Fluid-containing emphysematous bullae: a spectrum of illness.

Fluid-containing emphysematous bullae are an under-reported complication of chronic obstructive pulmonary disease. The roles of bronchoscopy in the work-up and of antibiotics in the treatment are undefined. This study reports the combined results from the analysis of 16 cases treated at the present authors' institution and 36 previously reported cases. The median age at presentation was 58 yrs and the median duration of follow-up was 60 weeks. A third of the patients were asymptomatic, while two-thirds presented with symptoms, including 10% who had evidence of a severe lung infection. Methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa and Bacteroides melaninogenicus were cultured from the bullae fluid in three symptomatic patients. Sputum and blood cultures were uninformative. Bronchoscopy, performed in two-thirds of the cases, added no diagnostic information. Antibiotic treatment did not result in a more rapid resolution of the air fluid level. Percutaneous drainage was safe and effective in four patients. In conclusion, patients with fluid-containing bullae present with a spectrum of illness. Antibiotic treatment does not hasten radiographic resolution and bronchoscopy has no diagnostic or therapeutic role.

Neuroactive steroids: potential therapeutic use in neurological and psychiatric disorders.

Neuroactive steroids are a novel class of positive allosteric modulators of the GABAA receptor. Although neuroactive steroids are endogenous neuronal modulators, synthetic entities with improved oral bioavailability have recently been developed. These compounds demonstrate efficacy as anticonvulsants against a range of convulsant stimuli and demonstrate anti-epileptogenic activity in a kindling model of epilepsy. Efficacy has also been reported in preclinical models of anxiety, insomnia, migraine and drug dependence. Clinical evidence to date is generally supportive of these findings and indicates that neuroactive steroids are generally well tolerated. Taken as a whole, current data suggest that neuroactive steroids could have a future role in clinical practice. In this article, Maciej Gasior, Richard Carter and Jeffrey Witkin review preclinical and clinical evidence that forms the basis for predicting the potential therapeutic application of neuroactive steroids.

Acute and chronic effects of the synthetic neuroactive steroid, ganaxolone, against the convulsive and lethal effects of pentylenetetrazol in seizure-kindled mice: comparison with diazepam and valproate.

A high-affinity positive modulator of the GABA(A) receptor complex, ganaxolone, is a 3beta-methylated analog of the naturally occurring neuroactive steroid allopregnanolone. In the present study, ganaxolone was tested for its ability to (1) suppress seizures (clonic and tonic) and lethality induced by pentylenetetrazol (PTZ) in PTZ-kindled mice (anticonvulsive effect) and (2) to attenuate the development of sensitization to the convulsive and lethal effects of PTZ in kindled mice (anti-epileptogenic effect) when given as a pretreatment prior to each PTZ injection during kindling acquisition. Two classical antiepileptic drugs, diazepam and valproate, were tested for comparison. All three drugs dose-dependently suppressed tonic seizures and lethality induced by PTZ in kindled mice; only ganaxolone was effective against clonic seizures. Ganaxolone showed anti-epileptogenic properties as it reduced the sensitivity of kindled mice to the convulsive (clonic and tonic seizures) and lethal effects of PTZ. Diazepam showed anti-epileptogenic effects against tonic seizures and lethality, but not clonic seizures; valproate was ineffective in preventing development of any of these effects. Sensitivity to PTZ-induced seizures and lethality was not affected in mice with a history of repeated treatment with ganaxolone, diazepam, or valproate. The drugs had effects on ambulatory activity that ranged from no effect (ganaxolone) through moderate impairment (diazepam) to marked disruption (valproate). Taken together, the results of the present study add to accumulating evidence of the unique anticonvulsive/behavioral profile of neuroactive steroids.

Synthesis of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2, 3-benzodiazepin-4-ones as novel and potent noncompetitive AMPA receptor antagonists.

