Endotoxin-induced reduction of social investigation by mice: interaction with amphetamine and anti-inflammatory drugs.

Previous studies indicate that some aspects of endotoxin-induced sickness behavior in rats may be mediated by interleukin-1 stimulated events and can be attenuated by corticosteroids, cyclooxygenase inhibitors and the interleukin-1-receptor antagonist. In the current studies, we replicate and extend these findings in adult male mice. A relatively low dose of lipopolysaccharide (LPS; 15 micrograms/kg, IP) was used to reliably induce a 50-60% reduction in the social investigation of a juvenile conspecific at 2-3 h after injection. Amphetamine (2.0-4.0 mg/kg, IP, 30 min pre-LPS) exacerbated LPS-induced decreases in investigation. Administration of methylprednisolone (10-30 mg/kg, IP), indomethacin (3-30 mg/kg, IP), and ibuprofen (1-100 mg/kg, IP) 1 h before LPS significantly reduced LPS-induced sickness behavior at several doses. Dexamethasone (0.1-10 mg/kg, IP) partially antagonized sickness. Representative flavonoids rohitukine (0.01-100.0 mg/kg, IP) and chrysin (0.01-10 mg/kg, IP) also antagonized LPS-induced deficits in social investigation. These studies replicate and extend previous studies in rat to demonstrate systematic effects of low doses of LPS, antagonism by anti-inflammatory drugs and enhancement of LPS effects by amphetamine. The latter findings are consistent with a modulatory role for adrenergic activation on interleukin-1 release stimulated by endotoxicity.

Pharmacological activity and safety profile of P10358, a novel, orally active acetylcholinesterase inhibitor for Alzheimer's disease.

1-[(3-Fluoro-4-pyridinyl)amino]-3-methyl-1(H)-indol-5-yl methyl carbamate (P10358) is a potent, reversible acetylcholinesterase inhibitor that produces central cholinergic stimulation after oral and parental administration in rats and mice. P10358 is a 2.5 times more potent acetylcholinesterase inhibitor than THA in vitro (IC50 = 0.10 +/- 0.02 microM vs. IC50 = 0.25 +/- 0.03 microM). It also inhibits butyrylcholinesterase activity as potently as THA (IC50 = 0.08 +/- 0.05 microM vs. IC50 = 0.07 +/- 0.01 microM). Ex vivo, P10358 (0.2 - 20 mg/kg, p.o.) produced dose-dependent inhibition of brain acetylcholinesterase activity. At 10 and 20 mg/ kg, it produced profound and long-lasting hypothermia in mice. P10358 enhanced performance in rats in a step-down passive avoidance task (0.62 and 1.25 mg/kg) and in a social recognition paradigm (0.32, 0.64 and 1.25 mg/kg) in mice. It reversed scopolamine-induced deficits in the Morris Water maze in rats (1.25 and 2.5 mg/kg) and a higher dose elevated striatal homovanillic acid levels. These behavioral and biochemical effects are consistent with central cholinergic stimulation. Hemodynamic studies in the rat demonstrated a 16-fold separation between behaviorally active doses (1.25 mg/kg) and those that elevated arterial pressure (20 mg/kg). Lethality in rats occurred at an oral dose of 80 mg/kg, but not at lower doses. Chemically, P10358 is an N-aminoindole and may not have the hepatotoxic liability associated with aminoacridine structure of tacrine. P10358 had weak affinity (>10 microM) at a variety of aminergic and peptidergic receptors and uptake carriers. These properties suggest that P10358 may be a safe and promising symptomatic treatment for Alzheimer's disease.

Effects of chronic intrahippocampal infusion of lipopolysaccharide in the rat.

