The NK1 receptor antagonist aprepitant attenuates NK1 agonist-induced scratching behaviour in the gerbil after intra-dermal, topical or oral administration.

Experiments were conducted to develop a model to study the effect of oral and topical administration of the NK1 receptor antagonist aprepitant, on scratching behaviour in gerbils. The gerbil was selected due to its relevance for human NK1 receptor pharmacology. Intradermal injection of a specific NK1 receptor agonist GR73632 (100 nmol/100 µl) at the rostral back of gerbils produced scratching of the injection site. This could be attenuated by intradermal co-administration of a selective NK1 receptor antagonist aprepitant (30-100-300 nmol), demonstrating the role of dermal NK1 receptor in elicitation of scratching behaviour. Likewise, scratching was attenuated by oral (0.3-3-30 mg/kg) or topical application (0.01-0.1-1% w/v) of aprepitant and pharmacokinetic analysis of aprepitant levels in brain, blood and skin supported that efficacy of topically applied aprepitant was due to dermal rather than central target engagement. In conclusion, we showed that NK1 agonist-induced scratching in the gerbil can be reversed by systemic and topical administration of aprepitant. This test system may provide a useful model for the in vivo assessment of putative antipruritic agents.

Ventral striatal plasticity and spatial memory.

Spatial memory formation is a dynamic process requiring a series of cellular and molecular steps, such as gene expression and protein translation, leading to morphological changes that have been envisaged as the structural bases for the engram. Despite the role suggested for medial temporal lobe plasticity in spatial memory, recent behavioral observations implicate specific components of the striatal complex in spatial information processing. However, the potential occurrence of neural plasticity within this structure after spatial learning has never been investigated. In this study we demonstrate that blockade of cAMP response element binding protein-induced transcription or inhibition of protein synthesis or extracellular proteolytic activity in the ventral striatum impairs long-term spatial memory. These findings demonstrate that, in the ventral striatum, similarly to what happens in the hippocampus, several key molecular events crucial for the expression of neural plasticity are required in the early stages of spatial memory formation.

Cognitive and neural determinants of response strategy in the dual-solution plus-maze task.

Response strategy in the dual-solution plus maze is regarded as a form of stimulus-response learning. In this study, by using an outcome devaluation procedure, we show that it can be based on both action-outcome and stimulus-response habit learning, depending on the amount of training that the animals receive. Furthermore, we show that deactivation of the dorso-medial and the dorso-lateral striatum with Botulinum neurotoxin A, mimicked or abolished, respectively, the effects of practice on the sensitivity of the response strategy to outcome devaluation. These findings have relevant implications for the understanding of the learning mechanisms underlying different overt behaviors in this widely used maze task.

A Niclosamide-releasing hot-melt extruded catheter prevents Staphylococcus aureus experimental biomaterial-associated infection.

Biomaterial-associated infections are a major healthcare challenge as they are responsible for high disease burden in critically ill patients. In this study, we have developed drug-eluting antibacterial catheters to prevent catheter-related infections. Niclosamide (NIC), originally an antiparasitic drug, was incorporated into the polymeric matrix of thermoplastic polyurethane (TPU) via solvent casting, and catheters were fabricated using hot-melt extrusion technology. The mechanical and physicochemical properties of TPU polymers loaded with NIC were studied. NIC was released in a sustained manner from the catheters and exhibited in vitro antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis. Moreover, the antibacterial efficacy of NIC-loaded catheters was validated in an in vivo biomaterial-associated infection model using a methicillin-susceptible and methicillin-resistant strain of S. aureus. The released NIC from the produced catheters reduced bacterial colonization of the catheter as well as of the surrounding tissue. In summary, the NIC-releasing hot-melt extruded catheters prevented implant colonization and reduced the bacterial colonization of peri-catheter tissue by methicillin sensitive as well as resistant S. aureus in a biomaterial-associated infection mouse model and has good prospects for preclinical development.

GSK1614343, a novel ghrelin receptor antagonist, produces an unexpected increase of food intake and body weight in rodents and dogs.

