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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.

Voltage-gated Na(+) channels may play important roles in establishing pathological neuronal hyperexcitability associated with chronic pain in humans. Na(+) channel blockers, such as carbamazepine (CBZ) and lamotrigine (LTG), are efficacious in treating neuropathic pain; however, their therapeutic utility is compromised by central nervous system side effects. We reasoned that it may be possible to gain superior control over pain states and, in particular, a better therapeutic index, by designing broad-spectrum Na(+) channel blockers with higher potency, faster onset kinetics, and greater levels of state dependence than existing drugs. 2-[4-(4-Chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide (PPPA) is a novel structural analog of the state-dependent Na(+) channel blocker V102862 [4-(4-fluorophenoxy)benzaldehyde semicarbazone]. Tested on recombinant rat Na(v)1.2 channels and native Na(+) currents in cultured rat dorsal root ganglion neurons, PPPA was approximately 1000 times more potent, had 2000-fold faster binding kinetics, and > or =10-fold higher levels of state dependence than CBZ and LTG. Tested in rat pain models against mechanical endpoints, PPPA had minimal effective doses of 1 to 3 mg/kg p.o. in partial sciatic nerve ligation, Freund's complete adjuvant, and postincisional pain. In all cases, efficacy was similar to clinically relevant comparators. Importantly, PPPA did not produce motor deficits in the accelerating Rotarod assay of ataxia at doses up to 30 mg/kg p.o., indicating a therapeutic index >10, which was superior to CBZ and LTG. Our experiments suggest that high-potency, broad-spectrum, state-dependent Na(+) channel blockers will have clinical utility for treating neuropathic, inflammatory, and postsurgical pain. Optimizing the biophysical parameters of broad-spectrum voltage-gated Na(+) channel blockers may lead to improved pain therapeutics.

1. 4-(4-Fluorophenoxy)benzaldehyde semicarbazone (V102862) was initially described as an orally active anticonvulsant with robust activity in a variety of rodent models of epilepsy. The mechanism of action was not known. We used whole-cell patch-clamp techniques to study the effects of V102862 on native and recombinant mammalian voltage-gated Na+ channels. 2. V102862 blocked Na+ currents (I(Na)) in acutely dissociated cultured rat hippocampal neurons. Potency increased with membrane depolarization, suggesting a state-dependent mechanism of inhibition. There was no significant effect on the voltage dependence of activation of I(Na). 3. The dissociation constant for the inactivated state (K(I)) was approximately 0.6 microM, whereas the dissociation constant for the resting state (K(R)) was >15 microM. 4. The binding to inactivated channels was slow, requiring a few seconds to reach steady state at -80 mV. 5. The mechanism of inhibition was characterized in more detail using human embryonic kidney-293 cells stably expressing rat brain type IIA Na+ (rNa(v)1.2) channels, a major Na+ channel alpha subunit in rat hippocampal neurons. Similar to hippocampal neurons, V102862 was a potent state-dependent blocker of rNa(v)1.2 channels with a K(I) of approximately 0.4 microM and K(R) approximately 30 microM. V102862 binding to inactivated channels was relatively slow (k(+) approximately = 1.7 microM(-1) s(-1)). V102862 shifted the steady-state availability curve in the hyperpolarizing direction and significantly retarded recovery of Na+ channels from inactivation. 6. These results suggest that inhibition of voltage-gated Na+ channels is a major mechanism underlying the anticonvulsant properties of V102862. Moreover, understanding the biophysics of the interaction may prove to be useful in designing a new generation of potent Na+ channel blocker therapeutics.

