m-CPP hypolocomotion is selectively antagonized by compounds with high affinity for 5-HT(2C) receptors but not 5-HT(2A) or 5-HT(2B) receptors.

The ability of m-CPP [1-(m-chlorophenyl)piperazine] to produce hypolocomotion is well documented. This effect has been postulated to be due to activation of the 5-HT(2C) receptor. It is only recently that the tools necessary to clearly delineate which serotonin receptors are involved in the mediation of m-CPP hypolocomotion have become available. We investigated the effects of the selective 5-HT(2A) antagonists, MDL 100,907 and ketanserin, the selective 5-HT(2B) antagonists, LY 202146 and LY 266097, the 5-HT(2B/2C) antagonist, SB 206553, and the selective 5-HT(2C) antagonist, SB 242084 on m-CPP-induced hypolocomotion and spontaneous locomotor activity in mice. Furthermore, we investigated the effects of the non-selective serotonin antagonists, ritanserin, LY 53857, mianserin and cyproheptadine on m-CPP hypolocomotion. Additionally, receptor-binding studies were employed as an in vitro assessment of relative affinities at the 5-HT(2A), 5-HT92B) and 5-HT(2C) receptors. Antagonists tested alone were without effect on spontaneous activity, with the sole exception of ketanserin, which decreased spontaneous activity at the high dose of 1 mg/kg. m-CPP-induced hypolocomotion was not significantly attenuated by various doses of MDL 100,907, ketanserin, LY 202146, LY 266097, ritanserin or cyproheptadine. In contrast, SB 206553, SB 242084, LY 53857 and mianserin were capable of reversing m-CPP-induced hypolocomotion. Consistent with previous suggestions, a detailed pharmacological evaluation with selective antagonists for the 5-HT2 family of receptors supports a primary role for the 5-HT(2C) receptor, and not 5-HT(2A) or 5-HT(2B) receptors, in mediating the hypolocomotion produced by m-CPP.

A comparison of the behavioural effects of 5-HT2A and 5-HT2C receptor agonists in the pigeon.

Activity at the 5-HT2A receptor versus that of the 5-HT2C receptor was studied in three behavioural paradigms. In pigeons trained to discriminate 0.32 mg/kg of 1-(2,5-diemethoxy-4-iodophenyl)-2-aminopropane (DOI) (a mixed 5-HT2A/C receptor agonist) from vehicle, quipazine (0.1-1 mg/kg) and m-chlorophenylpiperazine (mCPP) (1-3 mg/kg) substituted for DOI in a dose-related manner, and this generalization was blocked by MDL100907 (0.0001-0.01 mg/kg), a selective 5-HT2A receptor antagonist. RO60-0175 (a relatively selective 5-HT2C agonist) induced partial substitution at 3 mg/kg that was antagonized by both MDL100907 and by 3 mg/kg of SB242084, a relatively selective 5-HT2C antagonist. MK212 (a mixed 5-HT2C/A agonist) induced partial substitution that was antagonized by SB242084, but not by MDL100907. On a progressive ratio 5 operant schedule (PR5) for food reinforcement, DOI, quipazine, mCPP, MK212 and R060-0175 decreased the break point; mCPP, DOI, MK212 and quipazine also induced vomiting. Although MDL100907 antagonized both the reductions of break point and vomiting, SB242084 only partially attenuated the decrease in break point observed with MK212 and DOI, and was unable to eliminate vomiting. Thus pharmacological activity at the 5-HT2A receptor can be behaviourally distinguished from pharmacological activity at the 5-HT2C receptor in the pigeon. Furthermore, the decrease in the break point of a PR5 schedule induced by 5-HT2C receptor agonists may be related to decreased appetite, whereas that induced by 5-HT2A receptor agonists may be due to unrelated factors, such as emesis.

The effect of streptozotocin-induced diabetes on cell proliferation in the rat dentate gyrus.

