dependently and completely by CGS 21680 (A2 selective), only partially by cyclohexyladenosine (A1 selective), but were not blocked by 5'-N-ethylcarboxamidoadenosine (nonselective). CGS 21680 did not block responding on the CGS 15943-appropriate lever occasioned by 30 mg/kg of caffeine or 3.0 mg/kg of theophylline. These results suggest that stimulus control of behavior by CGS 15943 derives, in part, from blockade of A2-adenosine receptors located in the central nervous system. However, the potency order of methylxanthines as CGS 15943-like discriminative stimuli did not correlate with their relative affinities at either A2- or A1-adenosine receptors or their potencies for other known effects at the cellular level. Therefore, a novel mechanism of action might account for the CGS 15943-like discriminative effects of some or all of these drugs.     

Punished behavior: increases in responding after d-amphetamine

Responding maintained in squirrel monkeys under a 10-min fixed-interval schedule of food presentation was suppressed by presenting a shock after every 30th response (punishment). During alternate 10-min periods of the same experimental session, but in the presence of a different discriminative stimulus, responding either had no effect (extinction) or postponed delivery of an electric shock (avoidance). During sessions when the avoidance schedule was not in effect, d-amphetamine sulfate decreased punished responding. When the avoidance schedule was present during alternate 10-min periods, however, d-amphetamine (0.01 minus 0.56 mg/kg, i.m.) markedly increased responding during punishment components. Increases in responding during avoidance components were also evident. The effects of d-amphetamine on punished responding depend on the context in which that responding occurs.     

Opioid antagonist profile of SC nor-binaltorphimine in the formalin paw assay

The antinociceptive effects of mu and kappa agonists were examined after the systemic administration of the opioid antagonists nor-binaltorphimine (nor-BNI) and naloxone in the late response or tonic nociceptive phase of the mouse formalin assay. Initially, SC morphine (ED50, 0.97 mg/kg), racemic U-50488H (ED50, 0.79 mg/kg), (-)U-50488 (ED50, 0.41 mg/kg), and another agonist PD 117,302 (ED50, 0.28 mg/kg) were found to produce graded increases in the level of antinociception as measured by this procedure; naloxone, administered immediately before morphine and U-50488H, antagonized their antinociceptive actions. The effects of morphine and U-50488H then were evaluated 10 min to 96 h after the administration of nor-BNI. Subcutaneous nor-BNI at 30.0 mg/kg, but not at 3.0 or 10.0 mg/kg, attenuated the antinociceptive effects of morphine and U-50488H when the interval separating nor-BNI and the agonists was kept constant at 1 h. Time-course analysis of the effects of combinations of nor-BNI with morphine led to irregular findings: 10.0 mg/kg of nor-BNI lessened the effects of morphine (2.0 mg/kg) if the dosing interval was 10 min, whereas 30.0 mg/kg of nor-BNI attenuated the effects of morphine (2.0 mg/kg) if the dosing interval was 1 or 4 h; 10.0 mg/kg of nor-BNI also diminished the antinociceptive effects of U-50488H (1.7 mg/kg) only if the interval spacing the two drugs was 24 h. In comparison, a threefold higher dose of nor-BNI (30.0 mg/kg) reduced the effects of U-50488H (1.7 mg/kg) if the interval was 1 h or more. In these latter experiments, the antagonist effects of SC nor-BNI (30.0 mg/kg) were evident up to 96 h posttreatment. These results show that the mu opioid antagonist activity of nor-BNI is variable and that the kappa opioid antagonist selectivity of nor-BNI is a function of dose and treatment interval and is long-lasting even after systemic administration.     

Effects of d-amphetamine on responding of squirrel monkeys maintained under second-order schedules of food presentation, electric shock presentation or stimulus-shock termination

