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One of the cornerstones of translational research is the use of animal model systems, typically rodents, to inform drug discovery efforts about the potential therapeutic utility of a preclinical compound. A wide variety of pharmacological and genetic models have been developed to incorporate the neurochemical and pathological components of Alzheimer’s disease (AD). The complex etiology and heterogeneous pathology of this disease, together with the associated comorbidities such as depression and psychotic-like behavior such as paranoia pose significant challenges for animal model development and for the use of these models to facilitate the development of new drugs. A single model of AD that faithfully reflects both the pathological aspects as well as the behavioral phenotypes is unlikely. However, knowledge of the different models available and a detailed understanding of their features, including specifics of the background strain of a transgenic mouse, the specific mutation, and the progression of both pathological and behavioral changes can aid in selection and characterization of new therapeutics.

The molecular signalling pathway of cell migration and whether it can occur independently of the release of intracellular calcium is still not completely understood. Therefore we investigated here the molecular mechanisms of CCL3 induced cell migration and the importance of intracellular calcium for chemotaxis in more detail. We show that CCL3 induced cell migration is dependent on activation of PLC. Several PKC inhibitors block the release of intracellular calcium independently of CCL3 activation and do not affect cell migration. This confirms that the release of intracellular calcium is not necessary for chemotaxis towards CCL3 and that PKC inhibitors should be used with caution in calcium release assays.

Lever pressing of squirrel monkeys was maintained by a fixed-interval 3-min schedule of food presentation during which every 30th response also produced a brief electric shock. Lever pressing was suppressed during this stimulus (conflict or punishment) compared to that occurring prior to the introduction of shock or, with some monkeys, during an alternate stimulus in which punishment did not occur. PD 134308 (CI-988), administered i.m. (0.03-3.0 mg/kg), increased punished responding but had no effect on non-punished responding. Peak increases of 150% of control occurred at 3.0 mg/kg. There was no indication of sedation at the highest dose of PD 134308 (10.0 mg/kg). By comparison, chlordiazepoxide (1.0-10 mg/kg, i.m.) produced similar effects, except the magnitude of increases in punished responding reached approximately 200% of control performance levels and the higher doses reduced non-punished response rates. PD 134308 produces anxiolytic-like effects in this animal model of anxiety that would suggest potential clinical efficacy in humans of a novel class of compounds with actions at or modulated by cholecystokinin receptors.

A number of studies have shown significant interactions between neuronal systems involved with corticotropin-releasing factor (CRF) and either the clinical manifestation of depression and anxiety of the effects of antidepressant or anxiolytic drugs. In the present study, effects of CRF were studied alone and in combination with imipramine and with the sedative-hypnotic/anxiolytic drugs pentobarbital and chlordiazepoxide. Interactions of CRF with the novel, atypical anxiolytic buspirone were also examined. Interactions were evaluated through the use of schedule-controlled responding, responding suppressed by punishment, and drug discrimination procedures using the conditioned key-pecking response of pigeons. Effects of CRF were significantly enhanced when given in combination with imipramine with low noneffective imipramine doses potentiating the rate-reducing effects of CRF. Similarly, in pigeons trained to discriminate imipramine from saline, noneffective doses of CRF shifted the imipramine dose-response curve more than twofold to the left. Low doses of imipramine that produced saline key responding, produced imipramine-key responding when coadministered with CRF. The CRF antagonist α-helical CRF9–41 did not alter the rate-decreasing effects of imipramine. Effects of CRF on schedule-controlled responding were, however, antagonized by the administration of chlordiazepoxide and pentobarbital but not by buspirone, suggesting that CRF interacts with the GABA/benzodiazepine receptor mechanism complex but not with those systems involved in mediating the effects of buspirone. These results suggest that CRF interacts in significant ways with specific neurotransmitter systems subserving depression and anxiety.

The discovery that compounds acting through 5-hydroxytryptamine (5-HT) receptor subtypes can produce anxiolytic and/or antidepressant therapeutic effects in humans has resulted in considerable interest in the role of the 5-HT receptor system in both anxiety and depressive disorders. Because many of the clinically efficacious 5-HT 1A anxiolytic drugs are either ineffective or produce inconsistent results in traditional or standard types of preclinical punishment or conflict procedures with rodents and other nonhuman mammals, there is considerable need for alternative behavioral assays sensitive to and selective for these compounds. In contrast to data with nonhuman mammals, 5-HT 1A drugs are quite effective in pigeons studied under a punishment procedure. This paper reviews the use of the pigeon conflict procedure as a method for the detection and analysis of potential anxiolytic drugs acting through 5-HT 1A receptors. Additionally, recent studies, also with the pigeon, have indicated that, in contrast to the rat, it is possible to establish an antidepressant such as imipramine as a discriminative stimulus, and then to use this procedure to evaluate the neuropharmacological bases for the behavioral and, presumably, therapeutic actions of these drugs. Using the drug discriination procedure, it has been possible to examine a number of selective compounds that substitute for imipramine, thereby clarifying specific substrates for the antidepressant activity of this and related drugs. The pigeon promises to be a useful species in the pharmacological analyses of novel anxiolytic drugs and provides new approaches to the analysis and understanding of traditional as well as the more recently introduced antidepressant drugs.