A group of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2, 3-benzodiazepin-4-ones was synthesized and assayed for antagonism of rat brain alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors expressed in Xenopus oocytes. The benzodiazepinones inhibited AMPA-activated membrane current responses in a manner consistent with noncompetitive, allosteric inhibition of the receptor-channel complex. The most potent compound in the series was 1-(4-aminophenyl)-7,8-(methylenedioxy)-3,5-dihydro-4H-2, 3-benzodiazepin-4-one (6), which had an IC50 of 2.7 microM. For comparison, the reference compound GYKI 52466 (2) had an IC50 of 6.9 microM. Compound 6 also had potent anticonvulsant activity in a mouse maximum electroshock-induced seizure (MES) assay: the ED50 was 2.8 mg/kg iv, whereas the ED50 for GYKI 52466 was 4.6 mg/kg iv. In contrast to a previous report, the 7,8-dimethoxy analogue of 6 was a low-potency AMPA antagonist (IC50 >100 microM) and weak anticonvulsant (ED50 >10 mg/kg iv). The benzodiazepinones described herein are potent noncompetitive AMPA receptor antagonists that could have therapeutic potential as anticonvulsants and neuroprotectants.

3 alpha-Hydroxy-3 beta-(phenylethynyl)-5 beta-pregnan-20-ones: synthesis and pharmacological activity of neuroactive steroids with high affinity for GABAA receptors.

Neuroactive steroids that allosterically modulate GABAA receptors have potential uses as anticonvulsants, anxiolytics, and sedative-hypnotic agents. Recently, a series of pregnanes substituted with simple alkyl groups at the 3 beta-position were synthesized and found to be active in vitro. The present report describes the synthesis of a series of substituted 3 alpha-hydroxy-3 beta-(phenylethynyl)pregnan-20-ones and their in vitro structure-activity relationship determined by their potency for inhibition of [35S]TBPS binding in rat brain membranes. Appropriate substitution of the phenyl group results in ligands with particularly high affinity for the neuroactive steroid site on GABAA receptors (e.g., 4-acetyl 28, IC50 10 nM). The potency of selected steroids was confirmed electrophysiologically in oocytes expressing cloned human GABAA alpha 1 beta 2 gamma 2L receptors (e.g., compound 28, EC50 6.6 nM). Consistent with their in vitro activity, some of the 3 beta-(phenylethynyl)-substituted steroids displayed anticonvulsant activity in the pentylenetetrazol (PTZ) and maximal electroshock (MES) tests following ip administration in mice. Notably, the 3 beta-[(4-acetylphenyl)ethynyl]-19-nor derivative 36 demonstrated an attractive anticonvulsant profile (PTZ and MES ED50 values of 2.8 and 9.2 mg/kg, respectively). A new pharmacophore for the neuroactive steroid site of GABAA receptors is proposed based upon the high affinity of certain substituted 3 beta-(phenylethynyl) steroids.

Pharmacology and neurochemistry of nefazodone, a novel antidepressant drug.

Nefazodone is a new antidepressant drug with a pharmacologic profile distinct from that of the tricyclic, monoamine oxidase inhibitor, and serotonin selective reuptake inhibitor antidepressants. Nefazodone was initially discovered for its ability to block 5-HT2A receptors and its reduced potency as an alpha 1-adrenergic blocker. It was later shown to inhibit both serotonin and norepinephrine uptake in vitro, attributes which most likely impart its clinical efficacy and which differentiate nefazodone from its chemical predecessor trazodone. The combination of these two mechanisms may ultimately result in a facilitation of 5-HT1A-mediated neurotransmission, which may be beneficial for treating symptoms of depression as evidenced by recent clinical findings. In addition, the preclinical profile of nefazodone demonstrates that it has decreased anticholinergic and antihistaminic activity relative to traditional agents. Clinical findings to date are consistent with these observations.

Discriminative stimulus properties of naloxone.