The effects of d-amphetamine (0.01-5.6 mg/kg i.m.) were studied on lever pressing of squirrel monkeys maintained under various second-order schedules by a visual stimulus (S) that, with separate monkeys, was occasionally paired with the presentation of either food, electric shock or with the termination of a stimulus in the presence of which shocks occurred. Under one condition, the first response after 5 min produced a 3-sec stimulus change and the fourth stimulus change was followed immediately by food delivery, electric shock presentation or by the termination of a stimulus in the presence of which shocks occurred [fixed-ratio (FR); fixed-interval (FI) [FR 4 (FI 5-min:S)]. The effects of d-amphetamine were also studied under the food- and shock-presentation schedules when food or shock occurred only once, at the end of each session, after completion of 53n 3-min fixed-intervals all of which ended with a brief stimulus change [FR 10 (FI 3-min : S)]. Under a third condition, each thirtieth response produced the 3-sec brief stimulus (FR 30 : S) and the first FR 30 completed after 5 min elapsed produced the stimulus followed by food or, with separate monkeys, electric shock [FI 5-min (FR 30:S)]. Low to intermediate doses of d-amphetamine (0.03-0.3 mg/kg) generally increased and higher doses (0.56-5.6 mg/kg) decreased responding under all conditions. The effects of d-amphetamine on responding maintained by brief stimuli under different types of second-order schedules are generally similar, regardless of the type of reinforcing event or particular second-order schedule.     

Pharmacological analysis of the heterogeneous discriminative stimulus effects of ethanol in rats using a three-choice ethanol-dizocilpine-water discrimination

The present study used a three-choice operant drug discrimination procedure to determine if NMDA-mediated discriminative stimulus effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate dizocilpine (0.17 mg/kg; i.g.) from ethanol (2.0 g/kg; i.g.) from water (4.7 ml; i.g.) using food reinforcement. Substitution tests were conducted following administration of the GABA(A) positive modulators allopregnanolone (5.6-30.0 mg/kg; i.p.), diazepam (0.3-10.0 mg/kg; i.p.) and pentobarbital (1.0-21.0 mg/kg; i.p.), the non-competitive NMDA antagonist phencyclidine (0.3-10.0 mg/kg; i.p.), the 5-HT1 agonists TFMPP (0.3-5.6 mg/kg; i.p.) and RU 24969 (0.3-3.0 mg/kg; i.p.), and isopropanol (0.10-1.25 g/kg; i.p.). Allopregnanolone, diazepam and pentobarbital substituted completely (>80%) for ethanol. Isopropanol partially (77%) substituted for ethanol. Phencyclidine substituted completely for dizocilpine. RU 24969 and TFMPP did not completely substitute for either training drug, although RU 24969 partially (62%) substituted for ethanol. Successful training of this three-choice discrimination indicates that the discriminative stimulus effects of 0.17 mg/kg dizocilpine were separable from those of 2.0 g/kg ethanol. The finding that attenuation of NMDA-mediated effects of ethanol occurred without altering significantly GABA(A)- and 5-HT1-mediated effects suggests that the NMDA component may be independent of other discriminative stimulus effects of 2.0 g/kg ethanol.     

Behavioral evaluation of modafinil and the abuse-related effects of cocaine in rhesus monkeys.

Modafinil is a central nervous system stimulant used to promote wakefulness, and it is being evaluated clinically as an agonist medication for treating stimulant abuse. This is the first report of the effects of modafinil on the abuse-related effects of cocaine in nonhuman primates. The behavioral effects of modafinil were examined in three studies. First, the discriminative stimulus effects of modafinil (3.2–32 mg/kg) were evaluated in rhesus monkeys (Macaca mulatta) trained to discriminate either low (0.18 mg/kg, IM) or high (0.4 mg/kg, IM) doses of cocaine from saline. Modafinil dose-dependently substituted for cocaine in 6 of 7 monkeys. In the second study, the effects of chronically administered modafinil (32–56 mg/kg/day, IV) on food- and cocaine-maintained (0.001–0.1 mg/kg/inj) operant responding were examined. Modafinil was administered 3 times/hr for 23 hr/day to ensure stable drug levels. Chronic treatment with 32 mg/kg/day modafinil selectively reduced responding maintained by intermediate and peak reinforcing doses of cocaine, but responding maintained by higher doses of cocaine was unaffected. Food-maintained behavior did not change during chronic modafinil treatment. In a third study, modafinil (32 and 56 mg/kg/day, IV) was examined in a reinstatement model. Modafinil transiently increased responding during extinction. These findings indicate that modafinil shares discriminative stimulus effects with cocaine and selectively reduces responding maintained by reinforcing doses of cocaine. In addition, modafinil reinstated cocaine-seeking behavior, which may reflect its cocaine-like discriminative stimulus effects. These data support clinical findings and indicate that these preclinical models may be useful for predicting the effectiveness of agonist medications for drug abuse treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of oral caffeine pretreatment on response to intravenous nicotine and cocaine.