In the search for more efficacious drugs to treat neuropathic pain states, a series of phenoxyphenyl pyridines was designed based on 4-(4-flurophenoxy)benzaldehyde semicarbazone. Through variation of the substituents on the pyridine ring, several potent state-dependent sodium channel inhibitors were identified. From these compounds, 23 dose dependently reversed tactile allodynia in the Chung model of neuropathic pain. Administered orally at 10 mg/kg the level of reversal was ca. 50%, comparable to the effect of carbamazepine administered orally at 100 mg/kg., (Copyright 2004 American Chemical Society)

A series of 3-(4-phenoxyphenyl)-1H-pyrazoles were synthesized and characterized as potent state-dependent sodium channel blockers. A limited SAR study was carried out to delineate the chemical requirements for potency. The results indicate that the distal phenyl group is critical for activity but will tolerate lipophilic (+pi) electronegative (+sigma) substituents at the ortho and/or para position. Substitution at the pyrazole nitrogen with a H-bond donor improves potency. Compound 18 showed robust activity in the rat Chung neuropathy paradigm.

Neuroactive steroids demonstrate pharmacological actions that have relevance for a host of neurological and psychiatric disorders. They offer protection against seizures in a range of models and seem to inhibit certain stages of drug dependence in preclinical assessments. The present study was designed to evaluate two endogenous and one synthetic neuroactive steroid that positively modulate the gamma-aminobutyric acid (GABA(A)) receptor against the increase in sensitivity to the convulsant effects of cocaine engendered by repeated cocaine administration (seizure kindling). Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) and ganaxolone (a synthetic derivative of allopregnanolone 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) were tested for their ability to suppress the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures in male, Swiss-Webster mice. Kindled seizures were induced by daily administration of 60 mg/kg cocaine for 5 days. All of these positive GABA(A) modulators suppressed the expression of kindled seizures, whereas only allopregnanolone and ganaxolone inhibited the development of kindling. Allopregnanolone and pregnanolone, but not ganaxolone, also reduced cumulative lethality associated with kindling. These findings demonstrate that some neuroactive steroids attenuate convulsant and sensitizing properties of cocaine and add to a growing literature on their potential use in the modulation of effects of drugs of abuse.

A new 5-HT(1A) silent antagonist 14 (5-HT(1A) IC(50)=2.2 nM) antagonizes the effects of agonists on reciprocal forepaw treading behavior, on neuronal firing in the rat dorsal raphé, and on 5-HT(1A) release in the raphé and hippocampus. While 14 alone was inactive in the social interaction paradigm, it completely reversed the social interaction activity of the serotonergic compounds (buspirone, 1, and 2).

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.

The purpose of this study was to evaluate the effects of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3alpha, 21-dihydroxy-3beta-trifluoromethyl-19-nor-5beta-pregnan-20-one), on gamma-aminobutyric acid(A) receptors in vitro and to define its anxiolytic-like effects and side effect profile in vivo. Co 2-6749 fully inhibited [(35)S]t-butylbicyclophosphorothionate binding in rat brain cortical membranes with an IC(50) value of 230 nM and in human gamma-aminobutyric acid(A) receptor subunit combinations of alpha1beta2gamma2L, alpha2beta2gamma2L, alpha3beta2gamma2L, alpha4beta3gamma2L, alpha5beta2gamma2L, and alpha6beta3gamma2L receptors (IC(50) values of 200, 200, 96, 2300, 210, and 2000 nM). Rats were trained in a Geller-Seifter operant conflict paradigm. Co 2-6749 caused a dose-related increase in punished responding with a minimum effective dose of 1.6 mg/kg, p.o., a wide therapeutic index relative to a decrease in unpunished responding and relative to ataxia, and no tolerance. Additionally, ethanol caused less than a 2-fold shift to the left in the dose-response function of Co 2-6749 in the rotorod procedure in rats. In a pigeon conflict paradigm, punished responding was maximally increased to 784% of vehicle control by 30 mg/kg, p.o., with a 2-h duration and no effect on unpunished responding at this dose. Similarly, punished responding in squirrel monkeys was maximally increased to 1774% of control by 10 mg/kg, p.o., with no effect on unpunished responding at this dose. With robust anxiolytic-like activity across species, a large separation between anxiolytic-like effects and sedation/ataxia, a minimal interaction with ethanol, a lack of tolerance, and apparent oral bioavailability, Co 2-6749 makes an ideal candidate for development as a novel anxiolytic drug.