Nonopioid-dependent pigeons were trained to discriminate IM injections of 30.0 mg/kg naloxone from water in the procedure in which 15 consecutive responses on one of two keys resulted in grain presentation. Naloxone-appropriate responding was maximal at doses of naloxone equal to and greater than the training dose. The onset of the naloxone discriminative cue was rapid (less than 5 min) and the duration of the cue was short (less than 60 min). Naltrexone (1.0-10.0 mg/kg). pentazocine (1.0-10.0 mg/kg), levallorphan (1.0-30.0 mg/kg), and nalorphine (3.0-30.0 mg/kg) produced dose-dependent increases in naloxone-appropriate responding, occasioning 100% naloxone-key selections. In contrast, cyclazocine, profadol, and diprenorphine, at doses up to those at which animals did not respond, produced only intermediate degrees of naloxone-appropriate responding. Morphine always produced selection of the water key. These results demonstrate that a pure opioid antagonist, such as naloxone, has discriminative stimulus effects in the nonopioid-dependent animals, that these stimulus effects are shared by certain other opioid antagonists, and that these effects are distinguishable from those produced by pure opioid agonists, such as morphine.

Pharmacological evaluation of a modified conflict procedure: punished drinking in non-water-deprived rats.

RATIONALE: Conflict procedures used to detect anxiolytic-like activity of drugs often rely on maintaining strict schedules of water or food availability. It is ethically and practically desirable to reduce such states of deprivation in animal testing. OBJECTIVE: The purpose of the present experiment was to develop and pharmacologically characterize a conflict drinking procedure that did not require the use of water-deprived animals. METHODS: Rats were tested during daily sessions with alternating unpunished drinking (no tone: lick = sucrose solution) and signaled punished drinking (tone: lick = sucrose + shock) components, and developed individual steady baselines over a brief training period (approximately 3-4 weeks). The drugs tested i.p. were the positive allosteric modulators of gamma-amino butyric acidA (GABA)A receptors, diazepam (0.03-30 mg/kg), chlordiazepoxide (0.03-30 mg/kg), lorazepam (0.03-10 mg/kg), zolpidem (0.3-10 mg/kg), pentobarbital (1-30 mg/kg), pregnanolone (1-30 mg/kg), and bretazenil (0.03-10 mg/kg); the 5-hydroxy tryptamine1A (HT)1A-mediated anxiolytics, buspirone (1-10 mg/kg) and ipsapirone (1-17 mg/kg); and the negative controls D-amphetamine (0.3-3 mg/kg), haloperidol (0.01-0.3 mg/kg), morphine (0.3-17 mg/kg), and imipramine (0.3-30 mg/kg). RESULTS: The experimental procedure was sensitive to increases in punished drinking by the GABAA-positive modulators, consistent with their known or putative anxiolytic activity. Further, the 5-HT1A-mediated anxiolytics increased punished drinking, although to a lesser extent and over a more narrow dose range than did the GABAergic drugs. In contrast, D-amphetamine, haloperidol, morphine, and imipramine failed to increase punished drinking up to doses that decreased unpunished drinking. CONCLUSIONS: The present results indicate that water deprivation is not a necessary condition to engender drinking conflict behavior or to obtain pharmacological effects similar to those obtained with other classical conflict procedures.

Neuroactive steroids attenuate cocaine-induced sucrose intake in rats, but not cocaine-induced hyperactivity in mice.

