Discovery of S-777469: an orally available CB2 agonist as an antipruritic agent

The discovery of novel CB2 ligands based on the 3-carbamoyl-2-pyridone derivatives by adjusting the size of side chain at 1-, 5- and 6-position is reported. The structure-activity relationship around this template lead to the identification of S-777469 as a selective CB2 receptor agonist, which exhibited the significant inhibition of scratching induced by Compound 48/80 at 1.0 mg/kg po and 10 mg/kg po (55% and 61%, respectively).     

A selective androgen receptor modulator with minimal prostate hypertrophic activity restores lean body mass in aged orchidectomized male rats

Androgens are required for the maintenance of normal sexual activity in adulthood and for enhancing muscle growth and lean body mass in adolescents and adults. Androgen receptor (AR) ligands with tissue selectivity (selective androgen receptor modulators, or SARMs) have potential for treating muscle wasting, hypogonadism of aging, osteoporosis, female sexual dysfunction, and other indications. JNJ-37654032 is a nonsteroidal AR ligand with mixed agonist and antagonist activity in androgen-responsive cell-based assays. It is an orally active SARM with muscle selectivity in orchidectomized rat models. It stimulated growth of the levator ani muscle with ED(50) 0.8 mg/kg, stimulating maximal growth at a dose of 3mg/kg. In contrast, it stimulated ventral prostate growth to 21% of its full size at 3mg/kg. At the same time, JNJ-37654032 reduced prostate weight in intact rats by 47% at 3mg/kg, while having no inhibitory effect on muscle. Using magnetic resonance imaging to monitor body composition, JNJ-37654032 restored about 20% of the lean body mass lost following orchidectomy in aged rats. JNJ-37654032 reduced follicle-stimulating hormone levels in orchidectomized rats and reduced testis size in intact rats. JNJ-37654032 is a potent prostate-sparing SARM with the potential for clinical benefit in muscle-wasting diseases.     

Effects of oral administration of tamoxifen, toremifene, dehydroepiandrosterone, and vorozole on uterine histomorphology in the rat

Tamoxifen, toremifene, DHEA, and vorozole inhibit tumor growth in rodent mammary carcinoma models and are promising chemotherapeutic agents for use against breast cancer development. In the present study, the effect of these agents on uterine histomorphology following oral administration to mature ovary-intact rats (n = 380) was examined. Animals received diet only (control), tamoxifen (0.4 and 1 mg/kg of diet; 10 mg/kg BW by daily gavage), toremifene (3-30 mg/kg of diet), DHEA (24-2000 mg/kg of diet), or vorozole (0.08-1.25 mg/kg BW by daily gavage) for 28 days and were either sacrificed or returned to a basal diet and then sacrificed 21 days later. Treatment with toremifene (all doses) or tamoxifen (1 and 10 mg/kg) for 28 days produced a decrease (P<0.05) in overall uterine size and myometrial thickness; however, uterine luminal and glandular epithelia cell height increased (P<0.05) compared with control. These compartmentalized uterotrophic and antiestrogenic effects of toremifene and tamoxifen were still apparent after 21 days post-treatment. Administration of DHEA (2000 mg/kg of diet) for 28 days had dramatic uterotrophic effects, increasing (P<0.05) overall uterine size and stimulating all three uterine compartments (epithelia, stroma, and myometrium). The other doses of DHEA, however, were not uterotrophic. Interestingly, after removal of DHEA from the diet, uterine weight and myometrial thickness decreased (P<0.05). Vorozole (1.25 mg/kg) administration for 28 days had differential, compartmentalized uterine effects, producing an increase (P<0.05) in epithelial cell height, a decrease (P<0.05) in stromal size, but no change in myometrial thickness. After 21 days postadministration of vorozole, luminal epithelial cell height was increased (P<0.05) compared with control. The data suggest that oral administration of tamoxifen, toremifene, DHEA, and vorozole results in differential, compartmentalized effects in the uterus that are highly dependent on treatment dose. The data may have implications for risk assessment of these agents prior to administration to healthy, cancer-free women.     