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.

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.

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.

Novel neuroactive steroids were evaluated for their effects on operant responding, rotorod motor performance, and electroencephalogram recording in rats. Co 134444, Co 177843, and Co 127501 were compared with the prototypical gamma-aminobutyric acid(A)-positive allosteric modulators triazolam, zolpidem, pentobarbital, pregnanolone, and CCD 3693. Each of the compounds produced a dose-related decrease in response rates under a variable-interval 2-min schedule of positive reinforcement in an operant paradigm. In addition, all compounds produced a dose-related increase in ataxia and significant increases in nonrapid eye movement sleep in this experiment or have been previously reported to do so. Co 134444, Co 177843, and Co 127501 increased nonrapid eye movement sleep at doses that had no effect on rapid eye movement sleep. All of the compounds were more potent at decreasing operant responding than they were at increasing ataxia. Furthermore, the potency of compounds to produce response-rate suppression in an operant paradigm appeared to be a better predictor of soporific potency than did potency in the rotorod assay. The screening for sedative-hypnotic activity resulted in the identification of the novel orally active neuroactive steroids Co 134444, Co 177843, and Co 127501.

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.

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.

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.

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.

Neuroactive steroids are positive allosteric modulators of gamma-aminobutyric acidA (GABAA) receptor complexes. Synthetic modification generally does not increase neuroactive steroid potency beyond that of the naturally occurring progesterone metabolite, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-P). Recently, it has been shown that introduction of appropriately para-substituted phenylethynyl groups at the 3beta-position of 5beta steroids increases receptor potency. The present report presents the synthesis and pharmacological profile of an analogous series of 5alpha steroids. The most striking feature of this series is the further enhancement of in vitro and in vivo potency obtained. In particular, 3beta-(p-acetylphenylethynyl)-3alpha-hydroxy-5alpha-pr egnan-20-one (Co 152791) was 11-, 16- and 49-fold more potent than 3alpha, 5alpha-P in modulating the binding of [35S]TBPS, [3H]flunitrazepam and [3H]muscimol, respectively, in rat brain membranes (Co 152791 IC50 or EC50 = 2-7.5 nM). Similarly, Co 152791 was 3- to 20-fold more potent than 3alpha,5alpha-P as an inhibitor of [35S]TBPS binding in human recombinant receptor combinations containing alpha1, alpha2, alpha3 or alpha5 and beta2gamma2L subunits (Co 152791 IC50 1.4-5.7 nM). Co 152791 displayed low efficacy and 3alpha,5alpha-P had low potency at alpha4/6beta3gamma2L GABAA receptor complexes. Interestingly, Co 152791 demonstrated remarkable potency as a potentiator of GABA-evoked currents in Xenopus oocytes expressing alpha1beta2gamma2L receptors (EC50 0.87 nM), being 184-fold more potent than 3alpha,5alpha-P. High in vitro potency was also reflected in enhanced in vivo activity in that Co 152791 exhibited exceptional anticonvulsant potency, protecting mice from pentylenetetrazol-induced seizures at a approximately 5-fold lower dose than 3alpha,5alpha-P after i.p. administration (Co 152791 ED50 0.6 mg/kg). Moreover, Co 152791 was orally active (ED50 1.1 mg/kg) and exhibited a therapeutic index of 7 relative to rotorod impairment. The remarkable potency of Co 152791 as a positive allosteric modulator of GABAA receptors may be explained by its interaction with an auxiliary binding pocket in the neuroactive steroid binding site. In addition, modification at the 3beta-position probably hinders metabolism of the 3alpha-hydroxy group contributing to the exceptional anticonvulsant potency of this compound relative to other neuroactive steroids.

