Eyelash loss in frontal fibrosing alopecia: Microscopic features of two cases.

BACKGROUND: To report two cases of eyelash loss in Frontal Fibrosing Alopecia, providing microscopic description of the eyelashes and possible association with Demodex folliculorum. CASE PRESENTATION: We present two cases of postmenopausal women diagnosed with frontal fibrosing alopecia who consulted the ophthalmology department for eyelid itching and eyelash loss. On examination, there were no signs of blepharitis, but loss of lashes was observed, and the remaining eyelashes detached easily from the eyelid. The eyelashes were examined microscopically. The bulbs were small and narrow, and the caliber of the lashes was irregular, with thinner and thicker areas. The pigment distribution was irregular; there were portions with greater or lesser accumulation. In the second case, clusters of Demodex folliculorum were observed near the eyelash root. CONCLUSION: This is the first microscopic description of eyelash loss in frontal fibrosing alopecia in the published literature. We describe small, narrow bulbs, irregular caliber of the eyelashes and irregular pigment distribution. In the second case, in which we found Demodex folliculorum infestation, there was eyelash loss even though the disease was not very advanced. We suggest that there might be an association whereby Demodex infestation might accelerate autoimmune inflammation, leading to premature eyelash loss.

[Bilateral hip fracture in a patient with Down syndrome]. / Fractura bilateral de cadera en un paciente con síndrome de Down.

There are few published data available about simultaneous bilateral hip fractures. We present the case of a 56-year-old man with Down syndrome and Alzheimer-like dementia with simultaneous bilateral hip fracture. A bilateral partial hip cemented arthroplasty was performed on this patient. The aim was to avoid the partial burden that could be caused by ostheosynthesis, due to the patient's lack of cooperation arising from his mental deterioration and his problems realizing everyday activities. He was able to walk unaided with complete autonomy until his death fourth years later. In our experience, one stage surgery for bilateral hip prosthesis is safe and provides good results in patients with severe mental impairment.

Micellar electrokinetic chromatography with laser induced fluorescence detection shows increase of putrescine in erythrocytes of Parkinson's disease patients.

A highly sensitive method was developed to measure putrescine by micellar electrokinetic chromatography with laser induced fluorescence detection with excellent linearity in the 1 nM to 3 µM range. The technique was tested on a drop of blood from Parkinson's disease patients obtained by finger prick. The results showed a statistically significant increase of putrescine in the erythrocytes compared to controls and a non-significant increase in plasma. This high level of putrescine does not constitute by itself proof that putrescine and polyamines are directly related to Parkinson's disease. However, the present results and several others addressed in the discussion suggest that these compounds might be causally involved in the pathophysiology of Parkinson's disease. In addition, the analytical method reported here may help to find new biomarkers for many diseases including Parkinson's disease.

[Rivaroxaban versus standard of care in venous thromboembolism prevention following hip or knee arthroplasty in daily clinical practice (Spanish data from the international study XAMOS)]. / Rivaroxaban frente al tratamiento estándar en la prevención del tromboembolismo venoso tras artroplastia de cadera o rodilla en la práctica clínica diaria (datos de España del estudio internacional XAMOS).

OBJECTIVE: To analyse the effectiveness and safety of rivaroxaban vs. standard treatment (ST) in the prevention of venous thromboembolism after hip or knee replacement in daily clinical practice in Spain. MATERIAL AND METHOD: A sub-analysis of the Spanish data in the XAMOS international observational study that included patients>18 years who received 10mg o.d. rivaroxaban or ST. FOLLOW-UP: up to 3 months after surgery. PRIMARY OUTCOMES: incidence of symptomatic/asymptomatic thromboembolic events, bleeding, mortality, and other adverse events; SECONDARY OUTCOMES: use of health resources and satisfaction after hospital discharge. RESULTS: Of the total 801 patients included, 410 received rivaroxaban and 391 ST (64.7% heparin, 24.0% fondaparinux, 11% dabigatran). The incidence of symptomatic thromboembolic events and major bleeding was similar in both groups (0.2% vs. 0.8% wit ST and 0.7% vs. 1.3% with ST [EMA criteria]/0.0% vs. 0.3% with ST [RECORD criteria]). The adverse events incidence associated with the drug was significantly higher rivaroxaban (overall: 4.4% vs. 0.8% with ST, P=.001; serious: 1.5% vs. 0.0% with ST, P=.03). The rivaroxaban used less health resources after discharge, and the majority considered the tolerability as «very good« and the treatment as «very comfortable¼. DISCUSSION: Rivaroxaban is at least as effective as ST in the prevention of venous thromboembolism prevention in daily clinical practice, with a similar incidence of haemorrhages. It provides greater satisfaction/comfort, and less health resources after discharge. These results should be interpreted taking into account the limitations inherent in observational studies.