Recent evidence has shown an association between diabetes mellitus and deficits in learning and memory. However, the mechanism by which cognitive abilities are impaired in diabetes has not been identified. The dentate gyrus of the hippocampus plays a significant role in spatial learning and memory. Studies in rodents show that learning tasks enhance neurogenesis in the dentate gyrus of the adult hippocampus. To investigate whether cognitive deficits in diabetes may be related to alterations in hippocampal neurogenesis, we measured the number of 5-bromo-2'-deoxyuridine (BrdU)-positive cells, an indicator of cell proliferation, in the dentate gyrus in an animal model of diabetes. Streptozotocin-induced diabetes produced a dramatic decrease in cell proliferation in the dentate gyrus as compared to controls. The results from this study suggest a potential role for alterations in neurogenesis in the cognitive decline observed in diabetes mellitus.

The novel 5-Hydroxytryptamine(1A) antagonist LY426965: effects on nicotine withdrawal and interactions with fluoxetine.

LY426965 [(2S)-(+)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]2-methyl- 2-phenyl-1-butanone monohydrochloride] is a novel compound with high affinity for the cloned human 5-hydroxytryptamine (HT)(1A) receptor (K(i) = 4.66 nM) and 20-fold or greater selectivity over other serotonin and nonserotonin receptor subtypes. Both in vitro and in vivo studies indicate that LY426965 is a full antagonist and has no partial agonist properties. LY426965 did not stimulate [(35)S]guanosine-5'-O-(3-thio) triphosphate (GTPgammaS) binding to homogenates of cells expressing the cloned human 5-HT(1A) receptor in vitro but did inhibit 300 nM 5-HT-stimulated [(35)S]GTPgammaS binding with a K(i) value of 3.07 nM. After both p.o. and s.c. administration, LY426965 blocked the lower lip retraction, flat body posture, hypothermia, and increase in rat serum corticosterone induced by the 5-HT(1A) agonist 8-OH-DPAT (8-hydroxy-2-dipropylaminotetralin). In pigeons, LY426965 dose-dependently blocked the stimulus cue induced by 8-OH-DPAT but had no 8-OH-DPAT-like discriminative properties. LY426965 completely reversed the effects of nicotine withdrawal on the auditory startle reflex in rats. In microdialysis experiments, LY426965 administered together with fluoxetine significantly increased extracellular levels of serotonin above those achievable with fluoxetine alone. In electrophysiological studies, the administration of LY426965 produced a slight elevation of the firing rate of 5-HT neurons in the dorsal raphe nucleus of anesthetized rats and both blocked and reversed the effects of fluoxetine on 5-HT neuronal activity. These preclinical results indicate that LY426965 is a selective, full 5-HT(1A) antagonist that may have clinical use as pharmacotherapy for smoking cessation and depression and related disorders.

The discriminative stimulus properties of LY233708, a selective serotonin reuptake inhibitor, in the pigeon.

RATIONALE: Understanding the contribution of the various serotonin (5-HT) receptor subtypes to the behavioral effects of selective serotonin reuptake inhibitors (SSRIs) may contribute to the discovery of increasingly effective drugs for the treatment of conditions such as depression, panic and obsessive-compulsive disorders. OBJECTIVES: A drug discrimination procedure was used to determine whether the administration of an SSRI was associated with a specific interoceptive stimulus cue and to what extent that cue was related to activation of the 5-HT(1A) receptor. METHOD: Pigeons were trained to discriminate 20 mg/kg of the short acting, SSRI, LY233708 dihydrochloride dihydrate [(-)-cis-1-(6-chloro-1,2,3,4- tetrahydro-1-methyl-2-naphthalenyl)piperazine] from saline. RESULTS: LY233708 induced a specific, dose-related stimulus cue. The SSRIs, fluoxetine and citalopram, induced dose-related responding on the LY233708-associated key. In contrast, nisoxetine, a selective norepinephrine uptake inhibitor, induced responding on the saline-associated key. The prototypical 5-HT(1A) agonist, 8-OH-DPAT [8-hydroxy-(2-di-n-propylamino)tetralin] substituted for LY233708. This generalization was blocked by the selective 5-HT(1A) antagonist, WAY-100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide]. CONCLUSION: These data demonstrate that an SSRI can induce a specific, stable discriminative stimulus that appears to involve activation of the 5-HT(1A) receptor in the pigeon.