RATIONALE: Neuroactive steroids, including the potent anticonvulsants ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) and Co 2-1068 (3beta-(4acetyl-phenyl)ethynyl-3alpha,21-dihydroxy-5beta+ ++-20-one-21-hemisuccinate), have recently been shown to protect against cocaine-induced seizures. OBJECTIVES: The purpose of the present experiments was to determine whether ganaxolone and Co 2-1068 attenuate acute behavioral effects of cocaine unrelated to seizures. METHODS: In the first experiment, the locomotor effects of Co 2-1068 (10-100 mg/ kg), pentobarbital (10-100 mg/kg) and haloperidol (0.03-0.3 mg/kg), alone or in combination with cocaine (5.6-30 mg/kg), were determined in mice. In the second experiment, the effects on sucrose intake of ganaxolone (4-16 mg/kg), Co 2-1068 (8-64 mg/kg), pentobarbital (4-32 mg/kg), and haloperidol (0.04-0.4 mg/kg), alone or in combination with cocaine (4-16 mg/kg), were determined in rats. RESULTS: Cocaine caused a dose-related increase in locomotor activity in mice, whereas Co 2-1068, pentobarbital and haloperidol caused dose-related decreases. The dopamine antagonist haloperidol, at a dose that had no effect on activity by itself, but not Co 2-1068 or pentobarbital, attenuated the cocaine-induced increase in locomotor activity. Cocaine, ganaxolone, Co 2-1068, and haloperidol produced dose-related decreases in sucrose intake in rats; the effects of pentobarbital on sucrose intake were variable. As with locomotor effects, haloperidol attenuated the cocaine-induced decrease in sucrose intake. In addition, cocaine-induced decreases in sucrose intake were attenuated by ganaxolone and Co 2-1068. Pentobarbital had no statistically significant effect on the cocaine dose-response function. CONCLUSIONS: These results suggest that the interaction of neuroactive steroids with cocaine extends to pharmacologic actions beyond anticonvulsant efficacy, but that the blockade of behavioral effects of cocaine by neuroactive steroids does not apply to all acute behaviors.

Modification of behavioral effects of drugs in mice by neuroactive steroids.

RATIONALE: Neuroactive steroids represent a novel class of potential therapeutic agents (epilepsy, anxiety, migraine, drug dependence) thought to act through positive allosteric modulation of the GABA(A) receptor. A synthetically derived neuroactive steroid, ganaxolone (3alphahydroxy-3beta-methyl-5alpha-pregnan-20-one), is in phase-II clinical trials for epilepsy. Unlike traditional anticonvulsants such as diazepam and phenobarbital, ganaxolone shows equipotent suppression of both the seizure activity and the behavioral effects of pentylenetetrazol (PTZ) administration. OBJECTIVES: The present study explored possible reversal by ganaxolone and related neuroactive steroids of some behavioral effects of additional pharmacological challenges. METHODS: Direct behavioral observation and photocell-counted locomotor activity of male, Swiss-Webster mice were made with various compounds alone and in conjunction with ganaxolone. RESULTS: Ganaxolone both prevented and reversed PTZ-induced locomotor depression in mice. Further, ganaxolone reversed the locomotor depression induced by other convulsant/anxiogenic stimuli: bicuculline, picrotoxin and, to a lesser extent, yohimbine. Ganaxolone failed to reverse the locomotor stimulation induced by cocaine, methamphetamine, dizocilpine, and phencyclidine. In addition to ganaxolone, the endogenous neuroactive steroids allopregnanolone and pregnanolone and the synthetic neuroactive steroid Co 2-1068 also reversed observed behaviors and locomotor depression induced by PTZ. CONCLUSIONS: The present findings support the unique pharmacological effects of neuroactive steroids as a novel class of positive allosteric modulators of GABA.

Behavioral characterization of Co 134444 (3alpha-hydroxy-21-(1'-imidazolyl)-3beta-methoxymethyl-5alpha- pregnan-20-one), a novel sedative-hypnotic neuroactive steroid.