Validity of magnetic resonance arthrography as a diagnostic tool in femoroacetabular impingement syndrome.

INTRODUCTION: Femoroacetabular impingement (FAI) is one of the main causes of hip pain in young adult and a contributory factor for development of early primary osteoarthritis. An accurate clinical diagnosis, supported by imaging studies, is important to determine the best treatment for the patient. The aim of this study is to determine the diagnostic correlation between direct magnetic resonance imaging (MRI) arthrography and the arthroscopic findings. MATERIALS AND METHOD: A review was performed on a series of 36 patients diagnosed with FAI, and who underwent hip arthroscopy surgery between 2009 and 2012. All of them had a direct MRI arthrography performed in our hospital. The presence of labral lesions, CAM deformity, and acetabular and femoral cartilage damage, were evaluated in both imaging techniques. RESULT: After analysing the results and taking the hip arthroscopy as 'gold standard', a sensitivity of 87% and a specificity of 77% were obtained, with a PPV of 87% for the diagnosis of labral lesions by direct MR arthrography. The specificity for CAM deformity was 100%, with a sensitivity of 79% and PPV of 100%. For chondral disorders lower values were found for both acetabulum and femoral head. For acetabular lesions the sensitivity was 78.5%, and specificity was 82% with a PPV of 73% and NPV of 80%. For femoral lesions, there was a sensitivity of 71.5%, a specificity of 73%, with a PPV of 62.5% and NPV of 80%. CONCLUSIONS: Due to the high sensitivity for the detection of labral lesions and the high specificity to detect CAM deformity, hip MR arthrography is a useful diagnostic tool for femoroacetabular impingement.

Effects of alcohol and polyphenols from beer on atherosclerotic biomarkers in high cardiovascular risk men: a randomized feeding trial.

BACKGROUND AND AIMS: Moderate alcohol consumption exerts a cardioprotective effect, but no studies have evaluated the alcohol-independent cardiovascular effects of the non-alcoholic components of beer. We aimed to evaluate the effects of ethanol and the phenolic compounds of beer on classical and novel cardiovascular risk factors. METHODS AND RESULTS: Thirty-three high risk male volunteers were included in a randomized, crossover feeding trial. After a washout period, all subjects received beer (30 g alcohol/d, 660 mL), the equivalent amount of polyphenols as non-alcoholic beer (990 mL), and gin (30 g alcohol/d, 100 mL) for 4 weeks. All outcomes were evaluated before and after each intervention period. Moderate alcohol consumption increased serum HDL-cholesterol (∼5%), ApoA-I (∼6%), ApoA-II (∼7%) and adiponectin (∼7%), and decreased serum fibrinogen (∼8%), and interleukin (IL)-5 (∼14%) concentrations, whereas the non-alcoholic fraction of beer (mainly polyphenols) increased the receptor antagonist of IL-1 (∼24%), and decreased lymphocyte expression of lymphocyte function-associated antigen-1 (∼11%), lymphocyte and monocyte expression of Sialil-Lewis X (∼16%) and monocyte expression of CCR2 (∼31%), and tumor necrosis factor (TNF)-ß (∼14%) and IL-15 (∼22%) plasma concentrations. No changes were observed in glucose metabolism parameters or in body weight and adiposity parameters. CONCLUSION: The phenolic content of beer reduces leukocyte adhesion molecules and inflammatory biomarkers, whereas alcohol mainly improves the lipid profile and reduces some plasma inflammatory biomarkers related to atherosclerosis.

