Arterial stiffness and SBP variability in children and adolescents.

BACKGROUND: The aim of this study was to explore the impact of ambulatory blood pressure (ABP) parameters on arterial stiffness measured by carotid-femoral pulse wave velocity (cf-PWV) in children and adolescents. METHOD: The study population consisted of 138 consecutive young patients (age range 4-20 years) referred to our hypertension center. Office blood pressure (BP), 24-h ABP monitoring and cf-PWV measurements were performed in all patients. Family history and smoking habits were also recorded. RESULTS: Among the study population, 10.6% had cf-PWV values equal to or higher than the 95th percentile of the study population. cf-PWV was higher in the hypertensive compared to the normotensive patients, classified by ABP levels even after adjustment for age and sex. Significant correlations were found between cf-PWV and age, weight, height, estimated central pulse pressure (PP), office SBP and DBP, and ABP parameters including 24-h SBP and DBP, weighted 24-h SBP variability, 24-h SBP and DBP load, 24-h mean arterial pressure (MAP), daytime and night-time SBP, daytime and night-time SBP variability, but not with office and 24-h heart rate, 24-h heart rate variability, 24-h daytime and night-time PP, DBP variability, ambulatory arterial stiffeness index and BMI z-score. In analysis of covariance, only weighted 24-h SBP variability (ß = 0.28, P < 0.05) and daytime SBP variability (ß = 0.15, P < 0.05) were the independent determinants of cf-PWV in children and adolescents. CONCLUSION: These data may suggest that increased SBP variability is closely associated with arterial stiffness in children and adolescents.

Antagonizing 5-HT2A receptors with M100907 and stimulating 5-HT2C receptors with Ro60-0175 blocks cocaine-induced locomotion and zif268 mRNA expression in Sprague-Dawley rats.

Serotonin (5-HT) plays a role in several psychiatric disorders including drug addiction. The 5-HT system modulates the activity of midbrain dopamine (DA) systems, and the behavioural effects of psychostimulants mediated by these systems. The direction of this modulation depends upon the 5-HT receptor subtypes involved, with 5-HT(2A) and 5-HT(2C) receptors having opposing effects. For example the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor agonist Ro60-0175 both attenuate several cocaine-induced behavioural and neurochemical effects. To investigate the possible brain regions involved in the interactions between 5-HT(2A) or 5-HT(2C) receptor ligands and cocaine-induced behaviour, we examined the effects of M100907 or Ro60-0175 on cocaine-induced locomotion and mRNA expression of the immediate early gene zif268. Sprague-Dawley rats were pre-treated with M100907 (0.5mg/kg), Ro60-0175 (1.0mg/kg) or vehicle, and then injected with cocaine (15mg/kg) or vehicle. Locomotor activity was monitored for 60 min before rats were sacrificed for zif268 mRNA in situ hybridization mapping. Cocaine increased locomotor activity and zif268 mRNA expression consistently in the nucleus accumbens core, the orbitofrontal cortex and the caudate. M100907 attenuated cocaine-induced locomotion and zif268 mRNA expression in these brain regions in a defined subset of rats but failed to alter any effects of cocaine in another defined subset of rats. Ro60-0175 blocked cocaine-induced locomotion and zif268 mRNA expression in similar brain regions. Our results suggest that despite the opposing actions of 5-HT at 5-HT(2A) and 5-HT(2C) receptors, ligands acting on these receptors likely modulate cocaine-induced locomotion via a common mechanism to influence DA-dependent circuitry.

Effects of the 5-HT2C receptor agonist Ro60-0175 and the 5-HT2A receptor antagonist M100907 on nicotine self-administration and reinstatement.

