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Rationale: Histamine H3 receptor antagonists, such as ABT-288, have been shown to possess cognitive-enhancing and wakefulness-promoting effects. On the surface, this might suggest that H3 antagonists possess psychomotor stimulant-like effects and, as such, may have the potential for abuse., Objectives: The aim of the present study was to further characterize whether ABT-288 possesses stimulant-like properties and whether its pharmacology gives rise to abuse liability., Methods: The locomotor-stimulant effects of ABT-288 were measured in mice and rats, and potential development of sensitization was addressed. Drug discrimination was used to assess amphetamine-like stimulus properties, and drug self-administration was used to evaluate reinforcing effects of ABT-288. The potential development of physical dependence was also studied., Results: ABT-288 lacked locomotor-stimulant effects in both rats and mice. Repeated administration of ABT-288 did not result in cross-sensitization to the stimulant effects of d-amphetamine in mice, suggesting that there is little overlap in circuitries upon which the two drugs interact for motor activity. ABT-288 did not produce amphetamine-like discriminative stimulus effects in drug discrimination studies nor was it self-administered by rats trained to self-administer cocaine. There were no signs of physical dependence upon termination of repeated administration of ABT-288 for 30 days., Conclusions: The sum of these preclinical data, the first of their kind applied to H3 antagonists, indicates that ABT-288 is unlikely to possess a high potential for abuse in the human population and suggests that H3 antagonists, as a class, are similar in this regard.

Blockade of the histamine H(3) receptor (H(3)R) enhances central neurotransmitter release, making it an attractive target for the treatment of cognitive disorders. Here, we present in vitro and in vivo pharmacological profiles for the H(3)R antagonist 2-[4'-((3aR,6aR)-5-methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-biphenyl-4-yl]-2H-pyridazin-3-one (ABT-288). ABT-288 is a competitive antagonist with high affinity and selectivity for human and rat H(3)Rs (K(i) = 1.9 and 8.2 nM, respectively) that enhances the release of acetylcholine and dopamine in rat prefrontal cortex. In rat behavioral tests, ABT-288 improved acquisition of a five-trial inhibitory avoidance test in rat pups (0.001-0.03 mg/kg), social recognition memory in adult rats (0.03-0.1 mg/kg), and spatial learning and reference memory in a rat water maze test (0.1-1.0 mg/kg). ABT-288 attenuated methamphetamine-induced hyperactivity in mice. In vivo rat brain H(3)R occupancy of ABT-288 was assessed in relation to rodent doses and exposure levels in behavioral tests. ABT-288 demonstrated a number of other favorable attributes, including good pharmacokinetics and oral bioavailability of 37 to 66%, with a wide central nervous system and cardiovascular safety margin. Thus, ABT-288 is a selective H(3)R antagonist with broad procognitive efficacy in rodents and excellent drug-like properties that support its advancement to the clinical area.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major toxicity of chemotherapy treatment for which no therapy is approved. Poly(ADP-ribose) polymerase (PARP)1/2 are nuclear enzymes activated upon DNA damage, and PARP1/2 inhibition provides resistance against DNA damage. A role for PARP inhibition in sensory neurotransmission has also been established. PARP inhibitors attenuate pain-like behaviors and neuropathy-associated decreased peripheral nerve function in diabetic models. The hypothesis tested was that PARP inhibition protects against painful neuropathy. The objective of this study was to investigate whether the novel, selective PARP1/2 inhibitors (ABT-888 and related analogues) would attenuate development of mechanical allodynia in vincristine-treated rats. PARP inhibitors were dosed for 2 days, and then co-administered with vincristine for 12 days. Mechanical allodynia was observed in rats treated with vincristine. PARP1/2 inhibition significantly attenuated development of mechanical allodynia and reduced poly ADP-ribose (PAR) activation in rat skin. The data presented here show that PARP inhibition attenuates vincristine-induced mechanical allodynia in rats, and supports that PARP inhibition may represent a novel therapeutic approach for CIPN., (© 2012 Peripheral Nerve Society.)

Mounting evidence suggests excessive glucocorticoid activity may contribute to Alzheimer's disease (AD) and age-associated memory impairment. 11β-hydroxysteroid dehydrogenase type-1 (HSD1) regulates conversion of glucocorticoids from inactive to active forms. HSD1 knock-out mice have improved cognition, and the nonselective inhibitor carbenoxolone improved verbal memory in elderly men. Together, these data suggest that HSD1 inhibition may be a potential therapy for cognitive deficits, such as those associated with AD. To investigate this, we characterized two novel and selective HSD1 inhibitors, A-918446 and A-801195. Learning, memory consolidation, and recall were evaluated in mouse 24 h inhibitory avoidance. Inhibition of brain cortisol production and phosphorylation of cAMP response element-binding protein (CREB), a transcription factor involved in cognition, were also examined. Rats were tested in a short-term memory model, social recognition, and in a separate group cortical and hippocampal acetylcholine release was measured via in vivo microdialysis. Acute treatment with A-801195 (10-30 mg/kg) or A-918446 (3-30 mg/kg) inhibited cortisol production in the ex vivo assay by ∼ 35-90%. Acute treatment with A-918446 improved memory consolidation and recall in inhibitory avoidance and increased CREB phosphorylation in the cingulate cortex. Acute treatment with A-801195 significantly improved short-term memory in rat social recognition that was not likely due to alterations of the cholinergic system, as acetylcholine release was not increased in a separate set of rats. These studies suggest that selective HSD1 inhibitors work through a novel, noncholinergic mechanism to facilitate cognitive processing.