Clinical and radiological short-term complications after single-stage bilateral uncemented total hip arthroplasty.

PURPOSE: Economic crisis time gives to efficient procedures an important role in healthy system. Total hip replacement is a common bilateral orthopedic procedure, but there exists an important controversy to perform it in single or two stages. Our aim is to report our clinical and radiological short-term complications of bilateral uncemented total hip arthroplasty in a single time. MATERIALS AND METHODS: We have retrospectively reviewed the patients treated between 2000 and 2011 in our center by bilateral uncemented total hip replacement in a single time. We have reviewed the medical history and analyzed by age, diagnosis and ASA parameters related to the procedure, hospital stay, transfusion requirements and clinical complications. Radiological evaluation was made with anteroposterior hip radiograph evaluation (acetabular radiolucencies and stem migration). Functional assessment was carried out by the Merle D'Aubigné score. RESULTS: Seventeen patients with mean age of 47.4 (18-68) years were reviewed with a mean follow-up of 44.3 (6-172) months. ASA distribution: 29.4 % grade I; 52.9 % grade II and 17.6 % grade III. Merlé D'Aubigné score improved from 11.01 to 16.45. Hospital stay was 6 days. Transfusion requirements were two hematic concentrates for each patient. Two external popliteal sciatic nerve neurapraxias fully recovered at follow-up. Radiological results showed one case of axial migration. CONCLUSIONS: With proper patient selection and multidisciplinary team, the bilateral uncemented total hip arthroplasty in a single time has low complication rates. Our results could be used in the development of future randomized controlled trials or prospective cohort studies. LEVEL OF EVIDENCE: IV.

Rivaroxaban is as efficient and safe as bemiparin as thromboprophylaxis in knee arthroscopy.

PURPOSE: The aim of this study is to compare effectiveness and safety profile of rivaroxaban with bemiparin in 3-week extended prophylaxis after knee arthroscopy. METHODS: Four hundred and sixty-seven patients were included in this review divided in two groups. One followed prophylaxis with rivaroxaban and the other one with bemiparin. All patients were interviewed and explored at 1 and 3 months postoperatively, looking for symptomatic signs of deep-vein thrombosis (DVT). In case of suspicion, diagnostic tests were performed. Collected data were age, sex, gender, diagnosis, time with ischemia, body mass index, concomitant diseases, concomitant therapy, DVT signs, treatment satisfaction, minor and major complications, treatment adherence and tolerability. RESULTS: No thromboembolic events were observed in any of the groups. In one case treated with rivaroxaban, the drug had to be withdrawn due to epistaxis. CONCLUSIONS: Our study showed that extended prophylaxis with 10 mg of rivaroxaban once daily for 3 weeks resulted as effective as bemiparin in knee arthroscopy thromboprophylaxis.

Protein tyrosine phosphatase 1B modulates GSK3ß/Nrf2 and IGFIR signaling pathways in acetaminophen-induced hepatotoxicity.