Synthesis and anticonvulsant activity of 3-aryl-5H-2,3-benzodiazephine AMPA antagonists.

A novel series of 3-aryl-5H-2,3-benzodiazepines with N-3 aromatic substituents has been synthesized. Good in vivo anticonvulsant activity of the new compounds has been demonstrated employing the maximal electroshock seizure test in mice. Evaluation of a subset of the compounds in the cortical wedge assay confirmed the new structures to be AMPA antagonists.

Influence of light cycle on response to 5-HT1A ligands in punished responding in rats.

Since the introduction of buspirone, the 5-HT1A receptor has been a focal point for serotonergic research into the treatment of anxiety. Two of the more commonly used methodologies for evaluating potential anxiolytics are the Geller-Seifter model and the elevated plus maze. In the Geller-Seifter model, administration of 5-HT1A agonists produce an anxiolytic-like profile consisting of an increase in the number of responses made during the punished component. An anxiolytic-like response in the elevated plus maze consists of an increase in the number of entries and/or time spent in the open arms of the maze. Recently, there have been reports of differential drug effects with 5-HT1A ligands in the elevated plus maze depending on when in the diurnal cycle the 5-HT1A agents were administered. The purpose of the current study was to characterize the response to 5-HT1A compounds in normal and reverse light cycle animals in the Geller-Seifter model. 8-OH-DPAT [(+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronapthalene] produced a decrease in unpunished responding and an increase in punished responding during both the light and dark phase. The administration of WAY 100,635 [N-¿2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl¿-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloridel alone was without effect in both the light and dark phase. Furthermore, pre-treatment with WAY 100,635 completely antagonized both the rate-decreasing effects in the unpunished component and the increase in punished responding observed with 8-OH-DPAT during both the light and dark phase. The results of the current study diverge from previous findings of sensitivity to the diurnal cycle in other models reflective of modulation of the 5-HT1A receptor. The robustness of the response, in this case punished lever pressing, may be less sensitive than other more naturalistic or ethological methods (i.e. elevated plus maze) in detecting the subtle changes in receptor function due to the diurnal cycle.

Selective serotonin reuptake inhibitors potentiate 8-OH-DPAT-induced stimulus control in the pigeon.

The effects of two selective serotonin reuptake inhibitors, fluoxetine and citalopram, and a nonselective monoamine reuptake inhibitor, imipramine, were characterized in pigeons that had been trained to discriminate 0.64 mg/kg of 8-hydroxy-(2-di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), a 5-HT1A receptor agonist, from saline. Neither fluoxetine, citalopram, nor imipramine generalized to the 8-OH-DPAT-induced stimulus cue. However, when administered in addition to 8-OH-DPAT, both fluoxetine (10 mg/kg) and citalopram (10 mg/kg) lowered the ED50 for generalization of 8-OH-DPAT from 0.16 mg/kg (8-OH-DPAT by itself) to 0.05 mg/kg (fluoxetine + 8-OH-DPAT) and 0.06 mg/kg (citalopram + 8-OH-DPAT). Under similar conditions, imipramine (1 mg/kg) had no effect on the generalization curve for 8-OH-DPAT. The data support the hypothesis that activation of the 5-HT1A receptor may be relevant to the mechanism of action of serotonin reuptake inhibitors.

Heteroatom-substitution as a strategy for increasing the potency of competitive NMDA antagonists.

We report the synthesis and characterization of compounds that are competitive NMDA receptor antagonists. Significant increases in affinity and potency were obtained by incorporation of a heteroatom into the substructure of the tetrazole-substituted amino acid LY233053.

Differentiation of 5-HT1A receptor ligands by drug discrimination.