D-amino acid oxidase (DAO), an enzyme that degrades d-serine, has been suggested as a susceptibility factor for schizophrenia. Here we sought to understand more about the behavioral consequence of lacking DAO and the potential therapeutic implication of DAO inhibition by characterizing a mouse strain (ddY/DAO(-)) lacking DAO activity. We found that the mutant mice showed enhanced prepulse inhibition responses (PPI). Intriguingly, DAO-/- mice had increased sensitivity to the PPI-disruptive effect induced by the competitive NMDA antagonist, SDZ 220-581. In the 24-h inhibitory avoidance test, DAO-/- mice were not different from DAO+/+ mice during the recall. In Barnes Maze, we found that DAO-/- mice had a shortened latency to enter the escape tunnel. Interestingly, although these mice were hypoactive when tested in a protected open field, they showed a profound increase of activity on the edge of the unprotected open field of the Barnes Maze even with the escape tunnel removed. This increased edge activity does not appear to be related to a reduced level of anxiety given that there were no significant genotype effects on the measures of anxiety-like behaviors in two standard animal models of anxiety, elevated plus maze and novelty suppressed feeding. Our data suggest that DAO-/- mice might have altered functioning of NMDARs. However, these results provide only modest support for manipulations of DAO activity as a potential therapeutic approach to treat schizophrenia., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Several studies have tested nicotinic receptor ligands in the 5-Choice Serial Reaction Time Task (5-CSRTT) with varying results. Some investigators have increased attentional demands by modifying task parameters or using aged or poor performing rats to observe treatment effects. This study examined the alpha4beta2 nicotinic agonist ABT-594 in the 5-CSRTT using a variety of manipulations to determine optimal conditions for observing enhancement. ABT-594 had no effect in drug-naïve adult rats that self-initiated trials. Constant trial presentation decreased accuracy and omissions, with the latter significantly attenuated by acute administration of ABT-594 (0.019-0.062 micromol/kg). Sub-chronic treatment (0.019 micromol/kg) initially impaired drug-naïve subjects, but significant improvements in accuracy and decreased omissions were observed after 5 days of dosing. In 18-22 month-old rats, attentional demands were altered by interspersing blocks of trials with different stimulus durations. Acute ABT-594 (0.062 micromol/kg) enhanced accuracy performance in poor performing rats (<70% accuracy) but not in those that performed well (>80% accuracy), while omissions were decreased in both groups. Sub-chronic treatment with (0.019 micromol/kg) decreased omissions in all rats, but enhanced accuracy primarily in poor performing rats. These experiments demonstrate that an alpha4beta2 nicotinic agonist can enhance attention, but accuracy effects may only be observed under specific conditions. Moreover, a reduction in omissions was more reliably observed than improvements in accuracy, resulting in a net increase in signals successfully detected., (2010 Elsevier Inc. All rights reserved.)

Several tetrahydroimidazopyrimidines were prepared using silver assisted cyclization as the key step. The binding affinities of compounds thus prepared were evaluated in vitro toward hCRF(1)R. Initial lead compound 16 (K(i)=32 nM) demonstrated modest putative anxiolytic effects in the mouse canopy test. Further optimization using parallel synthesis provided compounds with K(i)'s <50 nM., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Mutant Tg2576 mice which possess the human "Swedish" APP mutation have been shown to demonstrate both Abeta plaque pathology and memory deficits in behavioral tasks. These mice are routinely maintained on a mixed C57BL/6xSJL genetic background which exhibits a high frequency of retinal degeneration allele and high variability in many behavioral assays. The same APP mutation is also available maintained on a 129 genetic background, providing more genetic homogeneity, but little data are published regarding the effects of the mutation on this background. We investigated whether transgenic mice expressing the Swedish mutation on the 129 background show similar behavioral deficits and Abeta pathology as those on the mixed background. Mice on the 129 background were tested at 6-7, 11-12, or 18-19 months of age in locomotor activity, Y-maze spontaneous alternation, and contextual fear conditioning. Differences were detected between WT and Tg mice in locomotor activity at 6-7 and 18-19 months, Y-maze at 6-7 and 11-12 months, and fear conditioning at 6-7, 11-12, and 18-19 months. In contrast, Tg mice on the mixed B6/SJL background tested at 6-7 months only demonstrated significant impairment in the contextual fear conditioning assay and in the Y-maze in one of 2 cohorts tested. Despite the behavioral differences observed, similar Abeta pathology was observed between Tg mice on the two genetic backgrounds. These results indicate that mice on the 129 genetic background may generate more consistent and robust behavioral differences, providing a useful model for testing therapeutic agents for Alzheimer's disease., (Copyright 2009 Elsevier B.V. All rights reserved.)

The naturally occurring alkaloid, conessine (6), was discovered to bind to histamine H3 receptors in a radioligand-based high-throughput screen. Conessine displayed high affinity at both rat and human H3 receptors (pKi = 7.61 and 8.27) and generally high selectivity against other sites, including histamine receptors H1, H2, and H4. Conessine was found to efficiently penetrate the CNS and reach very high brain concentrations. Although the very slow CNS clearance and strong binding to adrenergic receptors discouraged focus on conessine itself for further development, its potency and novel steroid-based skeleton motivated further chemical investigation. Modification based on introducing diversity at the 3-nitrogen position generated a new series of H3 antagonists with higher in vitro potency, improved target selectivity, and more favorable drug-like properties. One optimized analogue (13c) was examined in detail and was found to be efficacious in animal behavioral model of cognition.