Ghrelin is a 28-amino-acid polypeptide expressed in the stomach and hypothalamus that stimulates GH secretion, increases food intake (FI) and promotes body weight (BW) gain most likely via activation of the growth hormone secretagogue receptor type 1a (GHSR1a). GSK1614343 is a novel selective and potent GHSR antagonist with no partial agonist properties, recently characterized as GH secretion inhibitor by Sabbatini et al. [Chem Med Chem 2010;5:1450-1455]. In the present study, GSK1614343 (10 mg/kg) was not able to antagonize ghrelin-induced food consumption in rat, but unexpectedly stimulated FI and BW gain in both rats and dogs, a profile associated with decreased ghrelin plasma level. Interestingly, GSK1614343 selectively reduced the pro-opiomelanocortin mRNA levels in rat hypothalami chronically treated with the compound. To better understand the observed effects, we administered GSK1614343 (30 mg/kg) to Ghsr null mice and measured body mass components (fat, lean and free fluid) by using a NMR spectrometer. The increases of FI and BW were abolished in Ghsr null mice, while fat and lean masses increased in wild-type mice. Taken together, these results indicate that the orexigenic effect of GSK1614343 is mediated by GHSR1a and that the weight gain could be attributed to the increase of both adiposity and muscle mass, but not to fluid retention. The observed dissociation between effects on GH secretion and effects on FI/BW is inconsistent with a simple hormone-receptor model, suggesting unknown underlying regulations of the ghrelin system whose understanding require further investigation.

Selective PDE inhibitors rolipram and sildenafil improve object retrieval performance in adult cynomolgus macaques.

RATIONALE: Selective phosphodiesterase (PDE) inhibitors improve the formation of hippocampus-dependent memories in several rodent models of cognition. However, studies evaluating the effects of PDE inhibition on prefrontal cortex-dependent cognition and in monkeys are rare. OBJECTIVES: The present study investigates the effect of the PDE4 inhibitor rolipram and the PDE5 inhibitor sildenafil on object retrieval performance. Object retrieval is a prefrontal cortical-mediated task, which is likely to capture attention and response inhibition. MATERIALS AND METHODS: The ability to retrieve a food reward from a clear box with an open side positioned in various orientations was assessed in adult male cynomolgus monkeys (Macaca fascicularis). RESULTS: Rolipram (0.003-0.03 mg/kg, intramuscular [i.m.]) and sildenafil (0.3-3 mg/kg, i.m.) dose-dependently increased correct first reaches during difficult trials, reaching significance at 0.01 and 1 mg/kg, respectively. For both drugs, correct reaches were increased approximately 20%; that is, performance was improved from approximately 50 to approximately 70% correct. CONCLUSIONS: Both rolipram and sildenafil improved object retrieval performance, thus demonstrating the cognition-enhancing effects of PDE inhibition on a prefrontal task of executive function in monkeys.

Co-activation of glutamate and dopamine receptors within the nucleus accumbens is required for spatial memory consolidation in mice.

RATIONALE: The nucleus accumbens receives glutamatergic and dopaminergic inputs converging onto common dendrites. Recent behavioral data demonstrated that intra-accumbens administrations of either glutamate or dopamine (DA) antagonist impair spatial memory consolidation. Thus, also based on the biochemical and molecular findings demonstrating interactions among the different receptors subtypes for glutamate and dopamine, it is conceivable that memory consolidation within this structure might be modulated by glutamate-dopamine receptor interactions. OBJECTIVES: The purpose of this study was to examine the effects of intra-accumbens co-administrations of glutamate and DA antagonists on the consolidation of spatial information. METHODS: On day 1, CD1 male mice were placed in an open field containing five different objects and immediately after three sessions of habituation the animals were injected intra-accumbens with either vehicle or low doses of the N-methyl-D: -aspartate (NMDA; AP-5 50 ng/side), the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA; DNQX 5 ng/side), the D1 (SCH23390 12.5 ng/side) and the D2 (sulpiride 25 ng/side) antagonists that were ineffective alone in disrupting object displacement. Separate groups were then focally injected with a combination of one of the glutamate antagonists with one of the dopamine antagonists. Twenty-four hours later, the ability of mice to discriminate object displacement was assessed. RESULTS: Controls and mice injected with ineffective doses of the NMDA, the AMPA, the D1 or the D2 antagonists were always able to react to the object displacement. On the contrary, the groups administered with the different combinations (AP-5 and SCH23390, AP-5 and sulpiride, DNQX and SCH23390, DNQX and sulpiride) of glutamate and dopamine antagonists did not discriminate the spatial change. CONCLUSIONS: These results demonstrate that glutamate-dopamine receptor interactions within the accumbens are essential for the consolidation process of spatial information.