Previous research suggests that under conditions of chronic daily caffeine administration, caffeine increases the effects of nicotine. Little is known about the effects of caffeine pretreatment on response to nicotine under infrequent caffeine administration conditions. The present study examined whether infrequent (not on consecutive days) acute oral caffeine administration alters subject-rated, physiological, and monetary value effects of intravenous nicotine in regular users of caffeine, tobacco, and cocaine. To determine the specificity of effects of caffeine on response to nicotine, the effects of caffeine administration on response to intravenous cocaine (another short-acting stimulant) were also studied. Fourteen (1 woman) volunteers participated in this 3–4 week, double-blind, inpatient study. Volunteers participated in 10 experimental conditions in pseudo-randomized order, in which oral caffeine (250 mg/70 kg) or placebo was administered 1 hr before an intravenous injection, consisting of nicotine (1 or 2 mg/70 kg), cocaine (15 or 30 mg/70 kg), or saline. Infrequent acute caffeine pretreatment attenuated the increase resulting from 2 mg/70 kg nicotine administration on ratings of “rush,” “good effects,” “liking,” “high,” and “drowsy/sleepy.” Caffeine had no significant effect on physiological response to nicotine. Caffeine had no significant effect on subject-rated and physiological response to cocaine, with the exception that caffeine significantly augmented blood pressure response to cocaine. In contrast to the previous research using chronic caffeine maintenance, these data suggest that infrequent acute caffeine administration may attenuate nicotine effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

SB 207499 (Ariflo), a second generation phosphodiesterase 4 inhibitor, reduces tumor necrosis factor alpha and interleukin-4 production in vivo

The ability of the second generation phosphodiesterase 4 inhibitor SB 207499 (Ariflo), [c-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-l-cyclohexane carboxylic acid], to inhibit inflammatory cytokine production in vivo was evaluated and compared to that of rolipram, a first generation phosphodiesterase 4 inhibitor. To examine human tumor necrosis factor alpha (TNFalpha) production, human monocytes were adoptively transferred into Balb/c mice and challenged with lipopolysaccharide (LPS). In this model, SB 207499 inhibited human TNFalpha production with oral ED50 of 4.9 mg/kg. Similarly, R-rolipram inhibited human TNFalpha production with an ED50 of 5.1 mg/kg, p.o. In contrast to their equipotent activity against TNFalpha production, SB 207499 (ED50 = 2.3 mg/kg, p.o.) was 10-fold less potent than R-rolipram (ED50 = 0.23 mg/kg, p.o.) in reversing reserpine-induced hypothermia, a model of antidepressant activity. In time course studies, SB 207499 (30 mg/kg, p.o.) inhibited TNFalpha production for at least 10 hr; substantial plasma concentrations of SB 207499 were detected over the same interval. The ability of SB 207499 to modulate interleukin-4 production in vivo was assessed in a chronic oxazolone-induced contact sensitivity model in Balb/c mice. In this model, topical administration of SB 207499 (1000 microgram) inhibited intralesional concentrations of interleukin-4 (55%; P <.01). The results demonstrate that SB 207499 is a potent inhibitor of inflammatory cytokine production in a variety of settings in vivo. Moreover, although it is as potent as R-rolipram in inhibiting TNFalpha production, it has substantially less central nervous system activity. Thus SB 207499 represents an excellent candidate with which to evaluate the antiinflammatory potential of PDE4 inhibitors.     