Acute hepatic failure secondary to acetaminophen (APAP) poisoning is associated with high mortality. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of tyrosine kinase growth factor signaling. In the liver, this pathway confers protection against injury. However, the involvement of PTP1B in the intracellular networks activated by APAP is unknown. We have assessed PTP1B expression in APAP-induced liver failure in humans and its role in the molecular mechanisms that regulate the balance between cell death and survival in human and mouse hepatocytes, as well as in a mouse model of APAP-induced hepatotoxicity. PTP1B expression was increased in human liver tissue removed during liver transplant from patients for APAP overdose. PTP1B was upregulated by APAP in primary human and mouse hepatocytes together with the activation of c-jun (NH2) terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), resulting in cell death. Conversely, Akt phosphorylation and the antiapoptotic Bcl2 family members BclxL and Mcl1 were decreased. PTP1B deficiency in mouse protects hepatocytes against APAP-induced cell death, preventing glutathione depletion, reactive oxygen species (ROS) generation and activation of JNK and p38 MAPK. APAP-treated PTP1B(-/-) hepatocytes showed enhanced antioxidant defense through the glycogen synthase kinase 3 (GSK3)ß/Src kinase family (SKF) axis, delaying tyrosine phosphorylation of the transcription factor nuclear factor-erythroid 2-related factor (Nrf2) and its nuclear exclusion, ubiquitination and degradation. Insulin-like growth factor-I receptor-mediated signaling decreased in APAP-treated wild-type hepatocytes, but was maintained in PTP1B(-/-) cells or in wild-type hepatocytes with reduced PTP1B levels by RNA interference. Likewise, both signaling cascades were modulated in mice, resulting in less severe APAP hepatotoxicity in PTP1B(-/-) mice. Our results demonstrated that PTP1B is a central player of the mechanisms triggered by APAP in hepatotoxicity, suggesting a novel therapeutic target against APAP-induced liver failure.

The Burch-Schneider antiprotrusio cage: medium follow-up results.

With the development of hip prosthesis, younger patients may need more than one revision surgery, with less bone stock available in each subsequent surgery. We retrospectively reviewed the hip revision surgeries in which a Burch-Schneider device has been used. Patients were classified according to the Paprosky score. Functional and clinical evaluation was assessed by the Merlé-Daubigné score. Radiolucencies were assessed by Gill's criteria. Sixteen patients with a mean age of 66.1 years were reviewed at a mean follow-up of 60.7 months. According to Paprosky classification, 18.7% were grade IIb, 56.3% grade IIIa and 25% grade IIIb. The mean Merlé-Daubigné score improved from 10 to 15 points. Radiologically, 12 patients had no radiolucencies, two had grade I radiolucencies and two had grade III radiolucencies. In greater than 50% of acetabular defects, the Burch-Schneider seems to be useful providing clinical and functional improvement. Immediately, non-progressive radiolucencies are not associated with implant loosening at the end of follow-up. The ischial flap should be inserted inside the ischial portion of the acetabulum.

Corticotropin-releasing factor in the nucleus accumbens shell induces swim depression, anxiety, and anhedonia along with changes in local dopamine/acetylcholine balance.

The nucleus accumbens shell (NAcS) has been implicated in controlling stress responses through corticotropin-releasing factor (CRF). In addition to studies indicating that CRF in the NAcS increases appetitive motivation, there is indirect evidence suggesting that NAcS CRF may also cause aversive responses and that these behaviors may be mediated through local dopamine (DA) and acetylcholine (ACh) systems. To provide a direct test of this hypothesis, we used male Sprague-Dawley rats with implanted cannulas aimed at the NAcS. Experiment 1 showed local CRF injection (10 or 50 ng/side) to increase immobility in the forced swim test and a CRF antagonist D-Phe-CRF ((12-41)) to attenuate this depressive-like behavior. In Experiment 2, injection of CRF (250 ng/side) also decreased the rats' preference for sucrose, while in Experiment 3, CRF (50 or 250 ng/side) induced anxiety-like behaviors in an elevated plus maze and open field. These same doses of CRF in Experiment 4 failed to alter the rats' locomotor activity, indicating that these behavioral changes were not caused by deficits in activity. In Experiment 5, results from in vivo microdialysis revealed that CRF in the NAcS markedly increased local extracellular ACh, while also producing a small increase in DA. These results show that NAcS CRF can generate a variety of aversive behaviors, including swim depression, anhedonia, and anxiety, in addition to approach behavior. They suggest that these behaviors may occur, in part, through enhanced activation of ACh and DA in the NAcS, respectively, supporting a role for this brain area in mediating the dual effects of stress.

Enhanced GABAergic tone in the ventral pallidum: memory of unpleasant experiences?