The reinforcing effects of nicotine are mediated in part by brain dopamine systems. Serotonin, acting via 5-HT(2A) and 5-HT(2C) receptors, modulates dopamine function. In these experiments we examined the effects of the 5-HT(2C) receptor agonist Ro60-0175 and the 5-HT(2A) receptor antagonist (M100907, volinanserin) on nicotine self-administration and reinstatement of nicotine-seeking. Male Long-Evans rats self-administered nicotine (0.03 mg/kg/infusion, IV) on either a FR5 or a progressive ratio schedule of reinforcement. Ro60-0175 reduced responding for nicotine on both schedules. While Ro60-0175 also reduced responding for food reinforcement, response rates under drug treatment were several-fold higher than in animals responding for nicotine. M100907 did not alter responding for nicotine, or food, on either schedule. In tests of reinstatement of nicotine-seeking, rats were first trained to lever press for IV infusions of nicotine; each infusion was also accompanied by a compound cue consisting of a light and tone. This response was then extinguished over multiple sessions. Injecting rats with a nicotine prime (0.15 mg/kg) reinstated responding; reinstatement was also observed when responses were accompanied by the nicotine associated cue. Ro60-0175 attenuated reinstatement of responding induced by nicotine and by the cue. The effects of Ro60-0175 on both forms of reinstatement were blocked by the 5-HT(2C) receptor antagonist SB242084. M100907 also reduced reinstatement induced by either the nicotine prime or by the nicotine associated cue. The results indicate that 5-HT(2C) and 5-HT(2A) receptors may be potential targets for therapies to treat some aspects of nicotine dependence.

The 5-HT2C receptor agonist lorcaserin reduces nicotine self-administration, discrimination, and reinstatement: relationship to feeding behavior and impulse control.

Lorcaserin ((1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl) is a selective 5-HT(2C) receptor agonist with clinical efficacy in phase-III obesity trials. Based on evidence that this drug class also affects behaviors motivated by drug reinforcement, we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement, as well as the stimulant and discriminative stimulus properties of nicotine in the rat. Acutely administered lorcaserin (0.3-3 mg/kg, subcutaneous (SC)) dose dependently reduced feeding induced by 22-h food deprivation or palatability. Effects up to 1 mg/kg were consistent with a specific effect on feeding motivation. Lorcaserin (0.6-1 mg/kg, SC) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement. In this dose range lorcaserin also reversed the motor stimulant effect of nicotine, reduced intravenous self-administration of nicotine, and attenuated the nicotine cue in rats trained to discriminate nicotine from saline. Lorcaserin also reduced the reinstatement of nicotine-seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement. Lorcaserin did not reinstate nicotine-seeking behavior or substitute for a nicotine cue. Finally, lorcaserin (0.3-1 mg/kg) reduced nicotine-induced increases in anticipatory responding, a measure of impulsive action, in rats performing the five-choice serial reaction time task. Importantly, these results indicate that lorcaserin, and likely other selective 5-HT(2C) receptor agonists, similarly affect both food- and nicotine-motivated behaviors, and nicotine-induced impulsivity. Collectively, these findings highlight a therapeutic potential for 5-HT(2C) agonists such as lorcaserin beyond obesity into addictive behaviors, such as nicotine dependence.

Arterial stiffness and 24 h ambulatory blood pressure monitoring in young healthy volunteers: the early vascular ageing Aristotle University Thessaloniki Study (EVA-ARIS Study).

Differences in 24 h blood pressure (BP) monitoring parameters such as average 24 h BP, day to night BP ratio and BP variability could have an impact in arterial stiffness. The study hypothesis was that despite similar average BP values in ambulatory blood pressure monitoring subjects with increased 24 h BP variability may have increased arterial stiffness. The study population consisted of 115 consecutive young healthy volunteers. Carotid-femoral PWV was measured in all subjects. Clinic BP was measured and an appropriate cuff was fitted on the non-dominant arm of each subject for a 24 h ambulatory blood pressure monitoring session. Waist to hip ratio as well as BMI was measured. Family history and smoking habits were recorded. In univariate analysis, estimated carotid-femoral PWV showed a significant correlation with age, weight, waist circumference, height, clinic systolic and diastolic BP, 24-h systolic and diastolic BP, 24-h pulse pressure, 24-h systolic and diastolic BP variability, daytime systolic and diastolic BP, daytime pulse pressure, daytime systolic and diastolic BP variability, nighttime systolic BP, nighttime pulse pressure and nighttime systolic BP variability. In multivariate regression analysis, age (B=0.95, P<0.001) and 24 h systolic BP variability (B=0.28, P<0.001) were independent determinanats of arterial stiffness. In conclusions, increased 24 h systolic BP variability is associated with arterial stiffness in young healthy volunteers. Pulse wave velocity in a young healthy population is useful to identify determinants of premature arterial stiffness, thus further elucidating the aspects of early vascular ageing.