Astrogliosis and microglial activation are associated with many neurodegenerative disorders including multiple sclerosis, its animal model experimental allergic encephalomyelitis, and Alzheimer's disease. To address the hypothesis that chronic astroglial or microglial activation could be contributing factors to neuronal death or injury, the immunostimulant lipopolysaccharide was infused into the hippocampus for 16 days using Alzet mini-osmotic pumps attached to a cannula. Placement of the cannula and infusion of vehicle for 16 days caused a hippocampal lesion with a volume of 0.5 +/- 0.1 mm3. Infusion of lipopolysaccharide at the dose of 2.0 micrograms/day produced a lesion of 4.9 +/- 1.3 mm3 (P < 0.01, Newman-Keuls), whereas, a lower dose of 0.2 microgram/day caused a lesion of 1.3 +/- 0.3 mm3 (P < 0.05). The lesion was defined as a focal necrotic reaction with fibrin deposits outlining an area at an early stage of encapsulation. No apparent neuronal loss was observed by Cresyl Violet staining outside the encapsulated necrotic area. There was a pronounced astrogliosis and an increase in activated macrophages throughout the lipopolysaccharide-infused hippocampus as determined by glial fibrillary acidic protein and ED-1 immunohistochemistry, respectively. Choline acetyltransferase and glutamic acid decarboxylase enzyme activities, used as functional measures of neuronal viability for cholinergic and GABAergic neurons, respectively, were unaffected in the hippocampus following a 16 day infusion of lipopolysaccharide at the doses of 0.2, 0.6 and 2.0 micrograms/day. In addition, unilateral infusion of lipopolysaccharide into the hippocampus did not affect 24 h locomotion when tested on day 13, body temperature or weight gain. Under the experimental conditions employed in the present study, chronic infusion of lipopolysaccharide into the hippocampus resulted in a dose-dependent focal necrotic lesion at the site of infusion. In tissue surrounding the encapsulated lesion, neurons were present among the reactive astrocytes and increased number of macrophages suggesting that astrocytes and macrophages can be activated without causing neuronal loss.

Antipsychotic agents antagonize non-competitive N-methyl-D-aspartate antagonist-induced behaviors.

Antipsychotic agents were tested for their ability to antagonize both dopaminergic-induced and non-competitive N-methyl-D-aspartate (NMDA) antagonist-induced behaviors. All of the agents dose-dependently antagonized the apomorphine-induced climbing mouse assay (CMA) and dizocilpine (MK-801)-induced locomotion and falling assay (MK-801-LF) with a CMA/MK-801-LF ratio of less than or equal to 1.6. However, clozapine and its structural analog olanzapine more potently antagonized MK-801-LF (1.1 and 0.05 mg/kg) than the CMA (12.3 and 0.45 mg/kg) and as a result had a CMA/MK-801-LF ratio of 11.2 and 9, respectively. Furthermore, phencyclidine (PCP) (2 mg/kg) can selectively induce social withdrawal in naive rats that were housed in pairs (familiar) for 10 days prior to testing without affecting motor activity. SCH 23390, raclopride, haloperidol, chlorpromazine and risperidone failed to reverse the social withdrawal induced by PCP up to doses which produced significant motor impairment. However, clozapine (2.5 and 5.0 mg/kg) and olanzapine (0.25 and 0.5 mg/kg) significantly reversed this social withdrawal in rats. Therefore, the non-competitive NMDA antagonists PCP and MK-801 can induce behaviors in Rodents which are selectively antagonized by clozapine and olanzapine. Furthermore, assessment of the effects of antipsychotic agents in the CMA, MK-801-LF and PCP-induced social withdrawal assays may provide a preclinical approach to identify novel agents for negative symptoms and treatment resistant schizophrenia.

D-cycloserine attenuates scopolamine-induced learning and memory deficits in rats.

The muscarinic antagonist scopolamine (SCOP; 1.0 mg/kg, ip) impaired both the acquisition of a learning task in the Morris water maze (MWM) and choice accuracy in the T-maze reinforced alternation procedure in rats. Acetylcholinesterase inhibitors (AChEIs) have been shown to attenuate these deficits. D-Cycloserine (DCS), a partial agonist at the strychnine-insensitive glycine site on the N-methyl-D-aspartate (NMDA) receptor complex, was investigated for its effects on SCOP-induced dementia in the MWM and T-maze paradigms. Combined administration of SCOP and DCS (3.0, 10.0, or 30.0 mg/kg, ip; 30 min pretreat) significantly reversed SCOP-induced deficits in the T-maze as measured by percentage correct choices. In addition, DCS (3.0 or 10.0 mg/kg, ip) significantly attenuated SCOP-induced deficits in the MWM as measured by latency to find the submerged platform. For comparison, the long-acting acetylcholinesterase inhibitor galanthamine (GAL) was tested in the T-maze (1.25, 2.5, or 5.0 mg/kg, ip) and the MWM (2.5 or 5.0 mg/kg, ip). GAL attenuated SCOP-induced deficits in both learning and memory models similar to DCS. These data suggest that the strychnine-insensitive partial glycine agonist, D-cycloserine, may be efficacious in disease states of central cholinergic hypofunction such as Alzheimer's disease.