A history of responding maintained by a shock-avoidance procedure can alter the effect of psychomotor stimulant drugs on punished responding. This study was designed to evaluate whether another type of historical intervention could also alter the effects of cocaine on punished responding and, as a result, clarify certain variables contributing to this effect. Lever pressing of four squirrel monkeys was suppressed by a punishment procedure consisting of a fixed-interval 5-min schedule of food presentation in which every 30th response also produced a 200-ms 5-mA electric shock. Cocaine (0.03-1.0mg/kg) had no effect on or reduced punished responding. Conditions were then changed and responding was maintained for several sessions by a differential reinforcement of low rate (DRL) schedule in which food was delivered only when one response followed another by at least 25s. The punishment schedule was then reinstated and the effects of cocaine redetermined; the dose-response curve was similar to that initially obtained. The monkeys then responded on a shock-avoidance schedule in which each response postponed the next scheduled shock for 25s; shocks occurred every 5s in the absence of responding. Subsequently, the shock-avoidance schedule was replaced by the punishment schedule and the effects of cocaine were redetermined. In contrast to the initial determination of the effects of cocaine on punished responding, and the effects obtained following training on the DRL schedule, cocaine then produced response rate increases or no change in rate at several doses that formerly reduced responding. These results demonstrate that the rate-decreasing effects of cocaine on punished responding may be reversed by a history of responding on a shock-avoidance schedule and also indicate that a history of responding on a DRL schedule is not sufficient to reverse the effects of cocaine. These data suggest that a history of responding under schedules, such as the DRL, that engender responding that is typically increased by psychomotor stimulant drugs, is not sufficient to reverse the effects of these drugs on punished responding. The reversal of the effects of cocaine on punished responding resulting from a history of avoidance responding appears to be attributable to factors other than the rate-increasing effect of cocaine on responding maintained by avoidance.

Previous research has demonstrated that the effects of d-amphetamine on punished lever pressing of squirrel monkeys are modified by an avoidance history in which lever pressing postpones shock. In the present experiment generalization of behavioral history across responses was assessed by determining the effects of d-amphetamine and cocaine on punished lever pressing of squirrel monkeys before and after exposure to an avoidance procedure in which a chain-pulling response postponed shock. The punishment schedule consisted of a fixed-interval 5-min schedule of food delivery in which every 30 lever presses produced a 5-mA electric shock. During avoidance sessions each chain pull postponed shock delivery for 25s; in the absence of chain pulling, shocks occurred every 5s. Only a single response manipulandum was present in each phase. Punished lever pressing was initially unaltered or decreased by d-amphetamine and cocaine. Following the chain-pull avoidance history, however, d-amphetamine produced dose-dependent increases in the punished lever pressing of all three monkeys at several doses that formerly did not alter or reduce responding; a similar pattern of results was obtained when cocaine was administered to two of the subjects. The effects of d-amphetamine and cocaine on punished lever pressing were subsequently determined within the context of a multiple schedule of lever-press punishment and chain-pull avoidance, with both manipulanda present simultaneously. The effects of the drugs on punished lever pressing within the multiple schedule were similar to their initial, pre-avoidance effects for the two monkeys whose responding was increased by both drugs in the preceding, post-avoidance phase. Chain pulling during the punishment component was dose-dependently increased, suggesting that chain pulling during punishment reduced the opportunity to exhibit increases in punishing lever pressing. The remaining monkey's punished lever pressing was increased by both drugs within the context of the multiple schedule. This experiment demonstrates that avoidance-dependent upward shifts in the dose-response curves of d-amphetamine and cocaine can occur when the punishment and avoidance responses differ, and that original effects can be partially restored when both responses are available simultaneously. The results suggest that generalization across responses of the effects of a critical behavioral history may be a general property of behavioral history phenomena within behavioral pharmacology. These findings underscore the generality and importance of behavioral history as a modulatory influence on the effects of abused drugs.