Pigeons were trained to discriminate 0.64 mg/kg (high dose) of 8-OH-DPAT (8-hydroxy-(2-di-n-propylamino)tetralin) from saline or were retrained to discriminate 0.16 mg/kg (low dose) of 8-OH-DPAT from saline. This resulted in a decrease of the ED50 for recognition of the 8-OH-DPAT cue from 0.14 to 0.04 mg/kg. Partial agonists for the 5-HT1A receptor (e.g., buspirone) were generalized fully in the low dose condition, but only partially in the high dose condition. Full antagonists, such as N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY-100635), antagonized the 8-OH-DPAT cue in both groups without producing generalization in either group. (-)-Pindolol produced full generalization in the low dose group, but antagonized the high dose stimulus cue. The behavioral effects of other compounds with 5-HT1A receptor activities (4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-pyridinyl-benz ami de hydrochloride (p-MPPI): (-)-1-(1H-indol-4-yloxy)-3-(cyclohexylamino)-2-propanol maleate ((-)-LY206130); racemic pindolol and idazoxan) also differed between groups. Comparing results obtained using differing training doses in the drug discrimination paradigm simplifies determination of the full agonist, partial agonist, or antagonist properties of compounds.

Behavioral pharmacology of olanzapine: a novel antipsychotic drug.

BACKGROUND: In this paper, we review the behavioral pharmacology of olanzapine and compare it to its in vitro profile and to clozapine and a number of other antipsychotic agents, and we estimate the likelihood that olanzapine will be an effective and safe antipsychotic with fewer side effects. METHOD: Since there is no model of schizophrenia, per se, a battery of behavioral assays was used. RESULTS: Behavioral assays confirmed the in vitro results that olanzapine interacts with dopamine, serotonin, and muscarinic receptor subtypes. Moreover, olanzapine appears to have a clozapine-like atypical profile based on (1) mesolimbic selectivity, (2) blocking 5-HT receptors at a lower dose than dopamine receptors, and (3) inhibiting the conditioned avoidance response (indicative of antipsychotic efficacy) at doses that are lower than those required to induce catalepsy (indicative of extrapyramidal side effects). No only is this profile similar to that of clozapine, but olanzapine has other similarities: olanzapine substitutes for clozapine in a drug discrimination assay; like clozapine and unlike "typical" antipsychotics, olanzapine increases responding in a conflict procedure; and olanzapine, like clozapine, reverses changes induced by antagonists of the NMDA receptor. CONCLUSION: On the basis of these findings, we predict that olanzapine will be an efficacious antipsychotic, active against both positive and negative symptoms, while producing fewer extrapyramidal symptoms than existing treatments.

Effects of a 5-HT1A receptor agonist on acute and delayed cyclophosphamide-induced vomiting.

LY228729 [(-)-4(dipropylamino)-1,3,4,5-tetrahydrobenz-[c,d]indole-6-carboxa mide]], an agonist at the 5-HT1A subtype of 5-HT receptor, was studied as an antiemetic in pigeons dosed with a highly emetic oncolytic agent, cyclophosphamide. An intramuscular injection of 0.32 mg/kg of LY228729 administered 15 min prior to the intravenous injection of 200 mg/kg of cyclophosphamide totally prevented the acute emetic response induced by cyclophosphamide. When used as a rescue therapy in a separate group of pigeons, LY228729 (0.32 mg/kg, i.m.) prevented further emetic episodes when it was administered after vomiting had already been induced by cyclophosphamide. Injections of LY228729 given at intervals over the next 2 d also attenuated the delayed emetic response induced by cyclophosphamide. LY228729 appears to be a broad spectrum antiemetic agent that is effective against the anticipatory, the acute and the delayed stages of emesis induced by oncolytic agents.

Anticonflict effects of 5HT(1A) agonists in pigeons are dependent on the level of response suppression.

