Vicki L. Coffin

The gerbil elevated plus-maze II: anxiolytic-like effects of selective neurokinin NK1 receptor antagonists.

Neurokinin NK1 receptor antagonists may have therapeutic potential in the treatment of anxiety and depression. Species variants in the NK1 receptor result in reduced affinity of NK1 receptor antagonists at rat and mouse NK1 receptors, making it difficult to test NK1 antagonists in traditional preclinical models of anxiety and depression. Gerbil NK1 receptors are similar in homology to the human NK1 receptor. In a companion article, we described the anxiety-like behavioral profile of gerbils on an adapted elevated plus-maze, and the ability of anxiolytic drugs to produce anti-anxiety effects in the gerbil elevated plus-maze. The aim of the present study was to determine whether oral (p.o.) administration of the NK1 receptor antagonists MK-869, L-742,694, L-733,060, CP-99,994, and CP-122,721 produced anxiolytic-like effects in the gerbil elevated plus-maze. Upon testing, all five NK1 antagonists produced anxiolytic-like effects. MK-869 (0.01–3 mg/kg) was the most potent NK1 antagonist, producing anxiolytic-like effects on percentage of open arm time, percentage of open arm entries, stretch-attend postures, and head dips at 0.03–0.3 mg/kg doses. L-742,694 (1–30 mg/kg) and L-733,060 (1–10 mg/kg) produced anxiolytic-like effects on percentage of open arm time and stretch-attend postures at 3–10 mg/kg doses. CP-99,994 (3–30 mg/kg) only produced an anxiolytic-like effect on stretch-attend postures. CP-122,721 (3–30 mg/kg) produced an anxiolytic-like effect on percentage of open arm time at 30 mg/kg. The order of potency of the NK1 antagonists to increase percentage of open arm time was very similar to their potency to block NK1 agonist-induced foot-tapping. These studies demonstrate that neurokinin NK1 receptor antagonists produce anxiolytic-like effects in a novel gerbil elevated plus-maze, and suggest that this is an appropriate model to test NK1 antagonists for preclinical anxiolytic activity.

The Gerbil Elevated Plus-Maze I: Behavioral Characterization and Pharmacological Validation

Several neurokinin NK1 receptor antagonists currently being developed for anxiety and depression have reduced affinity for the rat and mouse NK1 receptor compared with human. Consequently, it has proven difficult to test these agents in traditional rat and mouse models of anxiety and depression. This issue has been overcome, in part, by using non-traditional lab species such as the guinea pig and gerbil, which have NK1 receptors closer in homology to human NK1 receptors. However, there are very few reports describing the behavior of gerbils in traditional models of anxiety. The aim of the present study was to determine if the elevated plus-maze, a commonly used anxiety model, could be adapted for the gerbil. Using a specially-designed elevated plus-maze, gerbils exhibited an ‘anxious’ behavioral profile similar to that observed in rats and mice, i.e., reduced entries into, and time spent exploring, an open, aversive arm. The anxiolytic drugs diazepam (0.03–3 mg/kg i.p.), chlordiazepoxide (0.3–10 mg/kg i.p.), and buspirone (0.3–30 mg/kg s.c.) increased open arm exploration and produced anxiolytic-like effects on risk-assessment behaviors (reduced stretch-attend postures and increased head dips). Of particular interest, the antidepressant drugs imipramine (1–30 mg/kg p.o.), fluoxetine (1–30 mg/kg, p.o.) and paroxetine (0.3–10 mg/kg p.o.) each produced some acute anxiolytic-like activity, without affecting locomotor activity. The antipsychotic, haloperidol, and the psychostimulant, amphetamine, did not produce any anxiolytic-like effects (1–10 mg/kg s.c). The anxiogenic β-carboline, FG-7142, reduced time spent in the open arm and head dips, and increased stretch-attend postures (1–30 mg/kg, i.p.). These studies have demonstrated that gerbils exhibit an anxiety–like profile on an elevated plus-maze, and that the gerbil elevated plus-maze may have predictive validity for anxiolytics, and antidepressants with potential anxiolytic-like effects.

SCH 57790, a selective muscarinic M2 receptor antagonist, releases acetylcholine and produces cognitive enhancement in laboratory animals

The present studies were designed to assess whether the novel muscarinic M(2) receptor antagonist 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-1-piperazineacetonitrile (SCH 57790) could increase acetylcholine release in the central nervous system (CNS) and enhance cognitive performance in rodents and nonhuman primates. In vivo microdialysis studies show that SCH 57790 (0.1-10 mg/kg, p.o.) produced dose-related increases in acetylcholine release from rat hippocampus, cortex, and striatum. SCH 57790 (0.003-1.0 mg/kg) increased retention times in young rat passive avoidance responding when given either before or after training. Also, SCH 57790 reversed scopolamine-induced deficits in mice in a passive avoidance task. In a working memory operant task in squirrel monkeys, administration of SCH 57790 (0.01-0.03 mg/kg) improved performance under a schedule of fixed-ratio discrimination with titrating delay. The effects observed with SCH 57790 in behavioral studies were qualitatively similar to the effects produced by the clinically used cholinesterase inhibitor donepezil, suggesting that blockade of muscarinic M(2) receptors is a viable approach to enhancing cognitive performance.