Steep central islands after myopic photorefractive keratectomy

The nitric oxide synthase inhibitor 7-nitroindazole (7-NI) dose-dependently (3.0-30.0 mg/kg) displayed anxiolytic activity, as measured by an increase in open arm exploration time in the elevated plus-maze (EPM), following intraperitoneal (i.p.) administration in rats. Acute administration of 7-NI at 30.0 mg/kg significantly (P < 0.05) increased open arm exploration time by 176% compared to vehicle control, similar to the benzodiazepine diazepam at 1.0 and 3.0 mg/kg (+ 191 and + 200%, respectively). However, 39 h following subchronic 5-day administration of diazepam twice daily (bid) at 3.0 mg/kg, diazepam was devoid of anxiolytic activity at 1.0 mg/kg, as measured by no difference in open arm exploration time compared to vehicle control, while the 3.0 mg/kg dose still produced a significant (P < 0.05) 175% increase in open arm exploration time. In contrast, following subchronic administration of 7-NI (30.0 mg/kg, bid), a significant (P < 0.01) enhancement in open arm exploration time was observed at 30.0 mg/kg (+ 665% compared to control). Therefore, inhibition of nitric oxide synthase by 7-NI resulted in anxiolysis similar to diazepam following acute administration in the EPM. However, following subchronic administration, unlike diazepam which showed an attenuation of anxiolytic activity, 7-NI displayed enhanced anxiolytic efficacy and was devoid of tolerance.     

A history of postponing shock does not appear to alter the discriminative stimulus effects of cocaine

Previous research has shown that the rate of punished lever pressing of monkeys is typically decreased by cocaine administration. However, cocaine increases punished responding in monkeys with a history of responding maintained by the postponement of shock presentation. This raises the question of whether other behavioral effects of cocaine differ following a history of postponing shock. The present experiment examined whether a history of postponing shock alters the discriminative stimulus effects of cocaine. Three squirrel monkeys were trained to discriminate cocaine (0.56 mg/kg, intramuscular) from saline. Presses on the left lever produced food following saline injections whereas presses on the right lever were reinforced following administration of cocaine. Occasional test sessions were conducted in which cocaine (0.1-0.56 mg/kg), midazolam (0.03-0.56 mg/kg) or pentobarbital (0.3-5.6 mg/kg) was injected prior to the session and responding on either lever was reinforced. Discrimination training was discontinued during a second experimental phase in which responding was maintained by shock postponement. Pulling a chain postponed mild shocks for 25 s, whereas shocks occurred every 5 s in the absence of responding. Next, the drug discrimination dose-response curves were redetermined. The dose-response curves for all drugs before and after the shock postponement history were similar. This outcome suggests that the influence of a history of shock postponement is specific to punished responding.     

Mycotic sinusitis

Previous drug discrimination studies have elucidated the importance of gamma-aminobutyric acidA (GABAA), N-methyl-D-aspartate (NMDA) glutamate, and serotonin (5-HT) receptor systems in mediating the discriminative stimulus effects of ethanol. The present study used a three-choice operant drug discrimination procedure in an attempt to determine if salient GABAergic effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate pentobarbital (10.0 mg/kg; intragastrically (i.g.) from ethanol (2.0 g/kg; i.g.) from water (4.7 ml; i.g.) using food reinforcement. Stimulus substitution tests were conducted following the administration of allopregnanolone (1.0-17.0 mg/kg; intraperitoneally (i.p.)), diazepam (0.1-7.3 mg/kg; i.p.), midazolam (0.0056-17.0 mg/kg; i.p.), dizocilpine (0.01-0.56 mg/kg; i.p.), phencyclidine (1.0-5.6 mg/kg; i.p.), CGS 12066B (3-30 mg/kg; i.p.), RU 24969 (0.1-5.6 mg/kg; i.p.) and morphine (1 or 3.0 mg/kg; i.p.). Within the group, allopregnanolone and midazolam completely substituted (> 80%), and diazepam partly substituted (67%) for the discriminative stimulus effects of pentobarbital. Dizocilpine and phencyclidine partly substituted (58 and 57%, respectively) for ethanol without substantial pentobarbital-appropriate responding. RU 24969, CGS 12066B and morphine did not result in complete substitution for either ethanol or pentobarbital, although RU 24969 resulted in partial (68%) pentobarbital substitution. The ability to train the present three-choice discrimination in rats indicates that the discriminative stimulus effects of 10.0 mg/kg pentobarbital were separable from those of 2.0 g/kg ethanol. The results suggest that the pharmacological effects of ethanol, which can control behavior, may seemingly be modified by training conditions (two-versus three-choice discrimination procedures), to the extent that a receptor system prominently linked to the behavioral activity of ethanol (i.e. GABAA) appears no longer to be involved in the interoceptive effects of the drug.     