Anxiety is a phenomenon that has many different manifestations. In order to test whether or not agents targeted to treat anxiety may have the properties necessary to treat differing types of anxiety, we have studied a 8-OH DPAT, buspirone, LY228729, chlordiazepoxide and pentobarbital on three different punished responding procedures in pigeons. Procedure one was a fairly standard multiple FR30 FR30 punished responding model where responding into he punished component was suppressed by electric shock to 7-10% of responding in the unpunished component. Procedure two was similar except that responding during the punished component was suppressed more severely to 1-3% of control, using increased levels of shock. Procedure three was a VI30 schedule as the unpunished component, with concomitant FR5 shock in a second component, and concomitant FR20 shock in the third component. 5HT(1A) agonists, 8-OH DPAT, buspirone and LY228729 produced the typical large increases in punished responding in procedure one, were substantially less effective when shock levels were increased in procedure two, and produced differential results which were likely due to the schedule in procedure three. The more traditional anxiolytics, chlordiazepoxide and pentobarbital, were consistently effective across all three punished responding procedures. These results would seem to indicate that 5HT(1A) agonists may not be as broadly efficacious as traditional anxiolytics, and that the state or severity of anxiety may be an important variable to predict efficacy for 5HT(1A) agonists.

Structure-activity studies of 6-(tetrazolylalkyl)-substituted decahydroisoquinoline-3-carboxylic acid AMPA receptor antagonists. 1. Effects of stereochemistry, chain length, and chain substitution.

A series of 6-substituted decahydroisoquinoline-3-carboxylic acids were prepared as excitatory amino acid (EAA) receptor antagonists. These compounds are antagonists at the N-methyl-D-aspartate (NMDA) and 2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl) propanoic acid (AMPA) subclasses of ligand gated ion channel (ionotropic) EAA receptors. (3S,4aR, 6R,8aR)-6-(2-(1H-tetrazol-5-yl)ethyl)- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (9) is a potent, selective and systemically active AMPA antagonist. Other analogs from this series, including (3S,4aR,6S,8aR)-6-((1H-tetrazol-5-yl)methyl)- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (32) and (3S,4aR,6S,8aR)-6- (phosphonomethyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-ca rboxylic acid (61) are potent, selective, and systemically active NMDA antagonists. This and the subsequent publication look at the AMPA antagonist aspects of this SAR. Herein we report the effects of varying stereochemistry around the hydroisoquinoline ring; of tetrahydro-versus decahydroisoquinoline; of having the carboxylic acid at C-1 versus C-3; of varying the length of the carbon chain connecting a tetrazole to the bicyclic nucleus; and of holding the connecting chain constant at two atoms, the effect of heteroatom substitution in the position adjacent to the bicyclic nucleus and substitution with methyl or phenyl on the chain. Compounds were evaluated on rat cortical tissue for their ability to inhibit the binding of radioligands selective for AMPA ([3H]AMPA), NMDA ([3H]CGS 19755), and kainic acid ([3H]-kainic acid) receptors and for their ability to inhibit depolarizations induced by AMPA (40 microM), NMDA (40 microM), and kainic acid (10 microM). Our findings revealed that the optimal stereochemical array was the same for both NMDA (32 and 61) and AMPA (9) antagonists identified in this series and that the tetrahydroisoquinoline (25) and the C-1 carboxy (30) analogs of 9 are inactive. With a tetrazole in the distal acid position, an ethylene spacer (9) is optimal; substitution with oxygen or nitrogen on the chain in the position adjacent to the bicyclic nucleus significantly reduced activity, while substitution with a methyl or phenyl group on the chain was well tolerated.

Structure-activity studies of 6-substituted decahydroisoquinoline-3-carboxylic acid AMPA receptor antagonists. 2. Effects of distal acid bioisosteric substitution, absolute stereochemical preferences, and in vivo activity.