Automatic quantification of withdrawal from 5-day diazepam in rats: ultrasonic distress vocalizations and hyperreflexia to acoustic startle stimuli.

The purpose of the present work was to develop an objective and precise method to quantify withdrawal responses from anxiolytics relying on ethologically valid responses. Behavioral effects of diazepam withdrawal in rats are automatically measured that appear to correspond to clinically relevant disturbances in affective and sensory-motor functions. Ultrasonic vocalizations and startle reflexes in response to acoustic stimuli were measured as indices of withdrawal 24 h after 5 days of 2.5, 5 or 10 mg/kg diazepam, b.i.d., IP in male Long-Evans rats. About 60% of male rats emit 22-26 kHz ultrasonic calls when exposed to acoustic startle stimuli (18 presentations, 9 at 105 dB and 9 at 115 dB, each 30 s apart on average). Diazepam-withdrawn rats exhibited startle responses with larger maximal and average amplitude and emitted more frequent 22-26 kHz ultrasonic vocalizations than vehicle-treated control animals. The magnitude of the withdrawal changes in ultrasonic calls and in startle reflex amplitude increased significantly already at the low 2.5 mg/kg diazepam dose in spite of considerable individual variability. The increased ultrasound rates during diazepam withdrawal contrast with the suppressive effects of acutely administered diazepam in drug-naive rats. The current methodology offers the opportunity to more adequately characterize withdrawal from anxiolytic substances in a quantitative, objective and automated manner.

Morphine attenuates ultrasonic vocalization during agonistic encounters in adult male rats.

Ultrasonic vocalizations (USV) in rats may communicate "affective" states during pain, sex and aggression. This proposal was evaluated in an experiment with adult male Long-Evans rats during agonistic encounters; specifically, morphine and naltrexone effects were studied on different types of USV by intruder rats exposed to resident attacks and to "threat of attacks" (i.e., intruder residing within the home cage of the resident but prevented from physical contact by a wire mesh cage). Intruders readily emitted USV during agonistic encounters. These calls consisted primarily of two distinct distributions of pure tone whistles: 0.3-3 s, 19-32 kHz ("low") calls and 0.02-0.3 s, 32-64 kHz ("high") calls. Sonographic analysis revealed a considerable repertoire of frequency modulated calls. Different types of vocalizations proved to be differentially sensitive to the opiate treatments: morphine (1-10 mg/kg SC) dose-dependently decreased the rate, duration and pitch of both low and high frequency USV during the threat of attack; this decrease in rate and duration measures was naltrexone-reversible (0.1 mg/kg IP). Interestingly, audible vocalizations were also emitted but were unaffected by morphine in this dose range. Concomitant with the decrease in USV after morphine was a dose-dependent decrease in rearing, walking and nasal contact behavior with increases in submissive crouch behavior and tail flick analgesia. The decreases in rate and duration of both low and high USV and the pitch of specific frequency modulated calls after morphine administration may reflect an attenuation of affective aspects of pain, and the many characteristics of US (rate, duration, pitch, frequency modulation, pre-and suffix attributes and temporal structure) point to potentially diverse functions.(ABSTRACT TRUNCATED AT 250 WORDS)

Diazepam and gepirone selectively attenuate either 20-32 or 32-64 kHz ultrasonic vocalizations during aggressive encounters.

Ultrasonic vocalizations (USV) in rats may communicate "affective" states, as they occur only in highly significant behavioral contexts such as during sex, aggression, exposure to painful or startling events. This proposal was evaluated in an experiment with adult male Long-Evans rats during agonistic encounters; specifically, the effects of diazepam, flumazenil and gepirone were studied on different types of USV emitted by intruder rats exposed to resident attacks and to "threat of attacks" (i.e., intruder protected within the home cage of the resident by a wire mesh cage). USV were readily emitted during agonistic encounters and consisted primarily of two distributions of pure tone whistles: 0.3- to 3-s, 20- to 32-kHz ("low") signals and 0.02- to 0.3-s, 32- to 64-kHz ("high") signals. A considerable repertoire of frequency modulated signals was observed and proved to be sensitive to the anxiolytic treatments. Diazepam (1-6 mg/kg) dose-dependently decreased high frequency USV during the threat of attack and decreased the mean pitch of the most predominant vocalizations but did not affect low frequency USV or the audible squeals (AS) in response to bites. Gepirone (0.3-6 mg/kg) dose-dependently decreased low frequency USV and did not affect high frequency USV or AS. Responses to thermal pain stimuli remained unaltered by all drugs, while walking duration was decreased and crouch postures were increased after diazepam but not after gepirone administration. Gepirone in the present dose range had minimal effects on submissive, exploratory and locomotor behaviors. The pattern of results is consistent with the proposal that low frequency USV reflect a heightened affective state which is ameliorated with 5HT1A but not benzodiazepine anxiolytics, and suggests that the suppression of high frequency USV in reaction to attacks or threats coincides with the sedative or muscle relaxant properties of these compounds.