Acetylcholine Release in the Rat Prefrontal Cortex In Vivo: Modulation by α2-Adrenoceptor Agonists and Antagonists

Abstract: We have previously shown that the release of acetylcholine (ACh) in the medial prefrontal cortex of the conscious rat, as measured by microdialysis, is increased following intraperitoneal injection of the selective α₂-adrenoceptor antagonist (+)-efaroxan. To characterize further the receptor pharmacology of this response, the effects of other selective α₂-adrenoceptor ligands were examined. The α₂-adrenoceptor antagonists idazoxan (2.5 and 20 mg/kg), atipamezole (2.5 mg/kg), and fluparoxan (10 mg/kg) increased ACh outflow by up to 250–325% of basal levels over a 3-h period following intraperitoneal injection. The α₂-adrenoceptor agonists UK-14304 (2.5 mg/kg) and guanabenz (2.5 mg/kg) reduced ACh outflow by 80 and 60%, respectively. Clonidine (0.00063–0.16 mg/kg) had no significant depressant effect and at 2.5 mg/kg increased ACh outflow to 233% of basal levels. These results indicate a modulatory role for α₂-adrenoceptors on the release of ACh in the rat prefrontal cortex in vivo. Based on the facilitatory effects produced by the antagonists alone, this α₂-adrenoceptor modulation appears to be tonic and inhibitory. The ability of α₂-adrenoceptor antagonists to enhance ACh outflow suggests a therapeutic usefulness in disorders where cortical ACh release deficits have been implicated.     

Increase in the Extracellular Histamine Concentration in the Rat Striatum by μ-Opioid Receptor Activation

Abstract: The effects of morphine and selective ligands for μ-, κ-, and δ-opioid receptors on the extracellular histamine (HA) concentration in the striatum of freely moving rats were examined by in vivo microdialysis. On the day after implantation of the dialysis probe, the HA output per 30-min period was measured using HPLC-fluorometry. Morphine (3.8 mg/kg, s.c.) significantly increased the HA output by ∼200% 1–3 h after treatment. This effect was completely antagonized by naltrexone (1.6 mg/kg, s.c.). The HA output decreased to a level below 10% of the basal value by 4 h after treatment with ( S )-α-fluoromethylhistidine (77 mg/kg, s.c.). In such animals, morphine (3.8 mg/kg, s.c.) had no influence on the HA output. [ d -Ala²,MePhe⁴,Gly(ol)⁵]Enkephalin (DAGO; 0.2 µg, i.c.v.), a selective μ-agonist, significantly increased the HA output by ∼150% 0.5–1.5 h after treatment, and this effect was also completely blocked by naltrexone. A selective κ-agonist, U-50,488 (3.8 and 7.6 mg/kg, s.c.), and a selective δ-agonist, [ d -Pen², d -Pen⁵]enkephalin (0.5 and 2 µg, i.c.v.), had no effect on the HA output. These findings suggest that the stimulation of μ-opioid receptors by morphine and DAGO increases the extracellular HA concentration by accelerating HA release from nerve endings.     

Role of 5-hydroxytryptamine1B receptors and 5-hydroxytryptamine uptake inhibition in the cocaine-evoked discriminative stimulus effects in rats.