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.

Neuroactive steroids are naturally occurring or synthetically derived compounds many of which have anticonvulsant, anesthetic, anxiolytic, analgesic or hypnotic properties. The major site of neuronal activity appears to be with a specific steroid-sensitive site on the gamma-aminobutyric acidA receptor/chloride ionophore complex. Ganaxolone (3 alpha-hydroxy-3 beta-methyl-5 alpha-pregnan-20-one) is a synthetic neuroactive steroid protected from metabolic attack of the 3 alpha position. Ganaxolone is an efficacious anticonvulsant agent in a variety of acute seizure models, as well as in electrical and chemical kindling models, and is currently under Phase II clinical investigation for epilepsy. A prior observation that ganaxolone appeared to reverse the marked behavioral changes induced by the convulsant pentylenetetrazol (PTZ) was systematically examined in the present study. A model to quantify PTZ-induced behaviors is described and used to evaluate ganaxolone in comparison with the anticonvulsants valproate, ethosuximide, clonazepam, diazepam and phenobarbital. All compounds were compared using dose equivalents based on their respective ED50 values in preventing convulsions induced by 70 mg/kg PTZ. The ED50 and lower doses of ganaxolone prevented the observed behavioral effects of PTZ as well as its depressant effects on locomotor activity and rearing of mice. In contrast, the other anticonvulsants, if effective, were much less potent. Strikingly, most of the other anticonvulsants were incapable of preventing all the behavioral effects of PTZ. Only phenobarbital prevented all the behavioral effects of PTZ and only at doses 4 to 8 times the anticonvulsant ED50. Rather than normalizing behavior as ganaxolone did, however, phenobarbital resulted in supranormal behavioral responses (e.g., increases in activity). Repeated administration of PTZ did not decrease the protective efficacy of ganaxolone. The results document the unique pharmacological profile of ganaxolone and suggest additional potential benefits from its use as an antiepileptic. Furthermore, because behavioral effects of PTZ have been used to model anxiety and anxiety associated with withdrawal from drugs of abuse, ganaxolone may find additional therapeutic application in those areas.

Epilepsy continues to be a significant clinical problem as current medications neither adequately control seizures nor are free of untoward side-effects. Modulation of the neuroactive steroid site on the gamma-aminobutyric acid (GABA)A receptor complex may be an important new direction for pharmaceutical interventions in epilepsy. In this study we evaluated the protective actions of four neuroactive steroids, 3alpha-hydroxy-5alpha-pregnan-20-one, the 3beta-methylated analog, ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), 3alpha-hydroxy-5beta-pregnan-20-one and Co 2-1068 (3beta-(4acetylphenyl)ethynyl-3alpha,21-dihydroxy-5beta++ +-20-one-21-hemisuccinate), against several standard convulsive tests in male, Swiss-Webster mice. Consistent with their GABAergic actions, the neuroactive steroids as well as diazepam and phenobarbital dose-dependently protected against clonic convulsions induced by pentylenetetrazol; the N-methyl-D-aspartate receptor antagonist, dizocilpine, was ineffective. In contrast to diazepam and phenobarbital, however, all of the neuroactive steroids and dizocilpine produced full protection against cocaine-induced convulsions. Some of the neuroactive steroids, as well as dizocilpine, were efficacious against the seizures and lethality induced by N-methyl-D-aspartate. Pregnenolone, a steroid devoid of GABAergic activity, was not effective in any of the convulsant models. Although all of the compounds produced motor toxicity in high doses as measured by the inverted-screen test, the neuroactive steroids demonstrated an equivalent or improved separation between anticonvulsant potency and motoric impairment. Inactive doses of the neuroactive steroids markedly enhanced the anticonvulsant effects of diazepam against pentylenetetrazol without significantly increasing motor toxicity. This adjunct treatment resulted in protective indices ranging from 60 to 360 compared to 12 for diazepam alone. The distinct profile of anticonvulsant activity of the neuroactive steroids may be related to their combined actions on gamma-aminobutyric acid, N-methyl-D-aspartate receptors, or voltage-operated Ca++ channels. These results help to define the neuroactive steroids as a novel class of antiepileptic agents and suggest their potential in clinical practice.