Nocturnal penile tumescence and penile responses in the waking state in diabetic and nondiabetic sexual dysfunctionals.

This study compared diabetics with sexual dysfunction, nondiabetics with sexual dysfunction, and a group of controls on nocturnal penile tumescence (NPT) during three nights in a sleep laboratory, and penile response to erotic stimulation in the waking state on one of the nights. Both diabetic and nondiabetic dysfunctionals showed less erectile response to erotic films and tape than controls but did not differ from each other. In contrast, the diabetic dysfunctionals showed significantly weaker NPT response than both the nondiabetic dysfunctionals and the controls, and 58% of them (contrasted with 23% of nondiabetic dysfunctionals and 0% of controls) would be classified as organic using minimal NPT (less than 11.5 mm maximal increase in penile circumference during any nocturnal erection) as the sole criterion. There was a significant relationship between NPT and waking erections in response to erotic stimuli, especially in the diabetic dysfunctionals and the controls.

Do endocrines play an etiological role in diabetic and nondiabetic sexual dysfunctions?

Sexually dysfunctional diabetic and nondiabetic males were compared with a group of normal controls using different endocrinological, psychophysiological, and psychological parameters. One hundred male subjects participated in this study: 47 diabetics with sexual dysfunction (DD), 31 nondiabetics with sexual dysfunction (NDD), and 22 normal controls (C). They were evaluated by an internist (physical examination and medical history), a psychologist (psychological and sexual functioning tests), a psychiatrist (psychiatric history and mental status examination), a urologist (genitourinary physical examination), and an endocrine biochemist (evaluation of endocrine factors). Additionally, subjects were evaluated for nocturnal penile tumescence (NPT) during three nights in the sleep laboratory to obtain a differential diagnosis of impotence, that is, psychogenic vs. organic. Both sexually dysfunctional groups showed significant differences on several measures in the psychological and psychophysiological evaluations. There were also significant differences between these two groups and the control group. Plasma levels of total testosterone and serum levels of prolactin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) showed no significant differences among the three groups, but there were some significant correlations between the endocrine and psychological measures. No significant correlations were found between the endocrine and psychophysiological measures.

The Grafenberg spot and female ejaculation: a review of initial hypotheses.

A controversial set of hypotheses have been proposed as an explanation for nonvulval (i.e., nonclitoral) orgasms in women. First, women have a small sensitive area in the anterior wall of the vagina (the Grafenberg spot) which seems to trigger these "deeper" orgasms. Second, stimulation of this area may be associated with ejaculatory response during orgasm. Investigation of these hypotheses was conducted under laboratory conditions in an effort to assess their validity. Eleven women, six of whom claimed to be "ejaculators," were examined by two gynecologists. Gynecologists found an area similar to other descriptions of the Grafenberg Spot in four of the 11 women. It was not found more in ejaculators than nonejaculators. Examination of the ejaculate of six women failed to detect elevated levels of prostatic acid phosphatase and the substance appeared similar in biochemical properties to urine. A number of alternative explanations for the failure to confirm the hypotheses are offered.

A multidisciplinary approach to the evaluation and management of male sexual dysfunction.

We recently established a multidisciplinary center for the evaluation and treatment of male sexual dysfunction. The patients are seen in a single day by the endocrinologist, psychiatrist, psychologist, neurophysiologist and urologist. Laboratory studies include chemical and hormonal profiles, pudendal nerve latency testing and determination of the penile blood pressure. Nocturnal penile tumescence studies are done in selected cases. A diagnosis was made in 95 of 106 patients (90 per cent). The problem was psychogenic in 42 per cent of the patients, vascular and neurologic in 34 per cent, hormonal in 15 per cent, urologic in 7 per cent and medication-related in 2 per cent. The interdisciplinary approach to this problem allows for a more comprehensive and accurate evaluation, while providing a convenient service to the patient.