The histamine H3 receptor, first described in 1983 as a histamine autoreceptor and later shown to also function as a heteroreceptor that regulates the release of other neurotransmitters, has been the focus of research by numerous laboratories as it represents an attractive drug target for a number of indications including cognition. The purpose of this review is to acquaint the reader with the current understanding of H3 receptor localization and function as a modulator of neurotransmitter release and its effects on cognitive processes, as well as to provide an update on selected H3 antagonists in various states of preclinical and clinical advancement. Blockade of centrally localized H3 receptors by selective H3 receptor antagonists has been shown to enhance the release of neurotransmitters such as histamine, ACh, dopamine and norepinephrine, among others, which play important roles in cognitive processes. The cognitive-enhancing effects of H3 antagonists across multiple cognitive domains in a wide number of preclinical cognition models also bolster confidence in this therapeutic approach for the treatment of attention deficit hyperactivity disorder, Alzheimer's disease and schizophrenia. However, although a number of clinical studies examining the efficacy of H3 receptor antagonists for a variety of cognitive disorders are currently underway, no clinical proof of concept for an H3 receptor antagonist has been reported to date. The discovery of effective H3 antagonists as therapeutic agents for the novel treatment of cognitive disorders will only be accomplished through continued research efforts that further our insights into the functions of the H3 receptor.

Among the diverse sets of nicotinic acetylcholine receptors (nAChRs), the alpha7 subtype is highly expressed in the hippocampus and cortex and is thought to play important roles in a variety of cognitive processes. In this review, we describe the properties of a novel biaryl diamine alpha7 nAChR agonist, A-582941. A-582941 was found to exhibit high-affinity binding and partial agonism at alpha7 nAChRs, with acceptable pharmacokinetic properties and excellent distribution to the central nervous system (CNS). In vitro and in vivo studies indicated that A-582941 activates signaling pathways known to be involved in cognitive function such as ERK1/2 and CREB phosphorylation. A-582941 enhanced cognitive performance in behavioral models that capture domains of working memory, short-term recognition memory, memory consolidation, and sensory gating deficit. A-582941 exhibited a benign secondary pharmacodynamic and tolerability profile as assessed in a battery of assays of cardiovascular, gastrointestinal, and CNS function. The studies summarized in this review collectively provide preclinical validation that alpha7 nAChR agonism offers a mechanism with potential to improve cognitive deficits associated with various neurodegenerative and psychiatric disorders.

A new structural series of histamine H3 receptor antagonist was developed. The new compounds are based on a quinoline core, appended with a required basic aminoethyl moiety, and with potency- and property-modulating heterocyclic substituents. The analogs have nanomolar and subnanomolar potency for the rat and human H3R in various in vitro assays, including radioligand competition binding as well as functional tests of H3 receptor-mediated calcium mobilization and GTPgammaS binding. The compounds possessed favorable drug-like properties, such as good PK, CNS penetration, and moderate protein binding across species. Several compounds were found to be efficacious in animal behavioral models of cognition and attention. Further studies on the pharmaceutic properties of this series of quinolines discovered a potential problem with photochemical instability, an issue which contributed to the discontinuation of this series from further development.

Three novel heterocyclic benzofurans A-688057 (1), A-687136 (2), and A-698418 (3) were profiled for their in vitro and in vivo properties as a new series of histamine H(3) receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H(3) receptors, and when profiled in vivo for CNS activity, all were found active in an animal behavioral model of attention. The compound with the most benign profile versus CNS side effects was selected for greater scrutiny of its in vitro properties and overall drug-likeness. This compound, A-688057, in addition to its potent and robust efficacy in two rodent behavioral models at blood levels ranging 0.2-19 nM, possessed other favorable features, including high selectivity for H(3) receptors (H(3), K(i)=1.5 nM) versus off-target receptors and channels (including the hERG K(+) channel, K(i)>9000 nM), low molecular weight (295), high solubility, moderate lipophilicity (logD(pH7.4)=2.05), and good CNS penetration (blood/brain 3.4x). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP(450) inhibition. Even though pharmacokinetic testing uncovered only moderate to poor oral bioavailability in rat (26%), dog (30%), and monkey (8%), and only moderate blood half-lives after i.v. administration (t(1/2) in rat of 2.9h, 1.7h in dog, 1.8h in monkey), suggesting poor human pharmacokinetics, the data overall indicated that A-688057 has an excellent profile for use as a pharmacological tool compound.

8-Aryl-1,3a,7,8-tetraaza-cyclopenta[a]indenes represent a novel series of high-affinity corticotropin-releasing factor-1 receptor (CRF1R) antagonists. Herein we report the synthesis and SAR around the tricyclic core and the anxiolytic activity of an orally dosed exemplary compound 9d (K(i)=8.0 nM) in a mouse canopy model.

Rationale: Neuroleptic dysphoria encompasses a range of unpleasant subjective responses and, as a result, is difficult to study in preclinical animal models., Objective: Based on the learned helplessness model of depression, increases in escape failures (EFs) in the drug-induced helplessness test (DH) are proposed to reflect drug-induced depressive-like state, a contributing factor to neuroleptic dysphoria in humans., Materials and Methods: Effects of the typical antipsychotic haloperidol and the atypical antipsychotics risperidone, olanzapine, aripiprazole, quetiapine, and clozapine were investigated in the DH test. We further characterized this test by examining compounds affecting motor function, cognition, anxiety, and those with antidepressant activity., Results: The antipsychotics haloperidol, risperidone, aripiprazole, and olanzapine, all increased EFs, while quetiapine had no effect, and clozapine reduced EFs. Amphetamine, diazepam, and ciproxifan, had no effect on EFs. Scopolamine significantly reduced EFs and MK-801 showed a trend toward reducing EFs at doses not significantly sti mulating locomotor activity. Subchronic, but not acute, imipramine and subchronic fluoxetine significantly reduced EFs at doses significantly suppressing locomotor activity. Dissociation appears to exist between performance in the DH test and compound effects on catalepsy or locomotor activity., Conclusions: After discussing potential alternative interpretations of the drug-induced changes of EFs, we propose the DH test as a useful test for assessing a drug-induced, depressive-like state that may contribute to neuroleptic dysphoria.