RATIONALE: Neuroactive steroids have been shown to exhibit a wide range of behavioral activities that are similar but not identical to those of benzodiazepines. These activities include anticonvulsant, anxiolytic and sedative-hypnotic effects. OBJECTIVE: The purpose of the present study was to characterize Co 134444 (3alpha-hydroxy-21-(1'-imidazolyl)-3 -methoxymethyl-5alpha-pregnan-20-one), a novel sedative-hypnotic neuroactive steroid, in a variety of behavioral procedures. METHODS: Anticonvulsant effects were determined by the ability to protect against pentylenetetrazol- and maximal electroshock-induced seizures in mice and rats. Anxiolytic-like effects were determined using a punished drinking procedure in rats. Ataxic effects were determined using a horizontal wire procedure in mice and a rotorod procedure in mice and rats. The discriminative stimulus effects were evaluated in rats trained to discriminate pregnanolone from vehicle. RESULTS: Co 134444 exhibited oral anticonvulsant activity against pentylenetetrazol and maximal electroshock with ED50s of 9.8 and 20.6 mg/kg, respectively, in mice and 23.6 and 25.3 mg/kg, respectively, in rats. Anxiolytic-like efficacy was observed at a dose as low as 3.0 mg/kg, PO, in rats. Ataxic effects were observed with rapid onset and short duration. TD50s were 17.4 and 21.2 mg/kg orally in mice in the horizontal wire and rotorod procedures, respectively, and 39.0 mg/kg in rats using the rotorod. Co 134444 completely substituted for pregnanolone as a discriminative stimulus with little effect on response rate. CONCLUSIONS: Co 134444 exhibits a wide variety of behavioral effects; however, its rapid onset and short duration are consistent with its potential use as a sedative-hypnotic drug.

Positive allosteric modulators of the GABA(A) receptor: differential interaction of benzodiazepines and neuroactive steroids with ethanol.

Endogenous pregnane steroids, such as allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one; 3alpha, 5alpha-P) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one; 3alpha,5beta-P), allosterically modulate GABA(A) receptor function and exhibit behavioral effects similar to benzodiazepines, though acting at a distinct recognition site. Inasmuch as some positive allosteric modulators of GABA(A) receptor function exhibit profound interactions with ethanol, the effects of 3alpha,5alpha-P and 3alpha,5beta-P were compared to those of two benzodiazepines, triazolam and diazepam, on the motor function of mice and rats when administered either alone or in combination with ethanol. All four test compounds exhibited dose-related impairment of motor function in the horizontal wire task in mice and the rotorod task in rats. Ethanol caused a marked enhancement of triazolamand diazepam-induced motor impairment. In contrast, ethanol enhanced to a lesser extent the motor impairment induced by both neurosteroids in mice and not at all in rats. All four compounds increased ethanol-induced behavioral sleep time in mice, although the benzodiazepines did so at a much smaller fraction of their ataxic doses as compared to the neurosteroids. As one of the undesired side-effects of therapeutic use of benzodiazepines is their interaction with ethanol, development of neuroactive steroids as drugs may offer therapeutic advantages.

Reinforcing and discriminative stimulus effects of the neuroactive steroids pregnanolone and Co 8-7071 in rhesus monkeys.

RATIONALE AND OBJECTIVES: The present study was designed to assess possible abuse-related effects of the endogenous neuroactive steroid pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) and the orally bioavailable, water-soluble neuroactive steroid pro-drug Co 8-7071 (3alpha,21-dihydroxy-3beta-trifluoromethyl-5beta-pregnan-20- one, 21-hemisuccinate). METHODS: Four rhesus monkeys were prepared with chronic intravenous (i.v.) catheters and trained to press a lever under a ten-response fixed-ratio (FR) schedule of methohexital injection (0.1 mg/kg per injection). Three rhesus monkeys were trained to discriminate intragastric infusions of pentobarbital (10 mg/kg) from saline infusions under a FR5 schedule of stimulus-shock termination. RESULTS: At least two doses of pregnanolone (0.003-0.1 mg/kg per injection) maintained injections per session above saline levels in the four monkeys tested, whereas Co 8-7071 (0.01-1.0 mg/kg per injection) maintained injections per session above saline levels in two of four monkeys at relatively low levels of injections per session. In rhesus monkeys trained to discriminate pentobarbital, i.v. pregnanolone injections (0.1-1.7 mg/kg, 5-min presession) dose-dependently reproduced the discriminative stimulus effects of pentobarbital in all monkeys tested. Intravenous administration of Co 8-7071 (1-10 mg/kg, 5-min presession) resulted in a dose-dependent increase to >80% pentobarbital-appropriate responding in two of three monkeys tested. Following intragastric infusions of Co 8-7071 (1.0-30 mg/kg), > or =80% pentobarbital-appropriate responding occurred in one out of three monkeys at 10 mg/kg when administered 60 min before the session. When administered 120 min before the session, however, 10-30 mg/kg Co 8-7071 reproduced the discriminative stimulus effects of pentobarbital in each of the three monkeys tested. CONCLUSIONS: These data demonstrate barbiturate-like abuse-related effects that differed between two pregnane steroids. Whereas pregnanolone functioned as a reinforcer, suggesting that this compound has abuse potential, Co 8-7071 did not, despite having pentobarbital-like discriminative effects.