Mesolimbic dopamine pathways play a critical role in the behavioural effects of cocaine in rodents. Nonetheless, research has also demonstrated involvement of 5-hydroxytryptamine (5-HT; serotonin) transmission in these effects. The present study investigated the ability of selective 5-HT1B receptor ligands and a 5-HT reuptake inhibitor to substitute for or to alter (enhance or antagonise) the discriminative stimulus effects of cocaine. Male Wistar rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline (i.p.) in a two-choice, water-reinforced fixed ratio (FR) 20 drug discrimination paradigm. In substitution tests, the selective 5-HT1B receptor agonist 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94253; 2.5-5 mg/kg, i.p.) and the 5-HT reuptake inhibitor fluoxetine (5-10 mg/kg, i.p.) elicited ca. 40 and 0% drug-lever responding, respectively. In combination experiments, CP 94253 (2.5-5 mg/kg) given with submaximal doses of cocaine (0.3-2.5 mg/kg) produced a leftward shift in the cocaine dose-response curve; pretreatment with CP 94253 (5 mg/kg) prior to a dose of cocaine (2.5 mg/kg) which elicited lower than 40% drug-lever responding, caused full substitution. Fluoxetine (5 and 10 mg/kg) given in combination with a submaximal dose of cocaine (2.5 mg/kg) produced a 100% drug-lever responding. Pretreatment with the 5-HT1B receptor antagonists N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-1,1'-biphenyl-4 carboxamide (GR 127935; 0.5-5 mg/kg, s.c.) and 3-(3-dimethylamino)-propyl)-4-hydroxy-N-[4-(4-pyridinyl)-phenyl]benzamide (GR 55562; 1 mg/kg, s.c.) failed to modulate the dose-effect curve for cocaine (0.6-5 mg/kg). On the other hand, GR 127935 (5 mg/kg) and GR 55562 (1 mg/kg) significantly attenuated the enhancement of cocaine discrimination evoked by a combination of CP 94253 (5 mg/kg) or fluoxetine (5 mg/kg) and cocaine (2.5 mg/kg). These results indicate that 5-HT1B receptors are not directly involved in the cocaine-induced discriminative stimuli in rats. On the other hand, they indicate that pharmacological stimulation of 5-HT receptors--that also seem to be a target for fluoxetine-mediated increase in 5-HT neurotransmission--can enhance the overall effects of cocaine.     

Effects of natalizumab,an α4 integrin inhibitor,on fertility in male and female guinea pigs

BACKGROUND : Natalizumab is a humanized monoclonal immunoglobulin G4 antibody directed against the human α4 integrin subunit disrupting interaction with its ligands. As α4 integrins and/or their ligands appear to be involved in reproductive function, the effects of natalizumab on fertility in male and female guinea pigs were investigated. METHODS : Natalizumab was administered by bolus intravenous injection every other day at doses of 0, 3, 10, and 30 mg/kg. Males began treatment at least 28 days prior to mating until necropsy (approximately 3 to 5 days after mating). Dosing in females was done from gestational day (GD) of an existing pregnancy to GD 30 of a second pregnancy. RESULTS : In male guinea pigs, natalizumab treatment had no effect on sperm parameters, reproductive organ weights, organ-weight ratios, or histology of the testis or epididymis. Natalizumab did not affect the ability of treated males to produce pregnancies in untreated females. In female guinea pigs, no treatment-related changes were seen in uterine weights or ovary weights. Pregnancy rates were reduced in females treated with 30 mg/kg natalizumab, but not those treated with 3 or 10 mg/kg. Pregnancy rates were 63.3, 66.7, 66.7, and 29.6% for groups treated with 0, 3, 10, and 30 mg/kg, respectively. Effects observed at 30 mg/kg were at exposures 36-fold those observed in humans. CONCLUSIONS : Natalizumab had no effects on male fertility, but did result in a reduction in pregnancy rates in females treated with the high dose of 30 mg/kg. Birth Defects Res (Part B)86: 108-116, 2009. © 2009 Wiley-Liss, Inc.     

Metabotropic glutamate receptors and neuroadaptation to antidepressants: imipramine-induced down-regulation of beta-adrenergic receptors in mice treated with metabotropic glutamate 2/3 receptor ligands