Schizophrenic patients typically exhibit impairment of sensorimotor gating, which can be modeled in animal models such as the test of prepulse inhibition of startle response (PPI) in rodents. It has been found that antipsychotics enhanced PPI in DBA mice and reversed the PPI deficit induced by neonatal ventral hippocampal (NVH) lesions in rats. However, the relative involvement of D(3) and D(2) receptors in these effects is unknown since all antipsychotics are D(2)/D(3) antagonists with limited binding preference at D(2) receptors. Therefore, in the current study, we investigated the influence of several dopamine antagonists with higher selectivity at D(3) vs D(2) receptors on PPI in DBA/2J mice and in NVH-lesioned rats. The PPI in DBA/2J mice was enhanced by the nonselective D(2)/D(3) antagonists, haloperidol at 0.3-3 mg/kg, or risperidone at 0.3-1 mg/kg, while PPI-enhancing effects were observed after the administration of higher doses of the preferential D(3)/D(2) antagonist, BP 897 at 8 mg/kg, and the selective D(3) antagonists, SB 277011 at 30 mg/kg and A-437203 at 30 mg/kg. No effect was observed following the treatment with the selective D(3) antagonist, AVE 5997 up to 30 mg/kg. The PPI deficits induced by NVH lesions were reversed by haloperidol but not by the more selective D(3) antagonists, A-437203 and AVE 5997. BP 897 enhanced PPI nonselectivity, that is, in both lesioned and nonlesioned rats. In summary, the present study indicates that PPI-enhancing effects induced by antipsychotics in DBA/2J mice and in NVH-lesioned rats are unlikely to be mediated by D(3) receptors.

The recent development of a highly selective dopamine D4 receptor agonist, A-412997 (2-(3',4',5',6'-tetrahydro-2'H-[2,4'] bipyridinyl-1'-yl)-N-m-tolyl-acetamide), has provided a pharmacological tool with which to conduct systematic investigations into the putative role for dopamine D4 receptors in the central nervous system. These present studies evaluated the potential cognitive enhancing properties of A-412997 in rat models of ADHD (5-trial repeated acquisition inhibitory avoidance in Spontaneous Hypertensive Rat pups) and short-term memory (Social Recognition), in comparison with the less selective dopamine D4 receptor agonists PD168077 and CP226269. A-412997 showed significant dose-dependent efficacy in both models. PD168077 repeatedly improved acquisition in the 5-trial inhibitory avoidance model but failed to reach significance at any dose tested, although significantly improved social recognition was observed (albeit less potent than A-412997). CP226269 showed a significant enhancement in the 5-trial inhibitory avoidance model. These results support a role for the dopamine D4 receptor subtype in cognition.

7-Aryl-6,7-dihydroimidazoimidazoles represent a novel series of high-affinity corticotropin-releasing factor 1 receptor antagonists. Here, we report their synthesis and SAR as well as behavioral activity of two exemplary compounds, 7b and 7k, in a mouse canopy model of anxiety.

Despite the well-described attention and short-term memory enhancing effects of H3 receptor antagonists, and evidence to suggest a close relationship between central histaminergic and cholinergic systems, there is a paucity of evidence for a role for H3 receptor blockade in spatial learning. To address this, we investigated two H3 receptor antagonists in a visual discrimination water maze in rats, and in a Barnes circular maze in mice. Thioperamide and ciproxifan significantly attenuated a scopolamine-induced deficit in the water maze task, while only ciproxifan showed a modest attenuation in the Barnes maze. Taken together, these data suggest a role for H3 receptors in spatial learning that appears to be task-dependent.

Acute pharmacological blockade of central histamine H3 receptors (H3Rs) enhances arousal/attention in rodents. However, there is little information available for other behavioral domains or for repeated administration using selective compounds. ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] exemplifies such a selective, nonimidazole H3R antagonist with high affinity for rat (pK(i) = 8.9) and human (pK(i) = 9.5) H3Rs. Acute functional blockade of central H3Rs was demonstrated by blocking the dipsogenia response to the selective H3R agonist (R)-alpha-methylhistamine in mice. In cognition studies, acquisition of a five-trial, inhibitory avoidance test in rat pups was improved with ABT-239 (0.1-1.0 mg/kg), a 10- to 150-fold gain in potency, with similar efficacy, over previous antagonists such as thioperamide, ciproxifan, A-304121 [(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl) methanone], A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl) phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-furamide], and A-349821 [(4'-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone]. Efficacy in this model was maintained for 3 to 6 h and following repeated dosing with ABT-239. Social memory was also improved in adult (0.01-0.3 mg/kg) and aged (0.3-1.0 mg/kg) rats. In schizophrenia models, ABT-239 improved gating deficits in DBA/2 mice using prepulse inhibition of startle (1.0-3.0 mg/kg) and N40 (1.0-10.0 mg/kg). Furthermore, ABT-239 (1.0 mg/kg) attenuated methamphetamine-induced hyperactivity in mice. In freely moving rat microdialysis studies, ABT-239 enhanced acetylcholine release (0.1-3.0 mg/kg) in adult rat frontal cortex and hippocampus and enhanced dopamine release in frontal cortex (3.0 mg/kg), but not striatum. In summary, broad efficacy was observed with ABT-239 across animal models such that potential clinical efficacy may extend beyond disorders such as ADHD to include Alzheimer's disease and schizophrenia.