An endogenous neuroactive steroid, pregnanolone, and an orally available synthetic analog, CCD-3693, were administered to rats at the middle of their circadian activity phase (6 hr after lights off). Electroencephalogram-defined sleep-wake states, locomotor activity and body temperature were concurrently measured 30 hr before and after treatment. Identical procedures were used to test triazolam and zolpidem. Triazolam (0.1-1.6 mg/kg), zolpidem (2.5-10 mg/kg) and the neuroactive steroids (10-30 mg/kg) produced dose-dependent increases in non-rapid eye movement (NREM) sleep. At this dose and time of day (in which the rats were predominantly awake during the 6 hr before treatment) the neuroactive steroids appeared more intrinsically efficacious in promoting NREM sleep than the benzodiazepine ligands. The neurosteroids did not, however, significantly interfere with rapid eye movement sleep and were more selective in reducing (EEG) wakefulness, with relatively less locomotor activity impairment during waking than triazolam and zolpidem. In addition, the benzodiazepine receptor ligands showed distinct "rebound" wakefulness after the NREM sleep-promoting effect subsided, although the neuroactive steroids did not. In addition, in vitro binding studies and in vivo pharmacological data confirmed that CCD-3693 was orally active in standard tests of anxiety, anticonvulsant, loss-of-righting and passive avoidance.

Ganaxolone (CCD 1042) is a 3beta-methyl-substituted analog of the endogenous neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one. Ganaxolone inhibited binding of the gamma-aminobutyric acid (GABA)A receptor-chloride channel ligand t-[35S]butylbicyclophosphorothionate (IC50 of 80 nM) and enhanced binding of the benzodiazepine site ligand [3H]flunitrazepam (EC50 of 125 nM) and the GABA site ligand [3H]muscimol (EC50 of 86 nM), consistent with activity as a positive allosteric modulator of the GABA(A) receptor. Electrophysiological recordings showed that, whereas nanomolar concentrations of ganaxolone potentiated GABA-evoked chloride currents in Xenopus oocytes expressing the human GABA(A) receptor subunits alpha1beta1gamma2L, alpha2beta1gamma2L or alpha3beta1gamma2L, direct activation of chloride flux occurred to a limited extent only at micromolar concentrations. Ganaxolone was effective in nontoxic doses against clonic convulsions induced by s.c. pentylenetetrazol administration in mice and rats (ED50 values of 4.3 and 7.8 mg/kg i.p., respectively). Ganaxolone also exhibited potent anticonvulsant activity against seizures induced by s.c. bicuculline (ED50 of 4.6 mg/kg i.p.), i.p. TBPS (ED50 of 11.7 mg/kg i.p.) and i.p. aminophylline (ED50 of 11.5 mg/kg i.p.) in mice. Although ganaxolone effectively blocked tonic seizures induced by maximal electroshock in mice (ED50 of 29.7 mg/kg i.p.), it did so only at doses that produced ataxia on the Rotorod (TD50 of 33.4 mg/kg i.p.). Conversely, ganaxolone was a potent anticonvulsant against fully kindled stage 5 seizures induced by corneal kindling in rats (ED50 of 4.5 mg/kg i.p.), producing these effects at doses well below those that resulted in ataxia (TD50 of 14.2 mg/kg i.p.). The seizure threshold, as determined by an increase in the dose of i.v. infused pentylenetetrazol required to induce clonus, was also significantly elevated by nontoxic doses of ganaxolone in mice. In summary, these data indicate that ganaxolone is a high-affinity, stereoselective, positive allosteric modulator of the GABA(A) receptor complex that exhibits potent anticonvulsant activity across a range of animal procedures. The profile of anticonvulsant activity obtained for ganaxolone supports clinical evaluation of this drug as an antiepileptic therapy with potential utility in the treatment of generalized absence seizures as well as simple and complex partial seizures.