The nucleus accumbens (NAc) has emerged as an important part of the neural circuitry regulating depressive-like behaviors. Given that the NAc GABAergic medium spiny neurons project to the ventral pallidum (VP), it is reasonable to suggest that the VP may also be involved in these behaviors. Consequently, we explored the role of the VP GABAergic terminals during depressive-like behaviors in rats using the forced swim test (FST) and the sucrose preference test (SPT). Microdialysis coupled with micellar electrokinetic chromatography was used to monitor in vivo changes of GABA in the VP during the FST. GABA levels significantly increased during day-1 and day-2 during swimming, returning to the pre-swimming levels after the test. Basal concentrations of GABA on day-2 of the FST significantly increased with respect to day-1. In another set of experiments, intra-VP injections of vigabatrin (a GABA transaminase inhibitor) increased extracellular GABA and immobility behaviors in the FST while the direct GABAA receptor antagonist bicuculline reduced immobility behaviors. In the SPT, intra-VP vigabatrin injection significantly reduced preference for sucrose while bicuculline did not produce any change. At the postsynaptic side, we used semiquantitative RT-PCR to measure mRNA expression of 17 GABAA receptor subunits (α1-α6, ß1-ß3, γ2, δ, ε, θ, π, and ρ1-ρ3) in rats subjected to the FST. We found a significant reduction of α3 and γ2 subunit expression and an increase of δ subunit expression after day-2 in rats subject to the FST which might enhance tonic inhibition of the VP. Furthermore, immunoblot experiments revealed that protein expression of γ2 and δ subunits changed 6 days after FST in a way similar to mRNA expression. These results suggest that the enhanced VP-GABAergic tone might trigger a low motivational state, anhedonia and a possible memory mechanism for unpleasant experiences.

Underweight rats have enhanced dopamine release and blunted acetylcholine response in the nucleus accumbens while bingeing on sucrose.

The present study tested whether rats release more accumbens dopamine (DA) during a sugar binge when they are underweight vs. normal weight. Since acetylcholine (ACh) in the nucleus accumbens (NAc) normally increases as a meal progresses and satiety ensues, we also tested whether ACh release is altered when an animal has lost weight. Rats were maintained on daily 8-h access to chow, with 10% sucrose solution available for the first 2 h. Microdialysis performed on day 21, at normal body weight, revealed an increase in extracellular DA to 122% of baseline in response to drinking sucrose. Extracellular ACh peaked at the end of the meal. Next, the rats were food and sucrose restricted so that by day 28 they were at 85% body weight. When retested, these animals released significantly more DA when drinking sucrose (179%), but ACh release failed to rise. A control group was tested in the same manner but given sugar only on days 1, 21 and 28. At normal body weight, control animals showed a non-significant rise in DA when drinking sucrose on day 21. On day 28, at 85% body weight, the controls showed a small increase (124%) in DA release; however, this was significantly lower than the 179% observed in the underweight rats with daily sugar access. These findings suggest that when an animal binges on sugar and then loses weight, the binge releases significantly more DA and less ACh than when animals are at a normal body weight.

Feeding and systemic D-amphetamine increase extracellular acetylcholine in the medial thalamus: a possible reward enabling function.

Acetylcholine neurons that project forward from the midbrain are known to enable dopaminergic reward functions in the ventral tegmental area. The question is whether acetylcholine might also be released in the mediodorsal thalamus for the same general purposes. Rats with a microdialysis probe lodged in the mediodorsal thalamus were allowed to eat chow for 20 min after 16-h food deprivation or were given varying doses of D-amphetamine when fed ad libitum. The result in both cases was a significant increase in extracellular acetylcholine. During feeding, acetylcholine increased to 177% of baseline. In response to d-amphetamine (2.5 mg/kg), acetylcholine increased to 184%, and with a higher dose (5 mg/kg) to 400% of baseline. It is concluded that midbrain projections to limbic portions of the thalamus provide acetylcholine for behavioral activation. This cholinergic function theoretically plays a role in enabling the limbic circuits that pass through the thalamus for reinforcement of feeding and psychostimulant abuse.

Behavioral depression in the swim test causes a biphasic, long-lasting change in accumbens acetylcholine release, with partial compensation by acetylcholinesterase and muscarinic-1 receptors.