Histamine H3 receptor antagonists/inverse agonists have been proposed as potential therapeutic agents for the treatment of a number of neurological disorders ranging from attention deficit hyperactivity disorder and Alzheimer's disease to narcolepsy and schizophrenia. With respect to the latter, schizophrenic patients typically exhibit impaired prepulse inhibition (PPI) of startle, a reflex that can be modeled in many animal species. Certain strains of mice naturally display poor PPI and it was recently suggested that these mice might offer a new way to screen for novel antipsychotic compounds. To examine whether H3 receptor antagonists might enhance PPI in mice with naturally occurring deficits, DBA/2 and C57BL/6 were tested in a startle paradigm with three prepulse intensities: 5, 10 and 15 dB above background. Both thioperamide and ciproxifan enhanced PPI in the DBA/2 strain; thioperamide also showed a trend towards enhancing PPI in C57BL/6. Risperidone, an atypical antipsychotic, enhanced PPI in both the DBA/2 and the C57BL/6 strain. These data confirm previous reports describing a natural deficit in PPI in some mouse strains that is amenable to enhancement with known antipsychotics. Further, these data suggest that H3 receptor antagonists/inverse agonists have anti-psychotic potential for disorders such as schizophrenia.

2-arylamino-4-trifluoromethyl-5-aminomethylthiazoles represent a novel series of high-affinity corticotropin releasing factor-1 receptor (CRF(1)R) antagonists that are prepared in three steps in good overall yields. Herein, we report binding SAR as well as anxiolytic activity of an exemplary compound (7a, K(i)=8.6 nM) in a mouse canopy model.

Rationale: Attention deficit hyperactivity disorder (ADHD) is currently treated with psychomotor stimulants, including methylphenidate and amphetamine. Several adverse effects are associated with these drugs, however, such as agitation and abuse. H(3) receptor antagonists are under clinical investigation for ADHD., Objectives: To investigate the potential of thioperamide, a prototypical H(3) receptor antagonist, to enhance learning and attention while inducing no effects on locomotor stimulation and sensitization, or alterations in ACTH levels., Methods: Thioperamide (1, 3, 10, 30 mg/kg) was administered prior to testing in a multi-trial, inhibitory avoidance response in rat pups (five trials separated by 1 min) to evaluate attention/cognition. Locomotor sensitization and cross-sensitization was assessed following administration of methylphenidate (3 mg/kg), cocaine (10 mg/kg), or thioperamide (1, 3, 10 mg/kg)., Results: Thioperamide significantly enhanced performance of the five-trial inhibitory avoidance response with efficacy similar to that previously reported for methylphenidate. Administration of amphetamine, methylphenidate and cocaine produced significant locomotor sensitization, however. In contrast, thioperamide did not induce locomotor stimulation or sensitization, nor did it cross-sensitize to the stimulant effects of amphetamine or cocaine. The repeated administration of methylphenidate significantly elevated ACTH levels, while thioperamide did not affect this neuroendocrine endpoint., Conclusions: H(3) receptor blockade may offer a safer alternative to psychomotor stimulants for the treatment of ADHD.

Acute functional tolerance (AFT) manifests as rapid adaptation during a single ethanol exposure, leading to a decrease in the behavioral response to ethanol. In order to investigate the genetic and environmental components of the development of AFT, mice were selectively bred in replicate from HS/Ibg mice. High (HAFT) and low (LAFT) acute functional tolerance selected lines were bred to differ in the rate of development and magnitude of AFT to ethanol's intoxicating effects using a static dowel-balancing task. In the present set of experiments, HAFT and LAFT mice were tested for development of AFT on a fixed-speed rotarod using a protocol similar to that for which they were selected. HAFT mice developed greater AFT to ethanol than did LAFT mice. In a separate experiment, other mice from these lines were tested for initial sensitivity and the development of chronic tolerance to ethanol-induced hypothermia, and ethanol-induced incoordination in the grid test. Previous research has detected possible common genetic control of these phenotypes. No differences between lines were found in initial sensitivity to ethanol or in the development or magnitude of chronic tolerance in either test. These experiments show that genetic factors influencing the development of acute tolerance to ethanol-induced intoxication are at least partially distinct from those influencing initial sensitivity and the development of chronic tolerance to ethanol-induced hypothermia and incoordination. Furthermore, these experiments show that AFT measured by the stationary dowel generalizes to AFT measured by the fixed-speed rotarod.