Impulsive action induced by amphetamine, cocaine and MK801 is reduced by 5-HT(2C) receptor stimulation and 5-HT(2A) receptor blockade.

Previous work has shown that 5-HT(2C) receptor agonists and 5-HT(2A) receptor antagonists reduce impulsive action, as well as the locomotor stimulant effect of psychomotor stimulants. Since psychomotor stimulants also increase impulsive action we examined the effects of the 5-HT(2C) receptor agonist Ro60-0175, and the 5-HT(2A) receptor antagonist M100907 on impulsive action induced by amphetamine, cocaine and the NMDA receptor antagonist MK801 (dizocilpine). Impulsive action was measured in adult male Long-Evans rats as premature responding in the 5-choice serial reaction time (5-CSRT) test. Initially, we determined that amphetamine (0.3 mg/kg), cocaine (15 mg/kg) and MK801 (0.03 mg/kg) induced comparable premature response rates of approximately 50-70 per session, compared to 10-15 responses under baseline conditions. Each drug and its vehicle were then tested in combination with Ro60-0175 (0.1 and 0.6 mg/kg) or its vehicle, or M100907 (0.5 mg/kg) or its vehicle. At 0.1 mg/kg Ro60-0175 did not modify the effects of amphetamine, cocaine or MK801. In contrast, the 0.6 mg/kg dose reduced premature responses induced by amphetamine, cocaine and MK801. M100907 also reduced premature responding induced by all three of these drugs. In general, treatment with Ro60-0175 or M100907 by itself did not consistently alter any of the other aspects of task performance in the 5-CSRT test including number of trials completed, and accuracy of responding. These data show that activation of 5-HT(2C) receptors and blockade of 5-HT(2A) receptors have seemingly similar functional effects on a measure of impulsive action.

Mechanisms of obesity-induced hypertension.

The relationship between obesity and hypertension is well established both in children and adults. The mechanisms through which obesity directly causes hypertension are still an area of research. Activation of the sympathetic nervous system has been considered to have an important function in the pathogenesis of obesity-related hypertension. The arterial-pressure control mechanism of diuresis and natriuresis, according to the principle of infinite feedback gain, seems to be shifted toward higher blood-pressure levels in obese individuals. During the early phases of obesity, primary sodium retention exists as a result of increase in renal tubular reabsorption. Extracellular-fluid volume is expanded and the kidney-fluid apparatus is resetted to a hypertensive level, consistent with a model of hypertension because of volume overload. Plasma renin activity, angiotensinogen, angiotensin II and aldosterone values display significant increase during obesity. Insulin resistance and inflammation may promote an altered profile of vascular function and consequently hypertension. Leptin and other neuropeptides are possible links between obesity and the development of hypertension. Obesity should be considered as a chronic medical condition, which is likely to require long-term treatment. Understanding of the mechanisms associated with obesity-related hypertension is essential for successful treatment strategies.

Obesity and daytime pulse pressure are predictors of left ventricular hypertrophy in true normotensive individuals.

OBJECTIVE: To investigate predictors of left ventricular mass corrected for height2.7 (LVMI) and left ventricular hypertrophy in patients who were found to be normotensive with both office and 24-h ambulatory blood pressure (BP) measurements. METHODS: A total of 805 consecutive patients were analyzed. All patients underwent office BP measurements, 24-h ambulatory BP monitoring, laboratory measurements for cardiovascular risk factors and echocardiography. Individuals with both office and ambulatory normotension were characterized as true normotensive. RESULTS: LVMI was found to be 34.5 +/- 10.9 g/m2.7 in normal-weight patients and 48.7 +/- 13.0 g/m2.7 in obese patients (P < 0.0001). LVMI was found to be 41.7 +/- 10 g/m2.7 in overweight patients, significantly lower than the values of obese patients (P < 0.005) and higher than the values of normal-weight patients (P < 0.001). These results remained significant even after adjustment for age, sex, daytime and nighttime SBP, daytime and nighttime DBP, daytime and nighttime BP variability and daytime and nighttime pulse pressure (PP). In a multivariate analysis model, in which LVMI was the dependent variable and office SBP, office DBP, daytime and nighttime SBP and DBP, daytime and nighttime PPs and variabilities, day-night SBP ratio, fasting serum glucose, triglycerides, total cholesterol, age and BMI were inserted as independent variables with weighted least squares regression by sex, the predictors of LVMI were age, BMI and daytime PP (r2 = 0.31). Left ventricular hypertrophy was 17.67 times more likely in obese patients as compared with normal-weight true normotensive individuals. CONCLUSION: Obesity may represent a significant cardiovascular risk factor even in normotensive individuals. Other predictors of LVMI were ageing and daytime PP.