Ultrasounds during morphine withdrawal in rats.

Ultrasounds (US) in rats may communicate affective states, as they occur only in highly significant situations such as maternal care, sex and aggression. Withdrawal from morphine is a manipulation which dramatically alters autonomic, somatic and motor functions; the present experiment demonstrated the production of US in this context and the influence of previous social experience in their production. Sixty male Long-Evans rats with distinct social experiences (social inexperience, defeat or copulation) underwent 72 h of continuous morphine exposure (4 x 75 mg morphine or placebo pellets) and subsequent withdrawal. The rats were observed for 10 min in equally treated pairs and while solitary at 6, 24 and 96 h after pellet removal. US were emitted by all groups and consisted primarily of two distributions of pure tone whistles with little frequency modulation: 1-2 s 21-25 kHz ("low") signals and the more prevalent 0.02-0.1 s 44-52 kHz ("high") signals. Morphine withdrawn rats lost weight, displayed wet dog shakes, were hypoactive and emitted threefold more US vocalizations with a fourfold greater duration than placebo controls. Defeat-experienced morphine withdrawn rats were more hypoactive than either socially inexperienced or copulatory experienced rats while increasing vocalization rates and total duration. This increased duration of ultrasounds included a shift in the distribution of individual US durations from less than 0.3 s to greater than 1.0 s. US are readily emitted at high rates in morphine withdrawn laboratory rats, which may implicate an opioid involvement in their generation.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of mu and delta opioid agonists and antagonists on affective vocal and reflexive pain responses during social stress in rats.

The present experiments evaluated the influence of intraventricular mu and delta opioid receptors on affective vocal and reflexive responses to aversive stimuli in socially inexperienced, as well as defensive and submissive responses in defeated, adult male Long-Evans rats. Defeat stress consisted of: (1) an aggressive confrontation in which the experimental intruder rat exhibited escape, defensive and submissive behaviors [i.e., upright, supine postures and ultrasonic vocalizations (USV)], and subsequently, (2) protection from the resident stimulus rat with a wire mesh screen for 10-20 min. Defeat stress was immediately followed by an experimental session with tactile startle (20 psi). The mu opioid receptor agonists morphine (0.1-0.6 microg i.c.v.) and [D-Ala2-N-Me-Phe4-Gly5-ol]-enkephalin (DAMGO; 0.01-0.3 microg i.c.v.), and the delta opioid receptor agonist [D-Pen2,5]-enkephalin (DPDPE; 10-100 microg i.c.v.) dose-dependently decreased startle-induced USV and increased tail-flick latencies in socially inexperienced and defeated rats. Of greater interest, morphine, DAMGO and DPDPE increased the occurrence of the submissive crouch posture, and defeated rats were more sensitive than socially inexperienced rats to the startle-induced USV-suppressive and antinociceptive effects of morphine and DPDPE. The antinociceptive effects of DAMGO were likewise obtained at lower doses in defeated rats. Finally, the USV-suppressive effects of morphine and DAMGO were reversed with the mu receptor antagonist naltrexone (0.1 mg/kg i.p.), but the USV-suppressive effects produced by DPDPE were not reversed with the delta receptor antagonist naltrindole (1 mg/kg i.p.). These results confirm mu, but not delta opioid receptor activation as significant in affective vocal, passive-submissive behavior, as well as reflexive antinociception. Furthermore, similar to previous studies with restraint and electric shock stress, the facilitation of mu opioid effects on vocal responses and antinociception is consistent with the proposal that defeat stress activated endogenous opioid mechanisms.

