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Here we describe the properties of CP-154,526, a potent and selective nonpeptide antagonist of corticotropin (ACTH) releasing factor (CRF) receptors. CP-154,526 binds with high affinity to CRF receptors (K; < 10 nM) and blocks CRF-stimulated adenylate cyclase activity in membranes prepared from rat cortex and pituitary. Systemically administered CP-154,526 antagonizes the stimulatory effects of exogenous CRF on plasma ACTH, locus coeruleus neuronal firing and startle response amplitude. Potential anxiolytic activity of CP-154,526 was revealed in a fearpotentiated startle paradigm. These data are presented in the context of clinical findings, which suggest that CRF is hypersecreted in certain pathological states. We propose that a CRF antagonist such as CP-154,526 could affirm the role of CRF in certain psychiatric diseases and may be of significant value in the treatment of these disorders.Corticotropin releasing factor (CRF) is a 41-amino acid peptide initially identified as a hypothalamic factor responsible for stimulating corticotropin (ACTH) secretion from the anterior pituitary (1, 2). CRF causes a rapid increase in plasma ACTH and glucocorticoid levels when given intravenously (3). Activation of the hypothalamic-pituitary-adrenal (HPA) axis can also result from release of CRF from the paraventricular nucleus of the hypothalamus in response to various stressors (1, 4). In the central nervous system, both CRF-like immunoreactivity and high affinity CRF receptors are heterogeneously distributed in the brain (5, 6). Characterizations of these extrahypothalamic CRF systems demonstrate that, in parallel with its actions on the HPA axis, CRF also acts as a neurotransmitter or neuromodulator to coordinate stress-induced neural responses in the brain (7,8).Intracerebroventricular administration of CRF to rats leads to a constellation of neurochemical, neurophysiological, and behavioral sequelae that include activation of central noradrenergic systems and enhancement of behavioral responses to external stimuli (9-13). In this regard, increases in norepinephrine turnover (10) and in the firing rate of locus coeruleus neurons (13) have been observed following CRF injection. Physiological stressors such as nitroprusside infusions also increase locus coeruleus neuronal firing, an effect blocked by a CRF antagonist (a-helical CRF9-41) and consequently thought to be mediated by endogenous CRF (14,15). The response to hemodynamic stress in this case can be desensitized by chronic treatment with tricyclic antidepressants, suggesting that one possible mode of action of antidepressants might be to alter central CRF neurotransmission (16). In behavioral paradigms, CRF injection i.c.v. produces anxiogenic-like effects in several rodent models (e.g. 17-20). These effects are antagonized by central infusion of peptide antagonists (a-helical CRF9-41 and D-Phe CRF12-41), suggesting the involvement of CRF in anxiety and the utility of CRF antagonists as anxiolytics. The persistence ofbehavioral activation in hypophysectomize...

Muscarinic acetylcholine receptors are known to play key roles in facilitating cognitive processes. However, the specific roles of the individual muscarinic receptor subtypes (M 1 -M 5 ) in learning and memory are not well understood at present. In the present study, we used wild-type (M2 ϩ/ϩ ) and M 2 receptor-deficient (M2 Ϫ/Ϫ mice. Because impaired muscarinic cholinergic neurotransmission is associated with Alzheimer's disease and normal aging processes, these findings should be of considerable therapeutic relevance.

SUMMARY The scan speed limit of atomic force microscopes has been calculated. It is determined by the spring constant of the cantilever k, its effective mass m, the damping constant D of the cantilever in the surrounding medium and the stiffness of the sample. Techniques to measure k, k/m and D/m are described. In liquids the damping constant and the effective mass of the cantilever increase. A consequence of this is that the transfer function always depends on the scan speed when imaging in liquids. The practical scan speed limit for atomic resolution in vacuum is 0·1 μm/s while in water it increases to about 2 μm/s due to the additional damping of cantilever movements. Sample stiffness or damping of cantilever movements by the sample increase these limits. For soft biological materials imaged in water at a desired resolution of 1 nm the scan speed should not exceed 2 μm/s.

1 The selective NK, receptor antagonist, CP-99,994, produced dose-related (0.1-1.0 mg kg- ', s.c.) inhibition of vomiting and retching in ferrets challenged with central (loperamide and apomorphine), peripheral (CuS04) and mixed central and peripheral (ipecac, cisplatin) emetic stimuli. 2 Parallel studies with the enantiomer, CP-100,263 (1 mg kg-', s.c.), which is > 1 000 fold less potent as a NK1 antagonist, indicated that it was without significant effect against CuS04, loperamide, cisplatin and apomorphine-induced emesis. Against ipecac, it inhibited both retching and vomiting, expressing approximately 1/10th the potency of CP-99,994. 6 In dogs, CP-99,994 (40 gkg-' bolus and 300 jgkg-'h-', i.v.) produced statistically significant reductions in vomiting to CuS04 and apomorphine as well as retching to CuS04. 7 Together, these studies support the hypothesis that the NK, receptor antagonist properties of CP-99,994 are responsible for its broad spectrum anti-emetic effects. They also suggest that CP-99,994 acts within the brainstem, most probably within the nucleus tractus solitarius although the involvement of the area postrema could not be excluded.

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To determine how acetylcholine (ACh) modulates the somatodendritic processing of EPSPs, we performed whole‐cell recordings from CA1 pyramidal cells of hippocampal slices and examined the effect of the cholinergic agonist, carbachol (CCh), on α‐amino‐3‐hydroxy‐5‐methyl isoxazole‐4‐propionate (AMPA) EPSPs, miniature EPSPs, and EPSP‐like waveforms evoked by brief dendritic glutamate pulses (glutamate‐evoked postsynaptic potentials, GPSPs). Although CCh is known to enhance the intrinsic excitability of the neuron in several ways, activation of atropine‐sensitive (muscarinic) receptors on the apical dendrite or the soma of CA1 pyramidal cells consistently reduced the amplitude of EPSPs and GPSPs. Cholinergic inhibition of evoked and simulated EPSP waveforms displayed considerable voltage dependence, with the amplitude of the postsynaptic potentials progressively declining with membrane hyperpolarization indicating the involvement of an inwardly rectifying current. Extracellular Ba2+ (200 μm) and tertiapin (30 nm), a novel and selective blocker of G protein‐activated, inwardly rectifying K+ (GIRK) channels, completely blocked the effect of CCh on GPSP amplitude. Muscarinic reduction of GPSPs was not sensitive to the M1 receptor‐preferring antagonist, pirenzepine, but was suppressed by the M2 receptor‐preferring antagonist, methoctramine, and by the allosteric M2 receptor antagonist, gallamine. In voltage‐clamp recordings, CCh induced an ion current displaying inward rectification in the hyperpolarizing direction, which was identified as a GIRK current based on its sensitivity to low Ba2+ and tertiapin. Its pharmacological profile paralleled that of the cholinergic GPSP reduction. We link the observed reduction of postsynaptic potentials to the cholinergic activation of a GIRK conductance, which serves to partially shunt excitatory synaptic input.

CP-96,345, a nonpeptide substance P antagonist, is selective for the tachykinin NK1 receptor. The compound binds to a single population of sites in guinea pig brain and potently inhibits substance P-induced excitation of locus ceruleus neurons. CP-96,345 should be a useful tool for studying the action of substance P in the central nervous system.