Within-family selective breeding techniques have been used to create two lines of mice to be insensitive (HOT) and two lines to be sensitive (COLD) to the hypothermic effects of an acute 3.0-g/kg ethanol (EtOH) injection. Previous studies have found HOT mice to be relatively resistant to the development of tolerance to this effect, whereas COLD mice readily develop tolerance. The breeding program is currently in selected Generation 52, and the HOT and COLD mice differ by about 10 degrees C (average of both replicates) in their selected hypothermic response. Starting with selection Generation 20, separate lines of mice were inbred from the HOT-2 and COLD-2 selected lines, while selection continued for the original two replicate lines of HOT and COLD mice. To assess whether different dose treatments would produce differential tolerance development in the HOT and COLD selected lines, we administered different dose regimens across 5 days to HOT and COLD mice. The COLD mice developed tolerance while the HOT mice did not, regardless of total EtOH administered. In a separate study, we administered EtOH (3.0 g/kg) to mice for 3 days to assess a shorter tolerance paradigm. We also present here responses to the selection dose of 3.0-g/kg EtOH in the inbred HOT (IHOT-2) and COLD (ICOLD-2) mice tested after 41 generations of brother-sister mating. In addition, we report recent attempts to find doses of EtOH that would produce an equivalent initial hypothermic response in each of the six lines (HOT-1, COLD-1, HOT-2, COLD-2, ICOLD-2, and IHOT-2). When doses were selected to produce similar initial hypothermic sensitivity, tolerance was tested by giving three daily doses and examining the attenuation of the hypothermic response on the third day. All three COLD lines developed significant tolerance, while the HOT lines did not. The HOT and COLD mice provide a genetic model to study mechanisms mediating acute EtOH-induced hypothermia as well as tolerance development.

Rationale: We have previously shown that environmental novelty enhances the behavioral activating effects of amphetamine and amphetamine-induced expression of the immediate early gene c-fos in the striatal complex, particularly in the most caudal portion of the caudate. In contrast, we found no effect of novelty on the ability of amphetamine to induce dopamine (DA) overflow in the rostral caudate or in the core of the nucleus accumbens., Objectives: The twofold aim of the present study was to determine the effect of environmental novelty on (1) amphetamine-induced DA overflow in the shell of the nucleus accumbens and in the caudal portions of the caudate, and (2) glutamate and aspartate overflow in the caudal portions of the caudate., Methods: Two groups of rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopaminergic system received amphetamine (0.5 mg/kg, i.v.) in physically identical cages. For one group, the cages were also the home environment, whereas, for the other group, they were a completely novel environment. In vivo microdialysis was used to estimate DA, glutamate, and aspartate concentrations., Results: Environmental novelty enhanced amphetamine-induced rotational behavior (experiments 1-3) but did not alter amphetamine-induced DA overflow in either the shell of the nucleus accumbens (experiment 1) or the caudate (experiment 2). In addition, the ability of environmental novelty to enhance amphetamine-induced behavioral activation was not associated with changes in glutamate or aspartate efflux in the caudate (experiment 3)., Conclusions: The present data indicate that the psychomotor activating effects of amphetamine can be modulated by environmental context independent of its primary neuropharmacological actions in the striatal complex.

Neuromuscular impairment by ethanol likely involves complex effects on balance, gait, muscle strength, and other features of motor coordination. The present experiments showed that relative sensitivity to ethanol-induced motor impairment in serotonin 1B (5-HT(1B)) null mutant and control mice was task dependent. We found that ethanol-treated null mutant mice made fewer missteps on a balance beam than did ethanol-treated wild-type mice, and confirmed a previous finding of their lesser ethanol sensitivity in the grid test. The genotypes did not differ in ethanol sensitivity as measured by the screen test, static dowel, fixed-speed rotarod, accelerating rotarod, grip strength, or loss of righting reflex tests. These experiments suggest that within a behavioral domain, alternative tests of function are not equivalent, so multiple assessment tools should be used to avoid misinterpretation of gene function.

Background: Genetic and environmental factors contribute to an individual's sensitivity to ethanol, although the exact genes underlying ethanol's effects are not known. Quantitative trait locus (QTL) mapping is one successful method for provisionally identifying genes participating in the mediation of a given behavior. QTL analyses seek to identify associations between a quantitative response and previously mapped marker genes across genetically diverse individuals. Many QTL analyses have been performed in BXD recombinant inbred (RI) strains of mice derived from a cross of C57BL/6J (B6) and DBA/2J (D2) progenitor strains., Methods: We conducted a QTL analysis of ethanol-induced loss of righting reflex and ataxia using a panel of 25 BXD RI strains and the progenitors B6 and D2. We measured the duration of loss of righting reflex after injection and blood ethanol concentrations upon regaining of righting reflex. Ataxia was measured as the latency to fall from a vertical screen., Results: Genome-wide QTL analyses correlating strain means with allelic status at >1500 markers identified several associations (p < or = 0.01). These provisional QTLs were on all chromosomes except 2, 5, 12, 13, and X, and several map near potential candidate genes., Conclusions: These results suggest that ethanol sensitivity is determined by the actions of multiple genes and further suggest their general chromosomal map locations. These provisional linkages will now be confirmed or rejected using additional genetically segregating populations.

In recent years, it has become increasingly evident that there is a genetic component to alcoholism. Attempts to isolate alcoholism genes have met with modest success, in part because alcoholism is a multigenic trait. Recently, experimental animal models and novel genetic manipulations have provided several clues as to the specific genes involved in alcoholism, and extensive research has identified many genes that might influence responses to alcohol. Although not all of these might be proven to influence drug sensitivity, research has provided evidence for the involvement of a few genes. Ultimately, findings from animal models that investigate the function of specific genes could aid the development of pharmacotherapies to treat alcohol dependence.

This paper presents data concerning the dose-effect relationships of intravenously administered amphetamine and cocaine on two widely used measures of psychomotor activation: locomotor crossover activity in neurologically intact rats, and rotational behavior in rats with a unilateral 6-hydroxydopamine lesion. There were marked differences in dose-effect relationships, both as a function of drug and of behavioral measure. Amphetamine produced a linear increase in rotational behavior over a wide range of doses (the highest effective dose was 76.8 times the lowest), but a linear increase in locomotor crossover activity over only a narrow dose range (the highest effective dose was only four times the lowest). In contrast, for cocaine, the dose-effect relationships for the two behaviors were very similar, but for both behaviors the effective dose range was quite narrow, the highest effective dose being only between two and four times the lowest. The data highlight the advantages and disadvantages of these measures as indices of the psychomotor activating effects of psychostimulant drugs.