Interactions between social stress and morphine in the periaqueductal gray: effects on affective vocal and reflexive pain responses in rats.

RATIONALE: Endogenous opioid systems within the mesencephalic periaqueductal gray matter (PAG) appear to be intricately involved in many affective, defensive, submissive, and reflexive responses, and these systems are activated by aversive stimuli. OBJECTIVES: The present experiments evaluated the influence of opioid receptors within the PAG on affective vocal and reflexive responses to aversive stimuli in socially inexperienced, as well as defensive and submissive responses in defeated, adult male Long-Evans rats. METHODS: Defeat stress consisted of: (1) an aggressive confrontation with a "resident" stimulus rat in which the experimental "intruder" rat exhibited escape, defensive and submissive behaviors [i.e. upright, supine postures and ultrasonic vocalizations (USV)], and subsequently, (2) protection from the resident rat with a wire mesh screen for ca. 25 min. Defeat stress was immediately followed by an experimental session with thermal antinociceptive and tactile startle stimuli (20 psi airpuffs). RESULTS: The mu opioid receptor agonist morphine (0.3, 1, 3 microgram IC) attenuated startle-induced USV and the tail-flick reflex in socially inexperienced and defeated rats, with both groups of rats demonstrating equal sensitivity to morphine. Morphine decreased defeat-induced USV and increased the display of the crouch posture in defeated rats; these morphine effects in socially inexperienced and defeated rats were re- versed with the opioid receptor antagonist naltrexone (0.1 mg/kg IP). CONCLUSIONS: These results reveal that the ventrolateral PAG is an important site in which mu opioid receptor agonists such as morphine mediate affective vocal and submissive responses, yet this structure is not critical in the display of defeat stress-augmented effects of morphine. Endogenous opioid mechanisms appear to participate in the organization of defensive behavior, namely, to facilitate a shift from active to passive forms of coping.

Defeat engenders pentylenetetrazole-appropriate responding in rats: antagonism by midazolam.

Defeat and the threat of defeat by an aggressive conspecific is stressful and may engender an anxiety- or fear-like state in animals; the present experiment investigated whether defeat generalized to the discriminative stimulus properties of PTZ and how benzodiazepine receptors were involved in this generalization. Separate groups of male Long-Evans rats (Rattus norvegicus) were trained to discriminate 20 mg/kg pentylenetetrazole (PTZ) or 0.4 mg/kg midazolam (MDZ) from saline in a two-choice drug-discrimination task. After establishing stimulus control, PTZ- and MDZ-trained rats were exposed to an aggressive conspecific which resulted in defeat, as defined by the display of defensive and submissive postures as well as audible and ultrasonic vocalizations. Administration of saline after defeat resulted in greater than 80% PTZ lever selection in 15 out of 25 PTZ-trained rats; this effect was attenuated through pretreatment with MDZ (1 mg/kg). Furthermore, short-term defeat substitution for the PTZ discriminative stimulus was not accompanied by long-term changes in the post-defeat generalization curves for PTZ and MDZ when compared to pre-defeat generalization curves. Nor did defeat alter the antagonism of PTZ by diazepam (2.5 mg/kg) or MDZ by flumazenil (10 mg/kg). In order further to characterize the necessary features for defeat substitution for the PTZ discriminative stimulus, exposure to a threatening conspecific was also attempted by PTZ-trained rats protected from physical contact with a wire mesh cage. In these tests, saline continued to engender greater than 50% PTZ lever responding in 15 of 25 rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Diazepam withdrawal: effects of diazepam and gepirone on acoustic startle-induced 22 kHz ultrasonic vocalizations.