Quantitative analysis of the interaction between the agonist and antagonist isomers of picenadol (LY150720) on electric shock titration in the squirrel monkey.

The opioid mixed agonist-antagonist picenadol (LY150720) is a racemate whose resolution results in a highly stereospecific separation of opioid agonist and antagonist activity. Attenuation of the antinociceptive effects of the agonist (dextro) isomer LY136596 by the antagonist (levo) isomer LY136595 was evaluated quantitatively in squirrel monkeys responding under a schedule of electric shock titration through the use of a dose-ratio analysis. LY136596 (0.3-3.0 mg/kg) produced a dose-related increase in the intensity at which monkeys maintained the shock. Increases in shock intensity produced by LY136596 were antagonized by LY136595 (0.1-10.0 mg/kg); dose-response curves for LY136596 were shifted to the right in a parallel manner by increasing doses of LY136595. An apparent pA2 (Schild) plot obtained from these data yielded a line with a slope of -0.60 +/- 0.05 and an apparent pA2 value of 5.67 +/- 0.07. These data support previous suggestions that the antinociceptive activity of picenadol (LY150720) resides in the d-isomer (LY136596) and that the l-isomer (LY136595) acts to limit the analgesic efficacy of the racemate.

LSD and 5-HTP: tolerance and cross-tolerance relationships.

Tolerance and cross-tolerance relationships between lysergic acid diethylamide (LSD) and 5-hydroxytryptophan (5-HTP) were studied in rats trained on an operant task. The results demonstrated that behavioral tolerance to both compounds occur in the rat and that asymmetrical cross-tolerance relationships exist; that is, animals tolerant to 5-HTP were cross-tolerant to LSD, but animals tolerant to LSD were not cross-tolerant to 5-HTP.

Attenuation of normeperidine's suppressing effect on schedule-controlled behavior.

The purpose of the present study was to compare several central nervous system (CNS) depressant drugs in their ability to attenuate the suppressant effects of normeperidine on the responding of pigeons under a multiple fixed-ratio, fixed-interval schedule of grain presentation. The effects of pentobarbital (3 and 10 mg/kg i.m.), diazepam (1-10 mg/kg p.o.), clonazepam (0.03-3 mg/kg p.o.), aminooxyacetic acid (1-10 mg/kg i.m.), baclofen (5 and 10 mg/kg i.m.) and ethanol (0.5-2 g/kg p.o.) were determined alone and in the presence of 17.5 mg/kg (p.o.) of normeperidine, a dose which almost completely eliminates responding. Pentobarbital, diazepam and clonazepam attenuated the normeperidine-induced suppression of behavior, whereas aminooxyacetic acid, baclofen and ethanol failed to attenuate the effects of normeperidine. The results indicate that in the pigeon the non-opioid effects of normeperidine and related analogs are related to proconvulsive actions.

Capsaicin desensitization to plasma extravasation evoked by antidromic C-fiber stimulation is not associated with antinociception in the rat.