Chronic l-alpha acetylmethadol in rhesus monkeys: discriminative stimulus and other behavioral measures of dependence and withdrawal

This study characterized discriminative stimulus and other effects of naltrexone in rhesus monkeys treated daily with the long-acting opioid l-alpha acetylmethadol (LAAM). An initial dose-finding study assessed the rate-decreasing effects of naltrexone in three monkeys receiving LAAM daily (0.32-1.78 mg/kg); subsequently, these monkeys and a fourth received 1.0 mg/kg/12 hr of LAAM although discriminating between naltrexone and saline. Responding occurred on the saline lever after the administration of LAAM, whereas >90% drug-lever responding occurred after the administration of 0.1 mg/kg of naltrexone that also elicited signs of withdrawal. Naloxone and quadazocine, but not morphine, nalbuphine or ketamine, substituted for naltrexone. Morphine and nalbuphine shifted the naltrexone dose-effect curve to the right. Compared to precipitated withdrawal, deprivation-induced withdrawal occasioned less naltrexone-lever responding and fewer observable signs of withdrawal. Maximal naltrexone-level responding occurred 24 to 48 hr after the discontinuation of LAAM treatment; the frequency of other withdrawal signs also peaked 24 to 48 hr after the discontinuation of LAAM. Partial naltrexone-lever responding occurred for up to 10 days after discontinuation of LAAM treatment; 4 and 8 days after the discontinuation of LAAM treatment, 0.1 mg/kg of naltrexone did no further increase naltrexone-lever responding or withdrawal signs suggesting that less-then-maximal naltrexone-lever responding was not due to long-lasting effects of LAAM or its metabolites. The discriminative stimuli that are associated with LAAM deprivation might be different from the stimuli associated with either training condition. This study is the first antagonist discrimination in non-humans primates treated chronically with LAAM and the results indicate that the naltrexone stimulus is related to opioid withdrawal.     

Severe blepharoptosis: correction by orbicularis oculi muscle and orbital septum resection and advancement

It has been suggested that the increased reinforcement rate on a differential-reinforcement-of-low-rate of responding (DRL) schedule observed following acute antidepressant administration in the rat is due to an improvement in timing accuracy. The aim of the present work was to evaluate the effects of antidepressants in another schedule that requires accurate estimation of time intervals, the peak procedure. Three antidepressant drugs were tested, the tricyclic antidepressant imipramine (1.0-10.0 mg/kg, i.p.) and the 5-HT reuptake inhibitors, zimelidine (10.0-40.0 mg/kg, i.p.) and clomipramine (1.0-10.0 mg/kg, i.p.). For reference, the full benzodiazepine receptor agonist, diazepam (1.0-5.0 mg/kg, i.p.) and the psychomotor stimulant, d-amphetamine (0.5-1.5 mg/kg, s.c.) were also tested. All doses of d-amphetamine tested significantly increased lever-pressing rates, whereas all the other compounds induced significant decreases in lever-pressing rates. Overall, the time at which the maximal lever-pressing rate occurred was not altered by any of the compounds, suggesting that timing accuracy was not significantly affected by any of the compounds administered. The only exception was zimelidine (40.0 mg/kg), which reduced the time at which the maximal lever-pressing rate occurred, although lever-pressing rates were also significantly reduced at this dose. These data suggest that previously reported antidepressant-induced improvement in performance on the DRL schedule may not have been due to improved timing accuracy per se but may have been due to a decrease in lever-pressing rates.     

The opioid receptor antagonist nalmefene reduces responding maintained by ethanol presentation: preclinical studies in ethanol-preferring and outbred Wistar rats

