Marta Baviera

Dissociable Contribution of 5-HT1A and 5-HT2A Receptors in the Medial Prefrontal Cortex to Different Aspects of Executive Control such as Impulsivity and Compulsive Perseveration in Rats

Serotonin (5-HT) receptors are increasingly recognized as major targets for cognitive enhancement in schizophrenia. Several lines of evidence suggest a pathophysiological role for glutamate NMDA receptors in the prefrontal cortex in schizophrenia and associated disorders in attention and executive functioning. We investigated how the interactions between 5-HT1A and 5-HT2A and glutamate NMDA receptor mechanisms in the medial prefrontal cortex (mPFC) contribute to the control of different aspects of attentional performance. Rats were trained on a five-choice serial reaction time (5-CSRT) task, which provides indices of attentional functioning (percentage of correct responses), executive control (measured by anticipatory and perseverative responses), and speed. The competitive NMDA receptor antagonist CPP (50 ng/side) was infused directly into the mPFC 5 min after infusion of either 8-OH-DPAT (30 and 100 ng/side) or M100907 (100 and 300 ng/side) into the same brain area. Impairments in attentional functioning induced by CPP were completely abolished by both doses of 8-OH-DPAT or M100907. In addition, M100907 abolished the CPP-induced anticipatory responding but had no effects on perseverative over-responding, while 8-OH-DPAT reduced the perseverative over-responding but had no effects on anticipatory responding induced by CPP. The selective 5-HT1A receptor antagonist WAY100635 (30 ng/side) antagonized the effects of 8-OH-DPAT (100 ng/side). 8-OH-DPAT at 30 ng/side reduced the latency of correct responses in controls and CPP-injected rats and lowered the percentage of omissions in CPP-injected rats. The data show that 5-HT1A and 5-HT2A receptors in the mPFC exert opposing actions on attentional functioning and demonstrate a dissociable contribution of 5-HT1A and 5-HT2A receptors in the mPFC to different aspects of executive control such as impulsivity and compulsive perseveration.

The Serotonin 5-HT2A Receptors Antagonist M100907 Prevents Impairment in Attentional Performance by NMDA Receptor Blockade in the Rat Prefrontal Cortex

We investigated whether 5-HT2A receptors contribute to the control of attentional performance by glutamate NMDA receptor mechanisms in the medial prefrontal cortex (mPFC). We examined the effects of NMDA receptor blockade in the mPFC on attentional performance by infusing a competitive glutamate NMDA receptor antagonist, 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) into the mPFC of rats performing a task of divided and sustained visual attention. The five-choice serial reaction time task provides indices of attentional functioning (% correct responses), executive control (measured by anticipatory and perseverative responses) and speed. A dose of 10 ng CPP injected bilaterally into the mPFC increased anticipatory and perseverative responding; 50 ng reduced accuracy. Increasing the stimulus duration alleviated the CPP-induced accuracy deficit but did not reduce its effects on anticipatory and perseverative responses. CPP at 50 ng caused motor hyperactivity whereas lower doses had no effect. [R-(+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol] (M100907) (M100907), a 5-HT2A receptor antagonist, injected subcutaneously at 10 and 40 μg/kg, had no effect on accuracy but dose dependently reversed the impairment induced by 50 ng CPP. Both doses of M100907 completely abolished CPP-induced anticipatory but not perseverative over-responding. At the dose of 40 μg/kg M100907 reversed CPP-induced motor hyperactivity. This study provides evidence that the prefronto-cortical glutamate NMDA system may make an important contribution to the control of attention and executive functions. It also indicates that 5-HT2A receptors may serve to optimize attentional selectivity and improve some aspects of executive control.

The 5-HT2A receptor antagonist M100,907 prevents extracellular glutamate rising in response to NMDA receptor blockade in the mPFC