The involvement of adrenoreceptor blocking drugs with the 5-HT(1A)-mediated discriminative stimulus was studied in pigeons trained to discriminate the 5-HT(1A) receptor agonist 8-OH-DPAT (0.3mg/kg) from saline. Cumulative dose-response curves were determined for 8-OH-DPAT, the beta-adrenergic antagonist pindolol, the alpha(1)-antagonist prazosin, as well as for the 5-HT(1A) agonist buspirone, before, during and after (8-OH-DPAT and pindolol) chronic administration of 8-OH-DPAT (3.0mg/kg/day for 6 weeks). The dose-response curves for 8-OH-DPAT and buspirone, which substituted for 8-OH-DPAT, were shifted to the left during chronic 8-OH-DPAT administration. Prazosin did not substitute for 8-OH-DPAT at any time throughout the course of the study. Pindolol did not substitute for 8-OH-DPAT before chronic administration, but did so during and after 8-OH-DPAT was administered chronically. Chronic administration of 8-OH-DPAT resulted in a heightened sensitivity not only to the 5-HT(1A) agonists 8-OH-DPAT and buspirone, but also to what appear to be partial agonist effects of pindolol. This approach represents a first step in the in vivo characterization of changes in 5-HT(1A) sensitivity after chronic administration of 8-OH-DPAT using the drug discrimination procedure. This method may provide a useful behavioral model with which to investigate the mechanisms of anxiolytic and antidepressant effects of 5-HT(1A) agonists and beta-adrenoceptor blocking drugs that only become apparent after 2 to 4 weeks of chronic administration.

The discriminative stimulus effects of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists were investigated in animals trained to discriminate 1.5g/kg (pigeons) or 1.25g/kg (mice) ethanol from vehicle. Key-pecking of pigeons and lever responding of mice were maintained under fixed ratio schedules of mixed grain or milk reinforcement, respectively. Phencyclidine (PCP) and ketamine dose-dependently substituted for the ethanol stimulus in both species, with PCP being about 10-fold more potent than ketamine. In pigeons, PCP and ketamine fully substituted for ethanol at doses that did not significantly alter rates of responding; with mice, complete substitution was accompanied by response rate-decreasing effects. In pigeons, the highly selective NMDA receptor/ionophore antagonist MK-801 also substituted for ethanol at a dose that was accompanied by reduced response rates. Compounds that did not substitute for the ethanol stimulus were cocaine (both species), the 5-HT(1B) receptor agonist TFMPP (pigeon), the H(1) receptor antagonist hydroxyzine (mice), and the anticonconvulsants phenytoin and ethosuximide (mice). The present data show that PCP-like drugs that are antagonists of NMDA receptor-mediated neurotransmission share common discriminative stimulus effects with ethanol.

Lever pressing by squirrel monkeys and key pecking by pigeons were maintained under a multiple 3-min fixed-interval (FI), 30-response fixed-ratio (FR) schedule by the presentation of food. These responses, which differed under the two schedules, but were similar for both species, were used to compare the effects of antipsychotic compounds from different pharmacological classes. Except for differences in potency levels, the effects of intermediate doses of haloperidol and molindone were similar in monkeys and pigeons; these compounds decreased responding under the fixed-interval schedule at doses that did not affect fixed-ratio responding. Similar effects also occurred with chlorpromazine, promazine and thiothixene in pigeons. With monkeys, however, intermediate doses of promazine decreased fixed-ratio responding more than responding maintained under the fixed-interval schedule, while chlorpromazine and thiothixene produced similar effects on responding under both schedules. The effects of novel antipsychotic, clozapine, differed from those of the other agents in both monkeys and pigeons. With both species clozapine increased fixed interval responding at doses that did not affect responding under the fixed-ratio schedule. Doses required to reduce responding at least 50% were approximately 5 to 160 times greater for pigeons than for monkeys for all drugs except clozapine which was equipotent in both species. In monkeys the order of potency was haloperidol greater than molindone = thiothixene greater than chlorpromazine greater than clozapine greater than promazine, whereas in pigeons the order was haloperidol greater than thiothixene greater than clozapine greater than molindone greater than promazine greater than chlorpromazine.

The effects of MK-212 (6-chloro-2[1-piperazinyl]pyrazine), a centrally-active 5-hydroxytryptamine (5-HT; serotonin) agonist, were studied alone and in combination with the 5-HT antagonists, methysergide (0.01-0.1 mg/kg), metergoline (0.01-1.0 mg/kg) and ketanserin (0.01-3.0 mg/kg). Pigeons were maintained under a procedure where key pecks were reinforced under a multiple fixed-interval (FI) fixed-ratio (FR) schedule of food presentation. In the fixed-interval component, the first response after 3 min had elapsed, produced food, while in the fixed-ratio component, the thirtieth response was reinforced. The drug MK-212 (0.1-3.0 mg/kg) produced dose-related decreases in response rates under both components of the schedule. In smaller doses of MK-212 (0.3 and 1.0 mg/kg), the decrease in the response rate was greater in the fixed-interval component than in the fixed-ratio component. Small doses of methysergide (0.03 mg/kg) and metergoline (0.1 mg/kg), which had little effect when given alone, partially blocked the effects of MK-212 (1.7 and 3.0 mg/kg) in decreasing rate. Larger doses of these compounds, which sometimes increased the response rate when given alone, resulted in a more complete restoration of response rates when administered with MK-212. Ketanserin, a selective 5-HT2 antagonist, reversed the effects of MK-212 in some cases, but the patterning of responses remained disturbed.(ABSTRACT TRUNCATED AT 250 WORDS)