Antidepressant drugs have a clinical latency that correlates with the development of neuroadaptive changes, including down-regulation of beta-adrenergic receptors in different brain regions. The identification of drugs that shorten this latency will have a great impact on the treatment of major depressive disorders. We report that the time required for the antidepressant imipramine to reduce the expression of beta-adrenergic receptors in the hippocampus is reduced by a co-administration with centrally active ligands of type 2/3 metabotropic glutamate (mGlu2/3) receptors. Daily treatment of mice with imipramine alone (10 mg/kg, i.p.) reduced the expression of beta-adrenergic receptors in the hippocampus after 21 days, but not at shorter times, as assessed by western blot analysis of beta1-adrenergic receptors and by the amount of specifically bound [3H]CGP-12177, a selective beta-adrenergic receptor ligand. Down-regulation of beta-adrenergic receptors occurred at shorter times (i.e. after 14 days) when imipramine was combined with low doses (0.5 mg/kg, i.p.) of the selective mGlu2/3 receptor agonist LY379268, or with the preferential mGlu2/3 receptor antagonist LY341495 (1 mg/kg, i.p.). Higher doses of LY379268 (2 mg/kg, i.p.) were inactive. This intriguing finding suggests that neuroadaptation to imipramine--at least as assessed by changes in the expression of beta1-adrenergic receptors--is influenced by drugs that interact with mGlu2/3 receptors and stimulates further research aimed at establishing whether any of these drugs can shorten the clinical latency of classical antidepressants.     

Developmental toxicity of orally administered technical dimethoate in rats

BACKGROUND: Dimethoate (O,O-dimethyl-S-(N-methylcarbamoyl-methyl) phosphorodithioate), an organophosphate insecticide, was examined for its potential to produce developmental toxicity in rats after oral administration. METHODS: Pregnant Fischer 344 rats were given sublethal doses of 0 (corn oil), 7, 15, and 28 mg/kg/day dimethoate by gavage on gestation days (GD) 6-15. Maternal effects in 15 and 28 mg/kg/day dose groups included cholinergic signs such as tremors, diarrhea, weakness, and salivation, and depression in the maternal and fetal brain acetylcholinesterase (AChE) activities. Other maternal toxicity that included reduction in body weight and feed consumption was observed only in the treated group of 28 mg/kg/day. No maternal toxicity was apparent in the 7 mg/kg/day dose group. RESULTS: Maternal exposure to dimethoate during organogenesis significantly affected the number of live fetuses, early resorption, and mean fetal weight in the 28 mg/kg/day dose group. No external, visceral, and skeletal abnormalities were observed in any of the treated groups compared to the control. CONCLUSIONS: On the basis of the present results dimethoate can produce clinical signs of toxicity and significant inhibition of the maternal and fetal AChE activities in dose groups of 15 and 28 mg/kg/day and showed fetotoxicity without teratogenic effects at 28 mg/kg/day.     

Antifertility activity and toxicity of alpha-chlorohydrin aromatic ketal analogues in male rats

The antifertility activity and toxicity of alpha-chlorohydrin and seven aromatic ketal derivatives were investigated in male rats. At a dose of 5 mg/kg injected intraperitoneally each day for 14 days, alpha-chlorohydrin and the methoxy benzaldehyde derivative (compound 2) produced complete infertility. The benzaldehyde derivative (compound 1) was 89% effective and the other five compounds 71-25% effective. All compounds except the least effective antifertility agent, the methylbenzaldehyde derivative (compound 3), reduced the motility of sperm recovered from the epididymis. None of the compounds caused a decrease in body or testes weight but some increased adrenal weight.     

Differentiation of phencyclidine and sigma receptor types affecting the central inspiratory termination mechanism in cat

The effects of 1) the phencyclidine receptor ligand TCP, 2) sigma receptor ligands (+)3-PPP and DTG, and 3) N-methyl-D-aspartate receptor blockers MK-801 and dextrorphan were determined on a brainstem mechanism which controls the termination of the inspiratory phase of the breathing cycle. Inspiratory bursts were recorded from the phrenic nerve in decerebrate paralyzed cats ventilated by means of a phrenic driven servoventilator. The central mechanism which terminates inspiration was tested by withholding lung inflation, thus suppressing the contribution of the vagal feedback from the lungs to inspiratory termination. TCP increased the duration of test inspiration (tTi) by 17% at 0.03 mg/kg and by 14-fold (from 1.6 to 23 s) at 1 mg/kg. With dextrorphan, tTi was significantly increased at 3 mg/kg. In contrast, (+)3-PPP and DTG did not increase tTi at doses up to 10 mg/kg, although MK-801 (0.03 mg/kg), given after the sigma ligands, increased tTi by 59-90%. It is concluded that phencyclidine but not sigma receptor ligands block the central mechanism which terminates inspiration and that the likely site of action is the NMDA receptor complex.     