We have explored the excitatory amino acid antagonist activity in a series of decahydroiso-quinoline-3-carboxyic acids, and within this series found the potent and selective AMPA antagonist (3SR,4aRS,6RS,8aRS)-6-(2-(1H-tetrazol-5-yl )ethyl) decahydroisoquinoline-3-carboxylic acid (1). In this and the preceding paper, we looked at the structure-activity relationships for AMPA antagonist activity in this series of compounds. We have already shown that 1 had the optimal stereochemical array and that AMPA antagonist activity was maximized for a two-carbon spacer separating a tetrazole from the bicyclic nucleus. In this paper, we explored the effects of varying the distal acid and the absolute stereochemical preferences of many of these analogs. We looked at a variety of different acid bioisosteres, including 5-membered hetereocyclic acids such as tetrazole, 1,2,4-triazole, and 3-isoxazolone; carboxylic,phosphonic, and sulfonic acid; and acyl sulfonamides. Compounds were evaluated in rat cortical tissue for their ability to inhibit the binding of radioligands selective for AMPA ([3H]AMPA), NMDA ([3H]CGS 19755), and kainic acid ([3H]kainic acid) receptors and for their ability to inhibit depolarizations induced by AMPA (40 microM), NMDA (40 microM), and kainic acid (10 microM). A number of compounds from this and the preceding paper were also evaluated in mice for their ability to block maximal electroshock-induced convulsions and ATPA-induced rigidity in mice.

(3SR,4aRS,6SR,8aRS)-6-(1H-tetrazol-5-yl)decahydroisoquinoline-3-carboxylic acid, a novel, competitive, systemically active NMDA and AMPA receptor antagonist.

We report the synthesis and characterization of 6 (LY246492), which is a competitive N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) receptor antagonist. Tetrazole-substituted amino acid 6 was prepared in four steps from the recently described aldehyde 7. The optical isomers (-)-6 and (+)-6 were obtained from the same sequence of reactions using the corresponding isomers of 7. The compound displaces both NMDA and AMPA receptor binding and antagonizes depolarizations in cortical slices evoked by both NMDA and AMPA. In mice and pigeons, the compound showed antagonism of responses mediated through NMDA and AMPA receptors. Using the resolved optical isomers of 6, both NMDA and AMPA antagonist activities were found to reside in a single isomer, (-)-6.

Comparison of the antiemetic effects of a 5-HT1A agonist, LY228729, and 5-HT3 antagonists in the pigeon.

Vomiting may be induced by a variety of agents such as drugs, oncolytics, and provocative motion, as well as being conditioned to occur to environmental stimuli. Such emesis has recently been shown to be blocked by agonists at the 5-HT1A subtype of serotonin receptor. The antiemetic effects of LY228729 [(-)-4-(dipropylamine)-1,3,4,5-tetrahydrobenz-(c,d)indole-6- carboxamide], a 5-HT1A receptor agonist, were tested and compared to the antiemetic effects of the 5-HT3 receptor antagonists ondansetron, tropisetron, and MDL 72222 (3-tropanyl-3,5-dichlorobenzoate). The emetic stimuli tested are known to be blocked by 5-HT3 antagonists in species other than the pigeon. In the pigeon, LY228729 totally abolished vomiting induced by fully emetic doses of cisplatin (10 mg/kg), ipecac (3 ml/kg), emetine (10 mg/kg), and a 5-HT3 agonist, m-(chlorophenyl)-biguanide (1.25 mg/kg). MDL 72222 blocked ipecac-induced vomiting in a dose-related manner and was partially effective in attenuating cisplatin-induced emesis. Ondansetron and tropisetron were partially effective in blocking emetine- and mCPBG-induced vomiting. Ondansetron exhibited an intrinsic emetic response that could not be blocked by MDL 7222, but which was eliminated by LY228729. It was concluded that 5-HT1A agonists are more effective in the pigeon than are 5-HT3 antagonists against these types of emetic stimuli. These results broaden the range of emetic stimuli that are blocked by 5-HT1A agonists in the pigeon.

Schedule-controlled behavioral effects of the selective 2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic acid antagonist LY293558 in pigeons.