We recently found that intracortical injection of the selective and competitive N‐methyl‐d‐aspartate (NMDA) receptor antagonist 3‐(R)‐2‐carboxypiperazin‐4‐propyl‐1‐phosphonic acid (CPP) impaired attentional performance in rats and blockade of 5‐hydroxytryptamine (5‐HT)2A receptors antagonized this effect. Here, we used the microdialysis technique in conscious rats to study the effect of CPP on extracellular glutamate (GLU) in the medial prefrontal cortex (mPFC) and the regulation of this effect by 5‐HT2A receptors. Intraperitoneal injection of 20 mg/kg CPP increased extracellular GLU in the mPFC (201% of basal levels) but had no effect on 5‐HT. Intracortical infusion of 100 µm CPP increased extracellular GLU (230% of basal values) and 5‐HT (150% of basal values) in the mPFC, whereas 30 µm had no significant effect. The effect of 100 µm CPP on extracellular GLU was abolished by tetrodotoxin, suggesting that neuronal activity is required. Subcutaneous injection of 40 µg/kg M100,907 completely antagonized the effect of 100 µm cpp on extracellular GLU, whereas 10 µg/kg caused only partial attenuation. Likewise, intracortical infusion of 0.1 µm M100,907 completely reversed the increase of extracellular GLU induced by CPP. These findings show that blockade of NMDA receptors in the mPFC is sufficient to increase extracellular GLU locally. The increase of cortical extracellular GLU may contribute to CPP‐induced cognitive deficits and blockade of 5‐HT2A receptors may provide a molecular mechanism for reversing these deficits caused by dysfunctional glutamatergic transmission in the mPFC.

Drug utilization and polypharmacy in an Italian elderly population: the EPIFARM-elderly project†‡

To investigate the prescribing patterns and the prevalence of polypharmacy in community‐dwelling elderly people, and to analyze the association of chronic medications and number of drug prescriptions with age and sex.

Prevalence, incidence and mortality of diagnosed diabetes: Evidence from an Italian population-based study

Diabet. Med. 29, 385–392 (2012)

Endogenous serotonin and serotonin2C receptors are involved in the ability of M100907 to suppress cortical glutamate release induced by NMDA receptor blockade

Blockade of NMDA receptors by intracortical infusion of 3‐(R)‐2‐carboxypiperazin‐4‐propyl‐1‐phosphonic acid (CPP) increases glutamate (GLU) and serotonin (5‐HT) release in the medial prefrontal cortex and impairs attentional performance in the 5‐choice serial reaction time task. These effects are prevented by the 5‐HT2A receptor antagonist, (R)‐(+)‐(2,3‐dimethoxyphenyl)‐1‐[2‐(4‐fluorophenyl)ethyl]‐4‐piperidine methanol (M100907). We explored the roles of endogenous 5‐HT and 5‐HT1A and 5‐HT2C receptors in the mechanisms by which M100907 suppresses CPP‐induced release of cortical GLU and 5‐HT using in vivo microdialysis. CPP raised extracellular GLU and 5‐HT by about 250% and 170% respectively. The 5‐HT synthesis inhibitor, p‐chlorophenylalanine (300 mg/kg), prevented M100907 suppressing CPP‐induced GLU release. The effect of M100907 on these rises of GLU and 5‐HT and attentional performance deficit was mimicked by the 5‐HT2C receptor agonist, (S)‐2‐(6‐chloro‐5‐fluoroindol‐1‐yl)‐1‐methylethylamine fumarate, (Ro60‐0175, 30 μg/kg) while intra‐mPFC (SB242084, 6‐chloro‐5‐methyl‐1‐[[2‐[(2‐methyl‐3‐pyridyl)oxy]‐5‐pyridyl]carbamoyl]‐indoline, 0.1 μM), a 5‐HT2C receptor antagonist, prevented the effect of M100907 on extracellular GLU. The 5‐HT1A receptor antagonist, N‐[2‐[4‐(2‐methoxyphenyl)‐1‐piperazinyl]ethyl]‐N‐(2‐pyridinyl)cyclohexane carboxenide trihydrochloride (100 μM) abolished the effect of M100907 on the CPP‐induced 5‐HT release. The data show that blockade of 5‐HT2A receptors is not sufficient to suppress the CPP‐induced rise of extracellular GLU and 5‐HT and suggest that M100907 suppresses GLU release induced by CPP by enhancing the action of endogenous 5‐HT on 5‐HT2C receptors.