The relationship of capsaicin desensitization to the antinociception produced by acute capsaicin administration was studied in the rat. Cutaneous application of 1% capsaicin (3 x/day) for 1 day antagonized plasma extravasation evoked by either 5% capsaicin applied to the dorsal surface of the hindpaw or antidromic stimulation of the saphenous nerve. Treatment with either 1% or 5% capsaicin (3 x/day) for up to 4 days failed, however, to produce thermal antinociception as measured by the rat paw-withdrawal procedure. In contrast, intracutaneous injection of 100 micrograms capsaicin produced marked increases in paw-withdrawal response latencies for up to six hours after injection. These data demonstrate a dissociation between block of cutaneous plasma extravasation and thermal antinociception in the rat. The data provide in vivo evidence that desensitization of peripheral nociceptors by capsaicin cannot account for the antinociception observed following acute capsaicin administration. Finally, these data support the notion that some pharmacologic actions of capsaicin in the rat can be dissociated from frank neurotoxicity on the basis of concentration or dose.

Effects of norepinephrine and serotonin uptake inhibitors on the schedule-controlled behavior of the pigeon.

The effects of nortriptyline, amitriptyline, desipramine, chlorimipramine, protriptyline, doxepin, nisoxetine, fluoxetine and iprindole were determined on responding by pigeons under a multiple fixed-ratio 30-response, fixed-interval 10-minute schedule of grain presentation. Those drugs which have been shown to block uptake of norepinephrine decreased fixed-interval quarter-life values. Those which are considered most selective as norepinephrine uptake inhibitors also increased overall fixed-interval responding. These increases in fixed-interval responding, both on local and overall rates, in pigeons appear to be due to the actions of these drugs to inhibit uptake of norepinephrine rather than to other actions.

Effects of LY150720 (picenadol), a novel mixed-action opioid, on schedule-controlled responding in the squirrel monkey.

The opioid LY150720 is a racemic mixture whose resolution results in a highly stereospecific separation of agonist and antagonist activity. The effects of LY150720 (0.3-3.0 mg/kg), its agonist (dextro) isomer LY136596 (0.3-1.7 mg/kg) and morphine (0.03-1.0 mg/kg) were studied alone and in combination with naloxone (0.001-1.0 mg/kg) in squirrel monkeys whose responding was maintained under a multiple fixed-ratio 30-response fixed-interval 5-minute (mult FR-30 FI 5-min) schedule of food presentation. LY150720, LY136596 and morphine generally decreased responding under both schedule components, although in several instances increases in responding under the FI component were noted, particularly following LY150720 and LY136596. Naloxone (0.1-3.0 mg/kg) generally had little effect on responding, whereas the antagonist (levo) isomer LY136595 (0.3-10.0 mg/kg) decreased responding under both schedule components. The rate-decreasing effects of morphine, LY150720 and LY136596 were reversed by naloxone; doses of naloxone required to reverse the effects of all three drugs were comparable. When combined with morphine, naloxone restored rates and patterns of responding to control values, whereas combinations of LY150720 or LY136596 and naloxone increased responding under the FI component in excess of control values. These increases appear to be due to anticholinergic actions of LY150720 and LY136596, as they are reversed by physostigmine (0.01 mg/kg) and similar increases are produced by scopolamine (0.01-0.1 mg/kg).

Blockade of the behavioral effects of 5-HTP by the decarboxylase inhibitor Ro 4-4602.

Twenty male rats were trained to press a bar on a fixed-ratio (FR 32) schedule of water reinforcement. The behavioral effects of 5-HTP (50 mg/kg) were studied following pretreatment with small (50 mg/kg) and large (400 mg/kg) doses of the decarboxylase inhibitor Ro 4-4602. It was found that both doses of the pretreatment agent blocked the disruptive effects of 5-HTP. This result suggests that at least some of the effects of 5-HTP may be mediated peripherally.