Role of serotonin receptors in the delta-opioid immunosuppression

The present study indicates involvement of serotoninergic (5-HTergic) mechanisms in immunosuppression by DSLET (100 mkg/kg), a selective agonist of the delta2-opioid receptors, in CBA mice. 8-OH-DPAT (0.1 mg/kg), a selective agonist of the 5-HT(1A)-autoreceptors, WAY-100635 (1, 3 mg/kg) and ketanserin (1, 3 mg/kg), a selective antagonists of the postsynaptic 5-HT(1A)- and 5-HT(2A)-receptors, respectively, prevented immunosuppressive effect of DSLET. A possible differential role for 5-HT-receptors in delta-opioid immunosuppression is suggested.     

Repeated Administration of Mirtazapine Attenuates Oxaliplatin-Induced Mechanical Allodynia and Spinal NR2B Up-Regulation in Rats

Chemotherapic drugs may elicit acute or chronic peripheral neuropathies. Mirtazapine, as an antidepressant, is also used for the treatment of neuropathic pain. The current study aimed to investigate the effect of mirtazapine on the oxaliplatin-induced neuropathy in rats as well as the underlying mechanism. A neuropathy model was established in Sprague–Dawley rats by intraperitoneal (i.p.) injection of oxaliplatin 4 mg/kg twice a week for 4 weeks. The therapeutic potential of mirtazapine 10, 20, and 30 mg/kg/day per-orally for 28 consecutive days was evaluated. Subsequently, a dose of 1 mg/kg of WAY100635 i.p., a selective antagonist of 5-HT_1A receptor, was preadministrated before mirtazapine 20 mg/kg/day per-orally in oxaliplatin-induced neuropathy. The behavioral tests and the expression of NMDA receptor subunit NR2B were determined. The results displayed that repeated administration of mirtazapine 20 or 30 mg/kg/day for 28 consecutive days significantly attenuated the mechanical allodynia and the up-regulation of spinal cord NR2B but not the cold hyperalgesia in rats with oxaliplatin-induced neuropathy, which was reversed by WAY100635 preadministration. Our findings suggest that oxaliplatin-induced mechanical allodynia is associated with spinal NR2B up-regulation, which may be attenuated by mirtazapine administration.     

Reduced airway hyperresponsiveness by phosphodiesterase 3 and 4 inhibitors in guinea-pigs

The aim of the present study was to compare the effects of selective phosphodiesterase (PDE) 3, 4 and 5 inhibitors on antigen-induced airway hyperresponsiveness in sensitized guinea-pigs. When the sensitized guinea-pigs were orally pre-treated with the selective PDE4 inhibitor, Ro 20-1724 (30 mg/kg), and studied 48h after OA, a significant reduction (P<0.01) of the leftward shift of the dose-response curve to ACh was noted, whereas it was ineffective at the lower dose (10 mg/kg). Administration of the selective PDE3 inhibitor, milrinone (30 mg/kg) also elicited a significant reduction (P<0.01) of the airway hyperresponsiveness, whereas the PDE5 inhibitor zaprinast (30 mg/kg) was ineffective. These results show that both PDE3 and PDE4 inhibitors are able to inhibit the antigen-induced airway hyperresponsiveness in sensitized guinea-pigs and support the potential utility of selective PDE inhibitors in the treatment of asthma.     

Ribavirin-induced sperm shape abnormalities in Wistar rat.