The nucleus accumbens may play a role in acquisition and expression of behavioral depression as measured using the inescapable swim test. Previous work shows that a local injection of a cholinergic muscarinic-1 receptor agonist increases immobility and a specific muscarinic-1 antagonist acts as an antidepressant-like drug by increasing swimming escape efforts. The present study used microdialysis to monitor extracellular acetylcholine levels in the accumbens, fluorescent labeled toxins to monitor changes in acetylcholinesterase and muscarinic-1 receptors, and semiquantitative-polymerase chain reaction to detect changes in gene expression for the muscarinic-1 receptor. Microdialysis showed that acetylcholine levels did not change while an animal was swimming; however, a significant transient decrease occurred when the rat was returned to the dialysis cage, followed by a long-lasting increase that reached a maximum three hours after the test. Acetylcholine levels stayed high even 24 h after the initial test as evidenced by a significant elevation in basal level prior to the second swim. This increase in neurotransmitter may have been partially compensated by a significant increase in the degradative enzyme, acetylcholinesterase, and by a decrease in muscarinic-1 receptors and their gene expression. These results further demonstrate the importance of accumbens cholinergic function in the appearance of a depression-like state.

Sucrose sham feeding on a binge schedule releases accumbens dopamine repeatedly and eliminates the acetylcholine satiety response.

Drinking a sugar solution on an intermittent schedule can promote sugar bingeing and cause signs of dependence while releasing dopamine repeatedly like a drug of abuse. It is hypothesized that sweet taste alone is sufficient for this effect in sucrose bingeing rats. On the theory that acetylcholine in the nucleus accumbens plays a role in satiety, it is further hypothesized that purging the stomach contents will delay acetylcholine release. Rats with gastric fistulas and nucleus accumbens guide shafts for microdialysis were fed 12 h each day. During the first hour, fistulas were open for the sham-feeding group and closed for the real-feeding group, and 10% sucrose was the only food source. For the remaining 11 h, liquid rodent diet was available as well as the 10% sucrose to provide a balanced diet. In microdialysis tests during the first sugar meal on days 1, 2 and 21, extracellular dopamine increased at least 30% each day in both groups. Acetylcholine also increased during the sugar meals for the real-feeding animals, but not during sham feeding. In conclusion, the taste of sugar can increase extracellular dopamine in the nucleus accumbens without fail in animals on a dietary regimen that causes bingeing and sugar dependency. During sham feeding, the acetylcholine satiation signal is eliminated, and the animals drink more. These findings support the hypothesis that dopamine is released repeatedly in response to taste when bingeing on sweet food, and the acetylcholine satiety effect is greatly reduced by purging; this may be relevant to bulimia nervosa in humans.

Daily bingeing on sugar repeatedly releases dopamine in the accumbens shell.

Most drugs of abuse increase dopamine (DA) in the nucleus accumbens (NAc), and do so every time as a pharmacological response. Palatable food also releases accumbens-shell DA, but in naïve rats the effect can wane during a long meal and disappears with repetition. Under select dietary circumstances, sugar can have effects similar to a drug of abuse. Rats show signs of DA sensitization and opioid dependence when given intermittent access to sucrose, such as alterations in DA and mu-opioid receptors, cross-sensitization with amphetamine and alcohol, and behavioral and neurochemical signs of naloxone-precipitated withdrawal. The present experiment asks whether sucrose-dependent rats release DA each time they binge. We also predict that acetylcholine (ACh), which rises as the end of a meal, will be delayed in rats with intermittent access to sucrose. To create dependency, the experimental group (Daily Intermittent Sucrose) was maintained on a diet of 12-h food deprivation that extended 4 h into the dark, followed by 12-h access to a 10% sucrose solution and chow, daily, for 21 days. As the main result, these rats gradually increased their sucrose intake from 37 to 112 ml per day (from 13 to 20 ml in the first hour of access), and repeatedly increased extracellular DA to 130% of baseline as measured in the NAc shell by microdialysis during the first hour of sucrose access on day 1, day 2 and day 21. Three control groups failed to show a significant increase in extracellular DA on day 21: Sucrose only for 1 h on days 1 and 21 (Sucrose Twice), ad libitum access to sucrose and chow (Daily Ad libitum Sucrose), and intermittent chow instead of sucrose (Daily Intermittent Chow). Acetylcholine measured at the same time as DA, increased significantly toward the end and after each test meal in all groups. In the Daily Intermittent Sucrose group, the highest ACh levels (133%) occurred during the first sample after the sucrose meal ended. In summary, sucrose-dependent animals have a delayed ACh satiation response, drink more sucrose, and release more DA than sucrose- or binge-experienced, but non-dependent animals. These results suggest another neurochemical similarity between intermittent bingeing on sucrose and drugs of abuse: both can repeatedly increase extracellular DA in the NAc shell.