Muscarinic agonists and antagonists in the treatment of Alzheimer's disease☆

Alzheimers disease (AD) is a neurodegenerative disease characterized by cognitive impairment and personality changes. The development of drugs for the treatment of the cognitive deficits of AD has focused on agents which counteract loss in cholinergic activity. Although symptoms of AD have been successfully treated with acetylcholinesterase inhibitors (tacrine, donepezil. rivastigmine, galanthamine), limited success has been achieved with direct M1 agonists, probably due to their lack of selectivity versus other muscarinic receptor subtypes. Muscarinic M2 antagonists have been reported to increase synaptic levels of acetylcholine after oral administration to rats (e.g. BIBN-99, SCH-57790), but their selectivity versus other muscarinic receptor subtypes is modest. Exploration of a series of piperidinylpiperidines has yielded the potent and selective M2 antagonist SCH-217443. This antagonist has excellent bioavailability in rats and dogs and shows activity in a rat model of cognition.

The anxiolytic-like effects of the novel, orally active nociceptin opioid receptor agonist 8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510).

Orphanin FQ/nociceptin (OFQ/N) is the endogenously occurring peptide ligand for the nociceptin opioid receptor (NOP) that produces anxiolytic-like effects in mice and rats. The present study assessed the anxiolytic-like activity of 8-[bis(2-methylphenyl)-methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510), a novel potent piperidine NOP agonist (EC50 = 12 nM) that binds with high affinity (Ki = 0.3 nM) and functional selectivity (>50-fold over the μ-, κ-, and δ-opioid receptors). The anxiolytic-like activity and side-effect profile of SCH 221510 were assessed in a variety of models and the benzodiazepine, chlordiazepoxide (CDP), was included for comparison. The effects of chronic dosing of SCH 221510 were also assessed. Furthermore, the specificity of the anxiolytic-like effect of SCH 221510 was investigated with the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and the opioid receptor antagonist naltrexone. Like CDP (1–30 mg/kg i.p.), SCH 221510 (1–30 mg/kg p.o.) produced anxiolytic-like effects in the elevated plus-maze (rat and gerbil), Vogel conflict (rat), conditioned lick suppression (rat), fear-potentiated startle (rat), and pup separation-induced vocalization (guinea pig) assays. In the Vogel conflict, the anxiolytic-like effect of SCH 221510 (10 mg/kg) was attenuated by J-113397 (3–10 mg/kg p.o.), but not naltrexone (3–30 mg/kg i.p.). Additionally, the anxiolytic-like effects of SCH 221510 did not change appreciably following 14-day b.i.d. dosing in rats (10 mg/kg). Furthermore, unlike CDP, SCH 221510 (3–30 mg/kg) produced anxiolytic-like activity at doses that did not disrupt overt behavior. Collectively, these data suggest that NOP agonists such as SCH 221510 may have an anxiolytic-like profile similar to benzodiazepines, with a reduced side-effect liability.

Behavioral and physiological effects of xanthines in nonhuman primates

Abstract Caffeine and related xanthines can have significant behavioral effects on measures of locomotor activity, schedule-controlled behavior, drug self-administration, and learning and memory. Xanthines also produce numerous physiological effects including positive inotropic and chronotropic effects on the heart, decreased airway resistance in the lung, and respiratory stimulation. Due to the widespread use of xanthines as constituents of food and beverages and as therapeutic drugs, identification of mechanisms that mediate their pharmacological effects has considerable relevance for drug development and therapeutics. Two primary mechanisms involving the cyclic nucleotide system have been implicated as the bases for the effects of xanthines in the CNS. Many xanthines bind to specific adenosine recognition sites and block the actions of adenosine. Xanthines also inhibit cyclic nucleotide phosphodiesterases, the enzymes responsible for the hydrolytic inactivation of cyclic AMP and cyclic GMP. Recent research in nonhuman primates has characterized the behavioral, respiratory and cardiovascular effects of a number of xanthines and related drugs differing in affinity at different subtypes of adenosine receptors and in capacity to inhibit different molecular forms of PDE. The behavioral-stimulant effects of xanthines appear to be mediated principally by their adenosine-antagonist actions and may be limited by PDE inhibition. The respiratory-stimulant and cardiac effects of xanthines, on the other hand, appear to be linked more closely to their PDE- inhibiting actions than to adenosine antagonism. Converging lines of evidence suggest that adenosine A2 and cAMP-specific (possibly type IV) PDE mechanisms play especially prominent roles in mediating the behavioral and physiological effects of xanthines in nonhuman primates.