Nalmefene, the 6-methylene derivative of naltrexone, was examined after subcutaneous (s.c.) (0.0001 to 8.0 mg/kg) and oral (10 to 80.0 mg/kg) administration in ethanol (EtOH)-preferring rats whose responding (i.e., lever pressing) was maintained by the presentation of EtOH. Naltrexone (0.01 to 40 mg/kg) was used as a reference opioid antagonist. EtOH (10% v/v) and saccharin (0.025 to 0.1% w/v) solutions were concurrently available for 1 hr each day under a two-lever, fixed-ratio schedule in which four responses on one lever produced the EtOH solution and four responses on the other lever produced the saccharin solution. When basal response rates for saccharin were 10% that of EtOH, all routes of nalmefene administration reduced control levels of responding maintained by EtOH by 38 to 84%. When basal response rates for saccharin-maintained responding were 60% or 82% that of EtOH, only lower s.c. naltrexone (e.g., 0.01 to 0.025 mg/kg) and nalmefene (e.g., 0.01 to 0.10 mg/kg) doses produced a selective dose-dependent suppression of EtOH-maintained responding. Higher nalmefene (0.25 to 8.0 mg/kg) and naltrexone (1.0 to 20.0 mg/kg) doses failed to produce a dose-dependent suppression on EtOH or saccharin maintained responding. Both antagonists suppressed responding maintained by EtOH primarily during the initial 10-min period, with little additional suppression occurring across the remainder of the 60-min period. Subcutaneous nalmefene was 3200- to 6400-fold more potent than oral nalmefene, suggesting bioavailability was optimized using the s.c. route. Nalmefene (0.5 mg/kg, s.c.) treatment for 10 consecutive days produced mild tolerance development, whose effects dissipated by day 8. Naltrexone (10 to 40 mg/kg) and nalmefene (1.5 to 3.0 mg/kg), given 8 to 24 hr before the test session, reduced control levels of responding maintained by EtOH by 82%. Thus, immediate opioid receptor occupancy was not required to observe antagonism. These data demonstrate that, under a variety of experimental conditions, nalmefene is an effective antagonist of responding maintained by EtOH and lend support to clinical reports that nalmefene may function as an alternative pharmacotherapy to naltrexone to reduce EtOH-motivated behavior and prevent relapse.     

Analgesic, respiratory and heart rate effects of cannabinoid and opioid agonists in rhesus monkeys: antagonist effects of SR 141716A

This study characterized the antinociceptive, respiratory and heart rate effects of the cannabinoid receptor agonists Delta-9-tetrahydrocannabinol (Delta-9-THC) and WIN 55212 ((R)-(+)-2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol-[1,2,3-de]-1, 4-benzoxazin-6-yl)(1-naphtalenyl)methanone monomethanesulfonate), N-arachidonyl ethanolamide (anandamide) and the mu and kappa opioid receptor agonists heroin and U69593, alone and in conjunction with a cannabinoid receptor antagonist, SR 141716A [N-(piperidin-1-1-yl)-5-(4-chlorophenyl)-1(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride] and an opioid receptor antagonist, quadazocine, in rhesus monkeys (Macaca mulatta). Using 12 adult rhesus monkeys, latencies to remove the tail from a 50 degrees C water bath, respiration in 5% CO2 and heart rate were measured. When administered alone, SR 141716A (1.8, 5.6 mg/kg i.m.) did not alter nociception, respiration or heart rate. Delta-9-THC (0.1-10 mg/kg i.m.) and WIN 55212 (0.1-10 mg/kg i.m.) dose-dependently increased antinociception and dose-dependently decreased respiratory minute and tidal volumes and heart rate. These antinociceptive, respiratory and heart rate effects were reversed by SR 141716A but not by the opioid antagonist quadazocine (1 mg/kg i.m.). Anandamide (10 mg/kg i.m.) also produced antinociception. Heroin (0.01-10 mg/kg i.m.) and U69593 (0.01-3.2 mg/kg i.m.) also dose-dependently increased antinociception and decreased respiratory and heart rate measures; these effects were antagonized by quadazocine but not by SR 141716A. These results demonstrate selective and reversible antagonism of cannabinoid behavioral effects by SR 141716A in rhesus monkeys.     