The ability of amphetamine to produce heightened locomotor activity is thought to be due to its ability to enhance dopamine release from mesolimbic dopamine neurons. The mechanism by which amphetamine increases dopamine release is not well understood, but is thought to involve exchange diffusion with synaptosomal dopamine through the dopamine transporter. We recently reported that amphetamine-mediated dopamine release in the striatum is also dependent on protein kinase C activity. In the current study, we investigated the role of protein kinase C activity in the acute neurochemical and behavioral response to amphetamine in the nucleus accumbens. Consistent with previous results in the striatum, amphetamine-stimulated dopamine release from nucleus accumbens tissue was inhibited by the specific protein kinase C inhibitor Ro31-8220, but not by the relatively inactive analog bisindoylmaleimide V. In addition, the effects of protein kinase C activity on the acute behavioral response to amphetamine was examined by injecting Ro31-8220 into the nucleus accumbens 15 min prior to intra-accumbens amphetamine. Pretreatment with Ro31-8220 attenuated the motor-stimulant effects of intra-accumbens amphetamine relative to control subjects pretreated with vehicle. Bisindoylmaleimide V did not significantly inhibit the motor-stimulant effects of intra-accumbens amphetamine. These results suggest that the action of amphetamine in the nucleus accumbens in increasing dopamine release and locomotor activity is dependent on protein kinase C activity., (Copyright 1998 Elsevier Science B.V.)

In previous studies the repeated administration of 0.5 to 1.0 mg/kg of amphetamine i.v. failed to induce psychomotor sensitization if the drug was administered to animals living in the test environment (at home). The same doses did induce sensitization if animals were transported to the test environment for each drug treatment. The purpose of the present experiment was to determine the extent to which this effect of environment is dose dependent. Rats either lived in test cages or were transported from the animal colony to test cages where they received an i.v. infusion of one of five doses of amphetamine (0.125, 0.5, 1.0, 4.0 or 8.0 mg/kg) or saline each day for 5 consecutive days. Rotational behavior was used as an index of psychomotor activation. After a 6-day drug-free period all animals were challenged with 0.5 mg/kg of amphetamine to determine the pretreatment dose necessary to induce sensitization. The effect of the drug-treatment environment was to shift the dose-effect curve for the induction of sensitization, such that significantly lower doses were necessary to induce sensitization when amphetamine was given in a novel environment. With high doses, however, sensitization occurred regardless of environmental condition. It is concluded that the circumstances surrounding drug administration can powerfully modulate the ability of psychostimulants to induce sensitization, but this effect is dose dependent.

The acute psychomotor response and development of sensitization to amphetamine is attenuated if i.p. injections are given in the cage where a rat lives relative to when injections are given in a novel but physically identical test environment. Furthermore, when the environmental cues predicting i.p. injections are completely eliminated by using remotely activated i.v. injections in the home cage, 1.0 mg/kg amphetamine produces a very small acute response and no sensitization. The same treatments do produce sensitization if i.v. injections are signaled by placement of the rat in a novel test cage. The present experiment was designed to determine if there is a similar effect of environmental condition on the response to i.v. cocaine, and to what extent the effect may be dose-dependent. This was accomplished by comparing the psychomotor activating effects (rotational behavior) of repeated i.v. administrations of one of eight doses of cocaine (0.0, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, or 7.2 mg/kg) given in the home cage, with infusions of the same doses given in a novel test cage. There was no effect of environment on the acute psychomotor response to cocaine. There was, however, a significant effect of environment on the induction of sensitization. A higher dose of cocaine was required to induce sensitization when i.v. administrations were given in the home cage than when they were given in a physically identical but novel test environment. At high doses, however, cocaine induced sensitization regardless of environmental condition. The results suggest that the effect of this environmental manipulation is to shift the dose-effect curve for the induction of sensitization, and support the notion that the ability of psychostimulant drugs to induce sensitization can be modulated by the circumstances surrounding drug administration.

The conditions necessary to induce psychomotor sensitization and to promote its expression are not well understood. Two examples are reviewed here of how the circumstances surrounding drug administration ("set and setting") can powerfully modulate the sensitization produced by psychostimulant drugs, such as amphetamine or cocaine. In the first example it is suggested that repeated exposure to psychostimulant drugs may induce "neural sensitization" (i.e., produce relevant adaptations in the nervous system). The circumstances surrounding drug administration may determine, however, whether neural sensitization is expressed in behavior. In the second example it is suggested that the circumstances surrounding drug administration may determine whether sensitization is induced at all, or at least the rate and extent of sensitization produced by a given dose of a drug. It is concluded that psychomotor sensitization is not an inevitable consequence of exposure to psychostimulant drugs, but is the result of interactions amongst the pharmacological actions of drugs and the circumstances surrounding drug administration.

The repeated, intermittent administration of amphetamine produces a long-lasting sensitization to its behavioral activating effects. Excitatory amino acid receptors in the striatum have been implicated in the development of amphetamine sensitization, and one source of excitatory amino acid input to the striatum is the hippocampus. The purpose of this experiment, therefore, was to determine if an intact hippocampal system is necessary for either the development or expression of sensitization to the psychomotor activating effects of amphetamine. Rats received either fimbria-fornix lesions or sham lesions and approximately 2 weeks later received 10 injections of 3.0 mg/kg d-amphetamine or saline (IP) every other day. Rotational behavior was quantified as an index of amphetamine's psychomotor stimulant effects. Animals with a fimbria-fornix lesion were hyperresponsive to an acute injection of amphetamine, but animals with a fimbria-fornix lesion and control animals did not differ in the development of sensitization (i.e., the rate of sensitization). Furthermore, both groups expressed comparable sensitization (relative to their respective saline-pretreated control groups) when given a challenge injection of amphetamine. These results suggest an intact hippocampal system is not necessary for the development or expression of amphetamine sensitization.