Ribavirin (1-beta-D-ribofuranosyl-1,2,4, triazole-3 carboxamide) is a broad-spectrum antiviral drug. This study was aimed to investigate the mutagenicity of ribavirin on germ cells by employing sperm morphology assay. Male Wistar rats were treated with water, cyclophosphamide (CP) 40 mg/kg, and ribavirin 20, 100 and 200 mg/kg (i.p.) for 5 consecutive days at intervals of 24h. Following the last exposure, at 14, 28, 35, 42 and 70 days, the epididymal sperm smears were obtained and stained according to the standard procedure. One thousand sperms per animal were classified into normal and different abnormal types. Both CP and ribavirin-induced anomalies of head and tail of sperm except at 70 days. In CP groups, maximum incidence was observed at 28, 35 and 42 days. Ribavirin 20 mg/kg induced maximum incidence at 14 and 42 days, 100 mg/kg at 28 and 42 days and 200 mg/kg at 28-42 days. These results show that ribavirin is mutagenic to rat germ cells in a transient fashion.     

Structure-related inhibitory activity of oleanolic acid glycosides on gastric emptying in mice

We examined the effects of various oleanolic acid oligoglycosides obtained from traditional herbs on gastric emptying in non-nutrient meal- or nutrient meal-loaded mice. Test samples were given orally to fasted mice 0.5 h before loading of test meals. Oleanolic acid 3-O-monodesmosides [oleanolic acid 3-O-glucuronide (3, 12.5-50 mg/kg), momordin Ic (4, 25 and 50 mg/kg), momordin I (6, 12.5-50 mg/kg), and 28-O-deglucosyl-chikusetsusaponins IV (8, 12.5-50 mg/kg) and V (10, 50 mg/kg)] were found to show inhibitory effects on gastric emptying in 1.5% CMC-Na test meal-loaded mice. 4, 6, and 8 also inhibited gastric emptying in mice given 40% glucose test meal, milk test meal, and 60% ethanol test meal. 3 inhibited gastric emptying in mice given milk test meal or 60% ethanol test meal, but lacked significant inhibition in 40% glucose test meal-loaded mice. 10 (50 mg/kg) also slightly inhibited gastric emptying in milk test meal-loaded mice, but lacked the significant inhibition in mice given 40% glucose or 60% ethanol test meal. Whereas oleanolic acid 3,28-0-bisdesmosides [momordin IIc (5), chikusetsusaponins IV (7) and V (9)], oleanolic acid 28-O-monodesmoside [compound O (2)], and their common aglycon [oleanolic acid (1)] showed no such effects at dose of 50 mg/kg. 28-O-Deglucosyl-chikusetsusaponin V (10) showed a little inhibition in these experiments. These results indicate that both the 3-O-monodesmoside structure and 28-carboxyl group were confirmed to be essential for such activity, and the 28-ester glucoside moiety and 2'-O-beta-D-glucopyranoside moiety reduce the activity.     

AT2R agonist NP‐6A4 mitigates aortic stiffness and proteolytic activity in mouse model of aneurysm

Clinical and experimental studies show that angiotensin II (AngII) promotes vascular pathology via activation of AngII type 1 receptors (AT1Rs). We recently reported that NP‐6A4, a selective peptide agonist for AngII type 2 receptor (AT2R), exerts protective effects on human vascular cells subjected to serum starvation or doxorubicin exposure. In this study, we investigated whether NP‐6A4–induced AT2R activation could mitigate AngII‐induced abdominal aortic aneurism (AAA) using AngII‐treated Apoe^?/? mice. Male Apoe^?/? mice were infused with AngII (1 µg/kg/min) by implanting osmotic pumps subcutaneously for 28 days. A subset of mice was pre‐treated subcutaneously with NP‐6A4 (2.5 mg/kg/day) or vehicle for 14 days prior to AngII, and treatments were continued for 28 days. NP‐6A4 significantly reduced aortic stiffness of the abdominal aorta induced by AngII as determined by ultrasound functional analyses and histochemical analyses. NP‐6A4 also increased nitric oxide bioavailability in aortic tissues and suppressed AngII‐induced increases in monocyte chemotactic protein‐1, osteopontin and proteolytic activity of the aorta. However, NP‐6A4 did not affect maximal intraluminal aortic diameter or AAA incidences significantly. These data suggest that the effects of AT2R agonist on vascular pathologies are selective, affecting the aortic stiffness and proteolytic activity without affecting the size of AAA.     