Trends in drug prescriptions to diabetic patients from 2000 to 2008 in Italy's Lombardy Region: A large population-based study

OBJECTIVE To analyze the prescribing patterns of antidiabetic and cardiovascular medications among diabetics in the most highly populated Italian Region, from 2000 to 2008. METHODS Data were obtained from the Lombardy Region administrative health databases. The standardized prevalence of antidiabetic and cardiovascular drugs use was calculated within each study year. The prescription trends of initial treatment with antidiabetic drugs were also analyzed. RESULTS From 2000 to 2008 there was an increase in the proportion of patients treated with biguanides (from 53.4% to 66.5%; p<0.0001) while those receiving sulfonylurea decreased (from 78.6% to 56.4%; p<0.0001). A sharp increase of metformin (as monotherapy) as initial treatment was also observed (from 15.2% to 48.8%; p<0.0001). The percentage of patients receiving renin-angiotensin system inhibitors, lipid-lowering drugs and antiplatelets increased between 2000 and 2008, from respectively 45.1% to 63.3%, 13.6% to 43.2% and 21.6% to 40.9 (p<0.0001). Multivariate analyses indicated that changes in prescriptions were statistically significant for both antidiabetic and cardiovascular drugs. CONCLUSION This study documents progressive changes in the prescription of antidiabetic and cardiovascular drugs in accordance with guidelines. However, the use of metformin as first line therapy was still suboptimal and cardiovascular preventive strategies were only partially implemented in community practice.

Erratum: The serotonin 5-HT2A receptors antagonist M100907 prevents impairment in attentional performance by NMDA receptor in the rat prefrental cortex (Neuropsychopharmacology (2004) 29 (1637-1647) DOI: 10.1038/sj.npp. 1300479)

Correction to: Neuropsychopharmacology (2004) 29, 1637–1647. doi:10.1038/sj.npp.1300479. Following publication of the above paper, the author has identified an error with the name of one of the authors. Dr Carlis name is now correctly represented above.

Sex differences in cardiovascular outcomes, pharmacological treatments and indicators of care in patients with newly diagnosed diabetes: Analyses on administrative database

BACKGROUND The impact of diabetes on cardiovascular disease in both sexes is known, but the specifics have not been fully clarified. We investigated whether sex-related differences exist in terms of management and hospitalization in patients with newly diagnosed diabetes. METHODS We examined the rates of hospitalization for cardiovascular causes, mortality, treatments and management of patients with diabetes compared to subjects without, from administrative database. Interaction between sex and diabetes on clinical outcomes were calculated using a Cox regression model. Pharmacological treatments and recommended examinations by sex were calculated using logistic regression. RESULTS From 2002 to 2006, 158,426 patients with diabetes and 314,115 subjects without were identified and followed up for a mean of 33 months (± 17.5). Diabetes confers a higher risk for all clinical outcomes. Females with diabetes have a risk profile for hospitalization for coronary heart disease comparable to males without (4.6% and 5.3%). Interaction between sex and diabetes shows that females with diabetes had an added 19% higher risk of total death (95% CI 1.13-1.24). No differences were observed in hospitalizations, although females with diabetes were less likely to undergo revascularization after myocardial infarction. Females received cardiovascular prevention drugs less frequently than males and had a slight tendency to get fewer examinations. CONCLUSION Diabetes is linked to a higher increase of mortality in females relative to males. This might reflect sex differences in the use of revascularization procedures or therapeutic regimens. Closer attention and implementation of standard care for females are necessary from the onset of diabetes.

Diabetes mellitus as risk factor for atrial fibrillation hospitalization: Incidence and outcomes over nine years in a region of Northern Italy

AIMS Diabetes mellitus (DM) and atrial fibrillation (AF) are worldwide public health challenges and major causes of death and cardiovascular events. The association between DM and AF is controversial in literature and data on outcomes of individuals with both diseases have not been evaluated in population studies. We tested the hypothesis that DM is independently associated to AF hospitalization and assessed the risk of stroke and mortality in people with both conditions. METHODS We conducted a population-based cohort-study of DM patients and their corresponding controls identified in a administrative health database of the Lombardy Region. Both cohorts were followed for nine years. A multivariable Cox proportional-hazards-regression model was used to estimate the hazard ratio (HR) for first hospitalization for AF and for clinical outcomes. RESULTS Out of 9,061,258 residents, 285,428 (3.14%) DM subjects were identified, mean age 65.8±15 years, 49% were women. The cumulative incidence of AF in DM was 10.4% vs. 7.4% in non-DM. DM was a risk factor for AF (HR 1.32, 95% CI 1.30-1.34; p<0.0001). Oral anticoagulants were prescribed in 34.8% of DM patients with AF. DM associated with AF, presented the highest HR for stroke: 2.63; 95% CI 2.47-2.80 and for total death, HR 2.41; 95% CI 2.36-2.47. CONCLUSIONS In this population study, DM was an independent risk factor for AF hospitalization. DM patients with AF had the highest risk of stroke and total mortality. Early identification of AF and a structured plan to optimize the comprehensive management of DM and AF patients is mandatory.