Lecozotan (SRA-333): a selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties.

Recent data has suggested that the 5-hydroxytryptamine (5-HT)(1A) receptor is involved in cognitive processing. A novel 5-HT(1A) receptor antagonist, 4-cyano-N-{2R-[4-(2,3-dihydrobenzo[1,4]-dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide HCl (lecozotan), which has been characterized in multiple in vitro and in vivo pharmacological assays as a drug to treat cognitive dysfunction, is reported. In vitro binding and intrinsic activity determinations demonstrated that lecozotan is a potent and selective 5-HT(1A) receptor antagonist. Using in vivo microdialysis, lecozotan (0.3 mg/kg s.c.) antagonized the decrease in hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg s.c.) of 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) and had no effects alone at doses 10-fold higher. Lecozotan significantly potentiated the potassium chloride-stimulated release of glutamate and acetylcholine in the dentate gyrus of the hippocampus. Chronic administration of lecozotan did not induce 5-HT(1A) receptor tolerance or desensitization in a behavioral model indicative of 5-HT(1A) receptor function. In drug discrimination studies, lecozotan (0.01-1 mg/kg i.m.) did not substitute for 8-OH-DPAT and produced a dose-related blockade of the 5-HT(1A) agonist discriminative stimulus cue. In aged rhesus monkeys, lecozotan produced a significant improvement in task performance efficiency at an optimal dose (1 mg/kg p.o.). Learning deficits induced by the glutamatergic antagonist MK-801 [(-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] (assessed by perceptually complex and visual spatial discrimination) and by specific cholinergic lesions of the hippocampus (assessed by visual spatial discrimination) were reversed by lecozotan (2 mg/kg i.m.) in marmosets. The heterosynaptic nature of the effects of lecozotan imbues this compound with a novel mechanism of action directed at the biochemical pathologies underlying cognitive loss in Alzheimer's disease.

Galanin and alcohol dependence: neurobehavioral research.

It is known that microinjection of galanin (GAL) intraventricularly or in specific hypothalamic sites increases food consumption and, conversely, the intake of food increases the expression of GAL in hypothalamic sites. Ethanol (EtOH) is a calorie-rich food as well as a drug of abuse. The research reviewed here shows that GAL may play a similar role in alcohol intake. First, experiments in which GAL was microinjected into the third ventricle or the paraventricular nucleus (PVN) showed increases in EtOH consumption. The increase in EtOH consumption occurred during both the light and dark cycles after GAL injection in the third ventricle in rats with limited EtOH access. Injection of GAL did not increase food intake in rats that had been chronically drinking alcohol. GAL receptor blockade reversed these increases. Microinjection of GAL directly into the PVN also increased ad libitum EtOH intake and blockade of these receptors in the PVN inhibited ad libitum EtOH consumption. Secondly, rats administered EtOH showed increases in GAL in the PVN and related hypothalamic sites. EtOH injection and voluntary intake, both ad libitum and limited access, increased GAL gene and peptide expression in the PVN consistently across administration procedures. These experiments show that GAL injection increases alcohol intake and that the intake of alcohol increases GAL, suggesting a positive feedback relationship between alcohol intake and specific hypothalamic GAL systems. Such a relationship may contribute to the motivation to consume excessive alcoholic beverages and the development of alcohol dependence.