Cholinergic improvement of a naturally-occurring memory deficit in the young rat

In a single-trial, passive-avoidance response (PAR) paradigm, young rats at post-natal day (PND) 16 were found to exhibit a performance deficit that diminished progressively with age. When administered prior to training, single peripheral injections of cholinomimetic drugs, either a muscarinic agonist (arecoline, pilocarpine or oxotremorine), an acetylcholinesterase inhibitor (tacrine or E2020), or nicotine, increased the response latencies for young rats to that of adult levels in a dose-dependent manner (overall dose range = 0.003 microgram/kg-10 mg/kg). Neither the cholinergic antagonists scopolamine, atropine or mecamylamine, nor a series of non-cholinergic drugs, diazepam, haloperidol, phenobarbital, pargyline, D-amphetamine, imipramine, piracetam or N-methyl-D-aspartate (NMDA) increased PAR latencies. When 0.1 mg/kg scopolamine was given to young rats prior to arecoline, the dose-effect curve for enhanced latency times was shifted to the right. Higher doses of scopolamine completely blocked the effects of arecoline. Scopolamine (0.001-1.0 mg/kg) administered subsequent to, rather than before PAR training, blocked the usual arecoline-induced enhancement of response latencies. Alternatively, consolidation could be facilitated with different doses of tacrine (0.0003-10 mg/kg). These results demonstrate that young rats fail to remember the PAR but that retention for this task can be specifically enhanced with cholinomimetic drugs.

Selective antagonism of the anticonvulsant effects of felbamate by glycine

Glycine blocked the anticonvulsant effects of felbamate on electroshock- and NMDA-induced seizures in mice. In contrast to its effects on felbamate, glycine either potentiated or had no effect on the anticonvulsant actions of phenytoin, valproate, carbamazepine and phenobarbital on electroshock seizures in mice. The data support that the glycine-felbamate blockade is a specific interaction. Felbamate is likely to be the first clinically available anticonvulsant drug that acts through this unique mechanism.

[3H]SCH 39166, A New D1‐Selective Radioligand: In Vitro and In Vivo Binding Analyses

SCH 39166 {(‐)‐trans‐6,7,7a,8,9,13b‐hexahydro‐3‐chloro‐2‐hydroxy‐N‐ methyl‐5H ‐ benzo ‐[d]naphtho[2,1b]azepine} has recently been described as a selective D1 antagonist and has entered clinical trials for the treatment of schizophrenia. The tritiated analogue of this compound, [3H]SCH 39166, has now been synthesized and characterized for its in vitro and in vivo binding profiles. [3H]SCH 39166 binds to D1 receptors in a saturable. high‐affinity fashion, with a KDof 0.79 nM. In competition studies, D1‐selective antagonists like SCH 23390 displaced the binding of [3H]SCH 39166 with nanomolar affinities, whereas antagonists of other receptors exhibited poor affinity. In vivo, [3H]SCH 39166 bound to receptors in rat striatum in a fashion suggestive of D1 selectivity. Further. when the time course for the binding of [3H]SCH 39166 was compared with the behavioral time course of the unlabeled compound, the two durations of action were virtually indistinguishable. Similar studies were performed for SCH 23390 and its tritiated analogue, but the in vivo binding of this radioligand exhibited a duration of action far greater than the behavioral activity of the unlabeled drug. In concert, these data demonstrate that [3H]SCH 39166 selectively labels D1 receptors in vitro and in vivo, and that this drug is superior for in vivo imaging of the D1 receptor.

Analgesic and acute central nervous system side effects of the intravenously administered enkephalinase inhibitor SCH 32615

The analgesic and acute central nervous system (CNS) side effect potential of the enkephalinase inhibitor SCH 32615 (N-[L-(1-carboxy-2-phenyl)ethyl]-L-phenyl-alanine-beta-alanine) were evaluated after IV administration to mice, rats and squirrel monkeys. In mice, SCH 32615 caused dose-related suppression of acetic acid-induced writhing (minimal effective dose, MED = 3 mg/kg IV). In rats, SCH 32615 produced dose-related increases in the response latencies in the yeast inflamed-paw test (MED = 10 mg/kg IV). In squirrel monkeys, using a new hot-water bath tail-flick test, SCH 32615 significantly prolonged the escape latencies (MED = 100 mg/kg IV). These results in primates are the first data showing an analgesic action of an enkephalinase inhibitor in a reflex model of pain. When measured for its CNS side effect potential, SCH 32615 had no significant effects in rats (up to 100 times its analgesically active doses) or in monkeys (up to three times). In the mouse, at doses 100 times its minimal effective dose, SCH 32615 produced brief convulsions; these lasted only a minute, resolved quickly, and did not cause lethality. In contrast, in rats and squirrel monkeys, the standard opioid analgesic morphine produced profound CNS side effects; this was particularly notable in monkeys, in which morphines maximal analgesic effects were associated with near lethal respiratory depression. These data demonstrate that SCH 32615 produces selective analgesic actions and that its acute side effect liability is less than that seen with a clinically used standard.