Ginkgo biloba extract enhances male copulatory behavior and reduces serum prolactin levels in rats

The aim of this study was to investigate the effects of Ginkgo biloba extract (EGb 761) on male copulatory behavior in rats. EGb 761 (1 mg/ml) induced significant production of testosterone (T) in rat Leydig cells in vitro. Its effects on sexual behavior were then tested in Long-Evans male rats after 7, 14, 21, or 28 days of oral gavage of vehicle (distilled water) or EGb 761 at doses of 10, 50, or 100 mg/kg. Administration of 50 mg/kg of EGb 761 for 28 days and of 100 mg/kg for 14 or 21 days significantly increased intromission frequency compared to controls on the same day. An increase in ejaculation frequency was seen after treatment with 50 mg/kg of EGb 761 for 14, 21, or 28 days when compared to either the control group on the same day or the same group on day 0. A reduction in ejaculation latency was only seen after administration of 50 mg/kg of EGb 761 for 14 days compared to the vehicle-treated group. After treatment for 28 days, no significant difference was seen in mount latency, intromission latency, serum T levels, reproductive organ weight, sperm number, or levels of the metabolite of dopamine, 3,4-dihydroxyphenylacetic acid in the brain with any dose of EGb 761, but significantly reduced serum prolactin levels and increased dopamine levels in the medial preoptic area and arcuate nucleus were seen at the dose of 50 mg/kg. These findings show that EGb 761 (especially at the dose of 50 mg/kg) enhances the copulatory behavior of male rats and suggest that the dopaminergic system, which regulates prolactin secretion, may be involved in the facilitatory effect of EGb 761.     

Comparison of the effects of serotonin selective,norepinephrine selective,and dual serotonin and norepinephrine reuptake inhibitors on lower urinary tract function in cats

Previous studies showed that the dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitor, duloxetine, increases bladder capacity and urethral sphincter electromyographic (EMG) activity in a cat model of acetic acid-induced bladder irritation. The present study aimed to determine the relative importance of 5-HT versus NE reuptake inhibition for mediating these effects by examining drugs that are selective for either the 5-HT or NE system or both. Similar to duloxetine, venlafaxine (0.1 to 10 mg/kg), also a dual serotonin and norepinephrine reuptake inhibitor, produced marked increases in bladder capacity and EMG activity that were reversed by methiothepin (0.3 mg/kg). S-norfluoxetine (0.01 to 10 mg/kg), a serotonin selective reuptake inhibitor, produced small but significant increases in bladder capacity and EMG activity at doses of 3 and 10 mg/kg. Thionisoxetine (0.01 to 3.0 mg/kg), a NE selective reuptake inhibitor, produced no effects on bladder capacity or sphincter EMG activity. Surprisingly, co-administration of thionisoxetine and s-norfluoxetine up to doses of 1 mg/kg of each compound produced no effect on lower urinary tract function. These doses were the maximum that could be administered in combination due to drug-induced emergence of skeletal muscle activity in chloralose-anesthetized animals. These results indicate that there are unexplained pharmacological differences between the effects of single compounds that exhibit dual NE and 5-HT reuptake inhibition and a combination of compounds that exhibit selective NE and 5-HT reuptake inhibition on lower urinary tract function.     

5-HT3 receptors in selective animal models of cognition

Role of 5-HT3 receptors in cholinergic hypofunctional models of cognitive impairment in the elevated plus maze model and a passive avoidance model is studied. Cognitive impairment was caused by scopolamine (1 mg/kg, ip) in mice and 5-HT3 ligands mCPBG (1 and 5 mg/kg, ip) and ondansetron (0.5 and 5 mg/kg, ip) were administered before the pre-learning phase to study the effects on acquisition, while post-learning administration was used to determine the effects on consolidation. Ondansetron improved acquisition and retention in cholinergic hypofunctional models while mCPBG potentiated selected impaired cognitive indices. The results indicate the role of 5-HT3 receptors in cognition and that an ideal evaluation of 5-HT3 ligands in cognition should distinguish true cognitive effects from locomotor, motivational and emotional effects.