Behavioral effects of the selective 2-amino-3-(5-methyl-3-hydroxyisoxazol-4- yl)propanoic acid (AMPA) antagonist LY293558, along with its racemate (LY215490) and opposing enantiomer (LY293559) were evaluated in pigeons. When responding was maintained under a multiple fixed ratio 50 responses, fixed interval 5 minute (FRFI) schedule of food presentation, LY215490 completely antagonized the rate suppression induced by AMPA (10 mg/kg) and by the AMPA analog, 2-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionic acid (ATPA; 40 mg/kg) at 1.25 and 2.5 mg/kg, respectively. In contrast, LY215490, up to 10 mg/kg, was unable to antagonize the rate suppression induced by N-methyl-D-aspartic acid. LY293558, at 0.32 mg/kg, completely blocked the rate suppression produced by AMPA in both components of the multiple schedule. Similarly, LY293558, at 0.64 mg/kg, blocked the rate suppression induced by ATPA in both components. In contrast, the opposing enantiomer, LY293559, up to 10 mg/kg, was without effect on rate suppression produced by AMPA in this model. In additional studies, behavior was maintained under a schedule in which responding was maintained by food presentation in the presence of one key color and in the presence of a second key color, responding was maintained by food and simultaneously suppressed by electric shock ("punished responding"). LY215490 significantly increased punished responding at 10 and 30 mg/kg, whereas unpunished responding was unaffected until 56 mg/kg depressed it. LY293558 significantly increased punished responding at 3 mg/kg without having an effect on unpunished responding. LY293559, on the other hand, was unable to significantly increase punished responding at doses up to 175 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro and in vivo antagonism of AMPA receptor activation by (3S, 4aR, 6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl) ethyl] decahydroisoquinoline-3-carboxylic acid.

The in vitro and in vivo pharmacology of a structurally novel competitive antagonist for the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of excitatory amino acid receptors is described. LY215490, (+/-)(6-(2-(1-H-tetrazol-5-yl)ethyl) decahydroisoquinoline-3-carboxylic acid), was shown to displace selectively 3H-AMPA and 3H-6-cyano-7-nitro- quinoxaline-2,3-dione (3H-CNQX) binding to rat brain membranes. LY215490 potently antagonized quisqualate-and AMPA-induced depolarizations of rat cortical slices in a competitive manner, while requiring higher concentrations to antagonize the effects of N-methyl-D-aspartate (NMDA) and kainate. In slices of rat hippocampus, LY215490 also selectively antagonized AMPA-evoked release of 3H-norepinephrine. These AMPA receptor activities were due to the (-) isomer of the compound. (3S,4aR,6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl] decahydroisoquinoline-3-carboxylic acid (LY293558). LY215490 was centrally active following parenteral administration in mice as demonstrated by protection versus maximal electroshock seizures and decreases in spontaneous motor activity. LY215490 (its active isomer being LY293558) represents a novel pharmacological agent for in vitro and in vivo studies of AMPA receptor function in the CNS.

Olanzapine, an atypical antipsychotic, increases rates of punished responding in pigeons.

The effects of olanzapine [LY 170053; 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2, 3b] [1,5]benzodiazepine), a potential atypical antipsychotic, were determined in pigeons whose keypeck responding was punished. These effects were compared to the anxiolytic agents chlordiazepoxide and pentobarbital, and to other antipsychotic agents. Keypeck behavior was maintained under a multiple FR30 FR30 schedule, signalled by white and red stimulus lights, respectively. Each component of the schedule alternated every 3 min with a 30-s timeout. During the white keylight component, responding was maintained by food presentation. During the red keylight component, responding was maintained by food and simultaneously suppressed by electric shock presentation, with response rates being only about 5% of those during the white stimulus light. Olanzapine (0.01-1.0 mg/kg) increased punished responding at doses below those which had an effect on unpunished responding. Clozapine (0.01-1.0 mg/kg), ritanserin (0.1-3.0 mg/kg), and, to a lesser extent, risperidone (0.1-1.0 mg/kg) were also effective at increasing punished responding. Generally, the maximum effect seen with olanzapine was equal to that seen with ritanserin, and it exceeded that seen with clozapine. However, these effects were generally less than those seen with chlordiazepoxide and pentobarbital. Haloperidol (0.01-0.1 mg/kg) was completely without effect on punished responding, while it caused decreases in unpunished behavior. These results provide further evidence that olanzapine has a profile in behavioral tests unlike the typical antipsychotic haloperidol. Moreover, this profile is similar to clozapine, a clinically effective antipsychotic with an atypical profile.