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.

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.

The contribution of behavioral endpoint to results obtained in the 55 degrees C rat hot plate procedure was assessed. Specifically, the use of a hind paw lick-only endpoint was compared to that of a hind paw lick-or-jump endpoint. Effects of prototypical analgesic and non-analgesic compounds on response latency increases were determined under each condition. Whereas the effects of morphine, oxycodone and codeine were similar under each condition, effects of a number of non-analgesic agents differed markedly depending upon the endpoint used. Clozapine, chlorpromazine, thioridazine, atropine, scopolamine, benactyzine, yohimbine, idazoxan and cyproheptadine produced dose-dependent increases in response latency under the hind paw lick-only condition but did not increase latencies when the hind paw lick-or-jump endpoint was used. Haloperidol, sulpiride, benztropine, methyl atropine, phentolamine, prazosin, methiothepin, methysergide, diphenhydramine, pargyline and diazepam failed to increase response latencies under the hind paw lick-only condition. Moreover, whereas diazepam, chlorpromazine, pentobarbital, dantrolene and ethanol produced dose-dependent increases in the height required for successful aerial righting, increases in hind paw lick-or-jump latencies occurred only following near-anesthetic doses of pentobarbital and ethanol. These data indicate that the hind paw lick endpoint is susceptible to perturbation by extraneous pharmacologic activities. Drugs exerting muscarinic cholinergic and alpha 2-adrenergic antagonist effects are particularly able to disrupt this behavior. Disruption is not associated specifically with any other pharmacologic action, although other activities may interfere with the response. In contrast, the hind paw lick-or-jump endpoint fails to detect skeletal muscle relaxant activity and only detects gross motor impairment when near-anesthetic doses of drugs are used. The present data suggest that detection of non-analgesic drug activities by rat hot plate can be minimized by use of a hind paw lick-or-jump endpoint.

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.

The effects of naloxone and picrotoxin were determined alone and in conjunction with pentobarbital, diazepam or clonazepam, in pigeons responding under a multiple fixed-ratio 30-response, fixed-interval 5-min schedule of food presentation. Naloxone (10.0-80.0 mg/kg i.m.) and picrotoxin (0.1-0.56 mg/kg i.m.) alone produced only dose-related decreases in responding in both fixed-ratio and fixed-interval components. Pentobarbital (3.0 and 10.0 mg/kg i.m.) administered in combination with naloxone and picrotoxin shifted dose-response curves for both naloxone and picrotoxin to the right. In contrast, both diazepam (1.0-10.0 mg/kg p.o.) and clonazepam (0.3-3.0 mg/kg p.o.) attenuated the rate-decreasing effects of 0.56 mg/kg of picrotoxin, but not those of 80.0 mg/kg of naloxone. Dose-effect curves for naloxone and picrotoxin were then determined during daily administration of 10.0 mg/kg of diazepam. Dose-response curves for both naloxone and picrotoxin were shifted to the right under these conditions. These data support previous evidence that naloxone exerts gamma-aminobutyric acid-antagonistic effects in addition to its potent opioid-antagonistic effects.

Two pigeons were trained to discriminate intramuscular injections of 1.0 mg/kg morphine from water by presenting food after keypeck responses on one key when morphine was administered and after responses on a second key when water was administered. Following training, close to 100% of responses occurred on the appropriate key following administration of 1.0 mg/kg morphine or water. Morphine (0.1-5.6 mg/kg) produced dose-dependent increases in the percentage of morphine-appropriate responses (discriminative stimulus properties) and decreases in the rate of responding. A shift to the right of the morphine dose-effect curve for the discriminative stimulus properties of morphine resulted from a single injection of morphine (10.0 mg/kg) 24 hrs prior to testing (i.e., acute tolerance) but not from a single injection of pentobarbital (17.0 mg/kg). Tolerance to the discriminative stimulus properties of morphine was reversible within five days of the single injection. Tolerance did not develop to the effects of morphine on response rate. Naloxone antagonized both the discriminative stimulus properties and the response rate-decreasing effects of morphine. Thus, a single administration of morphine can alter morphine discriminability without affecting other aspects of 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.