Acute effects of pentobarbital in a monkey operant behavioral test battery

The effects of acute pentobarbital treatment were assessed using a complex operant test battery containing five tasks in which correct performance is thought to depend upon processes associated with short-term memory and attention [delayed-matching-to-sample (DMTS)], color and position discrimination [conditioned position responding (CPR)], motivation [progressive ratio (PR)], time perception [temporal response differentiation (TRD)], and learning [incremental repeated acquisition (IRA)]. Adult, male rhesus monkeys were tested 15 min after IV injection of saline or pentobarbital (1, 3, 5.6, 10, or 15 mg/kg). Behavioral endpoints measured included percent task completed, response rate or latency, and response accuracy. The order of task sensitivity to disruption by PBT was TRD > IRA = DMTS = PR > CPR, in which sensitivity was defined as a significant disruption in any aspect of task performance. PBT slowed response rates at 10.0 and/or 15.0 mg/kg in all tasks. Accuracy was decreased in the TRD task at > or = 5.6 mg/kg but doses of > or = 10.0 mg/kg were required to decrease accuracy in the IRA, DMTS, and CPR tasks. Thus, behavior thought to model time perception (TRD) was more sensitive than behavior modeling learning (IRA), short-term memory and attention (DMTS), and motivation (PR). CPR was the least sensitive behavior. Because pentobarbital exerts its effects at least in part via GABA systems, the effects in the current study were compared with those of a previous study of the acute effects of diazepam. The two compounds exerted fundamentally different effects on operant test battery performance.     

Acute effects of caffeine on several operant behaviors in rhesus monkeys

The acute effects of 1,3-trimethylxanthine (caffeine) were assessed using an operant test battery (OTB) of complex food-reinforced tasks that are thought to depend upon relatively specific brain functions, such as motivation to work for food (progressive ratio, PR), learning (incremental repeated acquisition, IRA), color and position discrimination (conditioned position responding, CPR), time estimation (temporal response differentiation, TRD), and short-term memory and attention (delayed matching-to-sample, DMTS). Endpoints included response rates (RR), accuracies (ACC), and percent task completed (PTC). Caffeine sulfate (0.175-20.0 mg/kg, IV), given 15 min pretesting, produced significant dose-dependent decreases in TRD percent task completed and accuracy at doses > or = 5.6 mg/kg. Caffeine produced no systematic effects on either DMTS or PR responding, but low doses tended to enhance performance in both IRA and CPR tasks. Thus, in monkeys, performance of an operant task designed to model time estimation is more sensitive to the disruptive effects of caffeine than is performance of the other tasks in the OTB.     

Behavioral effects of the delta-selective opioid agonist SNC80 and related compounds in rhesus monkeys

The behavioral effects of the nonpeptidic delta opioid agonist SNC80 and a series of related piperazinyl benzamides derived from the parent compound BW373U86 were evaluated in rhesus monkeys. SNC80 (0.1-10 mg/kg) decreased response rates maintained by food-reinforcement in a dose- and time-dependent manner, with maximal effects occurring within 10 min of intramuscular injection. The potency of SNC80 and five other piperazinyl benzamides in this assay of schedule-controlled responding correlated with their affinity at cloned human delta opioid receptors but not with their affinity for cloned human mu receptors. Moreover, the effects of SNC80 were selectively antagonized by the delta-selective antagonist naltrindole (1.0 mg/kg), but not by the mu selective antagonist quadazocine (0.1 mg/kg) or the kappa-selective antagonist norbinaltorphimine (3.2 mg/kg). These findings indicate that SNC80 functions as a systemically active, delta-selective agonist with a rapid onset of action in rhesus monkeys. The antinociceptive effects of SNC80 were examined in a warm-water tail-withdrawal assay of thermal nociception. SNC80 (0.1-10 mg/kg) produced weak but replicable antinociceptive effects that were antagonized by naltrindole (1.0 mg/kg). SNC80 antinociception was also dose-dependently antagonized by BW373U86 (0.56-1.0 mg/kg), which was inactive in this procedure. These findings suggest that SNC80 may have higher efficacy than BW373U86 at delta opioid receptors. Moreover, SNC80 at doses up to 32 mg/kg did not produce convulsions, which suggests that SNC80 may also be safer than BW373U86. The effects of SNC80 were also examined in monkeys trained to discriminate cocaine (0.4 mg/kg i.m.) or self-administer cocaine (0.032 mg/kg/injection,i.v.). In drug discrimination studies, SNC80 (0.1-10 mg/kg) produced a dose-dependent and naltrindole-reversible increase in cocaine-appropriate responding, and complete substitution for cocaine was observed in five of seven monkeys tested. However, SNC80 (1.0-100 micrograms/kg/injection) did not maintain responding in monkeys trained to self-administer cocaine. Thus, despite its ability to produce cocaine-like discriminative stimulus effects, SNC80 may have relatively low abuse potential.