It has proven difficult to demonstrate and study the "anxiogenic" quality of drug withdrawal states in animals. Ultrasonic vocalizations (USV) in response to acoustic startle stimuli have shown promise as a measure of affect and may represent "distress" responses during diazepam withdrawal. Three experiments evaluated the association between USV and "distress" by comparing the effects of diazepam as a prototypic benzodiazepine agonist and the putative anxiolytic gepirone with affinity for 5-hydroxytryptamine (5-HT1A) receptors in naive and diazepam-withdrawn subjects. Adult male Long-Evans rats were exposed to acoustic startle sessions consisting of nine 105 dB and nine 115 dB stimuli. USV at 20-30 kHz were readily emitted during startle and often commenced after the third or fourth stimulus presentation. Acutely, intraperitoneal (IP) administration of diazepam (0.1-3 mg/kg) and gepirone (0.1-1 mg/kg) decreased USV dose-dependently without affecting the startle reflex; gepirone also decreased tail flick latency. Startle-induced USV were also sensitive to the "anxiogenic" effects of withdrawal from diazepam exposure (0, 2.5, 5, 10 mg/kg b.i.d. IP x 5 days). Twenty-four hours after the last diazepam injection, rats were hyperreactive to startle stimuli and doubled their rate of USV over vehicle-treated controls. Gepirone (0.1-1 mg/kg IP), but not diazepam (3-20 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 10 mg/kg b.i.d. diazepam. Diazepam (2.5-10 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 2.5 mg/kg b.i.d. diazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic effects of E-2078, a stabilized dynorphin A(1-8) analog, in rhesus monkeys.

RATIONALE: E-2078 ([N-methyl-Tyr1, N-methyl-Arg7, D-Leu8] dynorphin A(1-8) ethylamide) is a dynorphin A(1-8) analog with a reduced tendency to be biotransformed, when compared to the unmodified opioid peptide. E-2078 has been found to produce kappa-opioid agonist effects in vivo in rodents. OBJECTIVE: In the present studies, we investigated whether systemically administered E-2078 could produce kappa-agonist effects in rhesus monkeys, in tests of antinociception, diuresis and ethyl-ketocyclazocine (EKC) discrimination. METHODS: E-2078 (0.32-18 mg/kg, SC, IM or IV) was tested in the warm water (50 degrees, 55 degrees C) tail withdrawal assay of thermal antinociception. The diuretic effects of E-2078 (0.056-1.8 mg/kg, SC) were also compared to those of the kappa-agonist, U69,593 (0.01-0.32 mg/kg, SC). Lastly, the effects of E-2078 (0.1-3.2 mg/kg, SC or IV) were studied in rhesus monkeys trained to discriminate EKC (0.0056 mg/kg SC) from vehicle, in a food-reinforced operant procedure. RESULTS: E-2078 did not produce thermal antinociception in rhesus monkeys following SC or IM administration, up to the largest doses presently studied (i.e., 18 and 10 mg/kg, respectively). E-2078 caused thermal antinociception by the IV route, but this effect was not apparently mediated by kappa- or mu-opioid receptors, as shown by its insensitivity to quadazocine (1 mg/kg) pretreatment. However, SC E-2078 caused diuresis, and this effect was blocked by quadazocine pretreatment, consistent with mediation by kappa-opioid receptors. E-2078 generalized in EKC-discriminating monkeys, but only after the largest dose (3.2 mg/kg), and only following IV administration. CONCLUSIONS: The present studies suggest that systemically administered E-2078 can produce some kappa-receptor mediated effects in rhesus monkeys, but its profile of action is not identical to non-peptidic kappa-agonists following all routes of administration, or across all experimental situations.

Aggression, anxiety and vocalizations in animals: GABAA and 5-HT anxiolytics.

A continuing challenge for preclinical research on anxiolytic drugs is to capture the affective dimension that characterizes anxiety and aggression, either in their adaptive forms or when they become of clinical concern. Experimental protocols for the preclinical study of anxiolytic drugs typically involve the suppression of conditioned or unconditioned social and exploratory behavior (e.g., punished drinking or social interactions) and demonstrate the reversal of this behavioral suppression by drugs acting on the benzodiazepine-GABAA complex. Less frequently, aversive events engender increases in conditioned or unconditioned behavior that are reversed by anxiolytic drugs (e.g., fear-potentiated startle). More recently, putative anxiolytics which target 5-HT receptor subtypes produced effects in these traditional protocols that often are not systematic and robust. We propose ethological studies of vocal expressions in rodents and primates during social confrontations, separation from social companions, or exposure to aversive environmental events as promising sources of information on the affective features of behavior. This approach focuses on vocal and other display behavior with clear functional validity and homology. Drugs with anxiolytic effects that act on the benzodiazepine-GABAA receptor complex and on 5-HT1A receptors systematically and potently alter specific vocalizations in rodents and primates in a pharmacologically reversible manner; the specificity of these effects on vocalizations is evident due to the effectiveness of low doses that do not compromise other physiological and behavioral processes. Antagonists at the benzodiazepine receptor reverse the effects of full agonists on vocalizations, particularly when these occur in threatening, startling and distressing contexts. With the development of antagonists at 5-HT receptor subtypes, it can be anticipated that similar receptor-specificity can be established for the effects of 5-HT anxiolytics.