The acute psychomotor response (rotational behavior in rats with a unilateral 6-OHDA lesion), and the development of sensitization, were studied in rats that received seven consecutive daily injections of amphetamine (Experiment 1) or cocaine (Experiment 2) either at home or in a 'novel' test environment. The home (HOME) and novel (NOVEL) cages were physically identical, but one group lived and was tested in these cages, whereas the rats in the other group were transported from the stainless steel hanging cages where they lived, to those NOVEl test cages, for each test session. In Exp. 1, the acute psychomotor response to 3.0 mg/kg of amphetamine i.p. and the development of sensitization (increase in the rotational response between the first and the the seventh test session) were greater in the NOVEL than in the HOME environment. In Expt. 2, there were no significant group differences in the acute response to 20 mg/kg of cocaine i.p., but the animals tested in the NOVEL environment showed greater sensitization than animals tested in the HOME environment. In addition, the animals pretreated with cocaine in the NOVEL environment, but not those pretreated with cocaine in the HOME environment, showed conditioned rotational behavior in response to an injection of saline. These data indicate that: (i) sensitization to the psychomotor activating effects of both amphetamine and cocaine is enhanced in a NOVEL environment; (ii) this phenomenon appears to the independent of the effects of the NOVEL environment on the acute response to these drugs; (iii) a robust conditioned psychomotor response to contextual cues develops only when cocaine treatments are given in the NOVEL test environment.

The effects of an acute systemic injection of methamphetamine (mAMP) or cocaine (COC) on motor behavior (stereotypy, locomotor activity, and rearing) and extracellular dopamine (DA) in the ventral striatum were compared in Lewis (LEW) versus Fischer 344 (F344) rats, using in vivo microdialysis in awake freely moving animals. In addition, the behavioral response to repeated mAMP injections (i.e. sensitization) was characterized in LEW and F344 rats, as was the possibility of strain differences in drug pharmacokinetics. The major findings were: (i) LEW rats showed greater behavioral activation to an acute injection of both mAMP and COC, as indicated by a shift to the left in the dose-effect curves relative to F344 rats. (ii) LEW rats were more susceptible to mAMP sensitization. (iii) An acute injection of mAMP or COC enhanced the extracellular concentration of DA to a greater extent in LEW rats, as indicated by a significant shift to the left in the dose-effect curve relative to F344 rats. (iv) Strain differences in the behavioral and neurochemical effects of these drugs were characterized largely by differences in the duration of the drug response. (v) LEW rats had higher plasma and brain levels of mAMP and COC than F344 rats, suggesting that strain differences in pharmacokinetics may contribute to strain differences in the behavioral and neurochemical effects of these drugs.

In two experiments, we examined the hypothesis that repeatedly adapting and readapting to two mutually conflicting sensory environments fosters the development of a separate adaptation to each situation (dual adaptation) as well as an increased ability to adapt to a novel displacement (adaptive generalization). In the preliminary study, subjects alternated between adapting their visuomotor coordination to 30-diopter prismatic displacement and readapting to normal vision. Dual adaptation was observed by the end of 10 alternation cycles. However, an unconfounded test of adaptive generalization was prevented by an unexpected prism-adaptive shift in preexposure baselines for the dual-adapted subjects. In the primary experiment, the subjects adapted and readapted to opposite 15-diopter displacements for a total of 12 cycles. Both dual adaptation and adaptive generalization to a 30-diopter displacement were obtained. These findings may be understood in terms of serial reversal learning and "learning to learn."

Objective: To examine differences between healthy elderly and young adults in daytime napping, nocturnal sleep, and 24-hour sleep/wake patterns. A second objective was to determine whether elderly subjects with more and less frequent naps differed in their clinical features or nocturnal sleep., Design: Survey by sleep/wake logs and polysomnography. Comparison by age., Setting: Sleep/wake logs were completed in the subjects' homes. Polysomnographic studies were conducted on an outpatient basis in a sleep and chronobiology research laboratory., Subjects: Convenience samples of forty-five healthy subjects over 78 years of age (21M, 24F) and 33 healthy adults between 20 and 30 years of age (20M, 13F)., Main Outcome Measures: Using self-reports, we estimated the frequency and timing of daytime naps; timing, duration, and quality of nocturnal sleep; and 24-hour patterns of sleep and wakefulness. Also polysomnographic sleep measures., Results: Compared to young adults, elderly subjects reported a greater mean number of daytime naps (P = .004), shorter nocturnal sleep with more wakefulness and earlier sleep hours (P less than .003 for each), and a trend for a shorter 24-hour sleep fraction. Among the elderly, more-frequent and less-frequent nappers did not differ in clinical ratings, self-report sleep measures, or polysomnographic measures. There was a trend for more sleep-disordered breathing and periodic limb movements in more frequent nappers., Conclusions: These findings are consistent with an age-related decrease in amplitude of the circadian sleep propensity rhythm, or with the expression of a semi-circadian (12-hour) sleepiness rhythm. However, we cannot exclude the additional possibility that napping results from lifestyle factors and nocturnal sleep pathologies in a subset of the elderly.