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.

The effects of 5-hydroxytryptophan (5-HTP) were studied in rats trained to press a lever under a fixed-ratio (Fr-32) schedule of water presentation. d-, l-and d,l-5-HTP all decreased responding in a dose-related manner. The levo isomer (12.5-25 mg/kg) was twice as potent as the racemic form (25-50 mg/kg) in this respect. Moderate doses of d-5-HTP (less than 100 mg/kg) did not affect responding, whereas 200 mg/kg produced almost complete suppression. The response decrement produced by 25 mg/kg l-5-HTP was completely antagonized by pretreatment with either 50 mg/kg or 400 mg/kg of the decarboxylase inhibitor, benserazide (Ro4-4602). The specific peripheral decarboxylase inhibitor, carbidopa (MK-486) (50 mg/kg) and the peripheral serotonergic antagonist, xylamidine tosylate (1 mg/kg) also antagonized the effects of 25 mg/kg l-5-HTP. These results suggest that at least some of the behavioral effects of 5-HTP are due to increases in levels or turnover of 5-HTP in peripheral serotonergic neuronal systems.

Rats learned to avoid a saccharin solution if their initial consumption of it was followed by intraperitoneal (IP) administration of 25 mg/kg l-5-hydroxytryptophan (l-5-HTP); this taste aversion learning did not occur in rats pretreated with 50 mg/kg (IP) of the aromatic l-amino acid decarboxylase inhibitor RO 4-4602 (benserazide). RO 4-4602 antagonized the l-5-HTP-induced elevation of 5-hydroxytryptamine (5-HT) in the mesentery but significantly increased the l-5-HTP-induced elevation of 5-HT in the brain. These results indicate that l-5-HTP-induced taste aversion is correlated with peripheral, but not central, elevation of 5-HT.

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.

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).

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.

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.

The mixed-action opioid picenadol (LY150720) is a racemic mixture whose resolution results in a stereoselective separation of agonist and antagonist activity. The effects of picenadol, its dextrorotatory isomer (LY136596) and morphine were studied alone and in combination with naloxone in squirrel monkeys responding under a schedule of electric shock titration. Shock intensity was scheduled to increase at 15-sec intervals in 30 steps from 0 to 5.5 mA. Completion of a fixed ratio 5-response requirement terminated the shock for a 15-sec time-out period after which shock resumed at the next lower intensity. Picenadol (0.1-17.5 mg/kg), the d-isomer (0.3-3.0 mg/kg) and morphine (0.3-5.6 mg/kg) produced dose-related increases in the intensity at which monkeys maintained the shock without decreasing responding in the presence of shock. Shock intensity increases produced by picenadol occurred over a broader dose range than with either the d-isomer or morphine. Increases in shock intensity produced by picenadol, the d-isomer and morphine were blocked by naloxone (0.001-1.0 mg/kg), although the effects of picenadol were less susceptible to antagonism. The effects of the levorotatory isomer of picenadol (LY136595) were also examined alone and in combination with morphine. The l-isomer (0.1-10.0 mg/kg) did not alter shock intensity when administered alone; however, in combination with morphine it produced a dose-dependent antagonism of the effects of morphine. The l-isomer was less potent than naloxone in this respect. These data support previous suggestions that the antinociceptive properties of picenadol arise from mu agonist actions of the dextrorotatory isomer and that the levorotatory isomer acts to limit the efficacy of the racemate.

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.