Oral self-administration of ethanol, phencyclidine, methadone, pentobarbital and quinine in rhesus monkeys.

RATIONALE: Simultaneous and sequential drug use among clinical populations is the norm, whereas the pattern of self-administration of multiple drugs among non-human primate populations has not been thoroughly explored. OBJECTIVES: To determine the relationship between the preferences and intakes of a large group of rhesus monkeys exposed to various orally available solutions. METHODS: Thirteen male and eleven female young adult rhesus monkeys (Macaca mulatta) were exposed to orally available drug solutions using a concurrent choice (drug and water) procedure, where fluid delivery was made contingent upon single spout contacts (fixed ratio one). RESULTS: Ethanol (0.25-16% w:v) produced biphasic effects on the number of fluid deliveries obtained, with peak ethanol preferences over water demonstrated at the 1-2% w:v concentrations. No preferences for the N-methyl-d-aspartate receptor antagonist phencyclidine or water were demonstrated at lower concentrations (0. 0078125-0.125 mg/ml) and, at higher concentrations (0.25, 0.5 mg/ml), a preference for water was demonstrated. The mu opioid receptor agonist methadone (0.001-0.3 mg/ml) and the prototypic bitter substance quinine (0.001-0.3 mg/ml) failed to produce preferences for drug or water. A large preference for water over the barbiturate pentobarbital (0.01-3 mg/ml) was also demonstrated. After rank-ordering the subjects based on their drug preferences or intakes, modest to no correlations across drugs were demonstrated. CONCLUSIONS: These results reveal that a robust ethanol preference is not predictive of a preference for drugs of abuse from other classes and suggests that fluid intakes were correlated, irrespective of the presence or absence of drug in the solution.

Diabetic home blood glucose monitoring using a direct reading glucose sensitive test strip.

The aim of this study was to assess the performance of the BM Test Glycemie 20-800. Twelve diabetic patients were studied using the BM Test Glycemie 20-800, compared with one of the commonly available reflectance meters. The correlation coefficient for the BM 20-800 strip versus reference blood glucose result was significantly better than the reflectance meter (p = 0.01). In a separate study, laboratory staff tested both methods and achieved results which were similar to those of the patients using the BM Test Glycemie 20-800, but better than those of the patients using the reflectance meters. The BM Test Glycemie 20-800 is a cheap, reliable and acceptable method for the measurement of blood glucose levels.

Role of orexin-1 receptor mechanisms on compulsive food consumption in a model of binge eating in female rats.

Orexins (OX) and their receptors (OXR) modulate feeding, arousal, stress, and drug abuse. Neural systems that motivate and reinforce drug abuse may also underlie compulsive food seeking and intake. Therefore, the effects of GSK1059865 (5-bromo-N-[(2S,5S)-1-(3-fluoro-2-methoxybenzoyl)-5-methylpiperidin-2-yl]methyl-pyridin-2-amine), a selective OX(1)R antagonist, JNJ-10397049 (N-(2,4-dibromophenyl)-N'-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]urea), a selective OX(2)R antagonist, and SB-649868 (N-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-1-benzofuran-4-carboxamide), a dual OX(1)/OX(2)R antagonist were evaluated in a binge eating (BE) model in female rats. BE of highly palatable food (HPF) was evoked by three cycles of food restriction followed by stress, elicited by exposing rats to HPF, but preventing them from having access to it for 15 min. Pharmacokinetic assessments of all compounds were obtained under the same experimental conditions used for the behavioral experiments. Topiramate was used as the reference compound as it selectively blocks BE in rats and humans. Dose-related thresholds for sleep-inducing effects of the OXR antagonists were measured using polysomnography in parallel experiments. SB-649868 and GSK1059865, but not JNJ-10397049, selectively reduced BE for HPF without affecting standard food pellet intake, at doses that did not induce sleep. These results indicate, for the first time, a major role of OX(1)R mechanisms in BE, suggesting that selective antagonism at OX(1)R could represent a novel pharmacological treatment for BE and possibly other eating disorders with a compulsive component.