Effects of 5-HT depletion in the frontal cortex or nucleus accumbens on response inhibition measured in the 5-choice serial reaction time test and on a DRL schedule.

Previous work has shown that global depletion of brain serotonin (5-HT) using the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) increases impulsive like behaviour measured as premature responding on the 5-choice serial reaction time (5-CSRT) test, and inefficient responding on a DRL20 schedule of food reinforcement. The present experiments examined whether these effects could be attributed to loss of 5-HT inputs to either the frontal cortex (FC) or the nucleus accumbens. Infusing 5,7-DHT into the FC depleted 5-HT by more than 80%. This did not alter premature responding on the 5-CSRT test, although the number of trials on which responses were omitted was reduced by this manipulation. Depletion of 5-HT in the FC did not alter responding on the DRL20 schedule, nor when the schedule value was increased to 40s. Infusing 5,7-DHT into the nucleus accumbens depleted 5-HT by greater than 80%, and modestly reduced 5-HT in the FC also. Depletion of 5-HT in the nucleus accumbens did not affect premature responding on the 5-CSRT test in rats trained on this test prior to the lesion. Acquisition of responding on this test was also not affected by this lesion. On the DRL20 schedule response rate was increased and the mean inter-response interval was significantly reduced in lesioned animals. Loss of 5-HT inputs to the FC does not appear to alter response inhibition, whereas loss of 5-HT innervation to the nucleus accumbens only affected inhibitory control on the DRL schedule. The behavioural profile of global 5-HT depletion cannot be accounted for by selective loss of 5-HT innervation to either the FC or the nucleus accumbens.

Gestational treatment with methylazoxymethanol (MAM) that disrupts hippocampal-dependent memory does not alter behavioural response to cocaine.

Schizophrenia is associated with increased rates of substance abuse that are thought to be the result of changes in cortical and mesolimbic dopamine activity. Previous work has shown that gestational methylazoxymethanol acetate (MAM) treatment induces increased mesolimbic dopamine activity when given around the time of embryonic day 17 (ED17), suggesting that MAM treatment may model some aspects of schizophrenia. Given that increased dopaminergic activity facilitates aspects of drug self-administration and reinstatement of drug seeking, the current experiments sought to assess cocaine self-administration in MAM treated animals. Experiment 1 examined the acquisition of cocaine self-administration in ED17 MAM and saline treated rats using a sub-threshold dose of cocaine. In experiment 2 ED17 MAM and saline treated animals were trained to self-administer cocaine and were then assessed under varying doses of cocaine (dose-response), followed by extinction and drug-induced reinstatement of responding. A subset of these animals was trained on a win-shift radial maze task, designed to detect impairments in hippocampal-dependent memory. In experiment 3, MAM and saline treated animals were assessed on a progressive ratio schedule of cocaine delivery. Finally, in experiment 4 MAM and saline treated animals were assessed on cocaine-induced locomotor activity across a range of doses of cocaine. MAM treatment disrupted performance of the win-shift task but did not alter cocaine self-administration or cocaine-induced locomotion. Implications of these results for the MAM model of schizophrenia are discussed.

Left ventricular mass in normotensive, prehypertensive and hypertensive children and adolescents.

The purpose of this study was to investigate differences in left ventricular mass index (LVMI) and the prevalence of left ventricular hypertrophy (LVH) in children and adolescents classified as normotensives, prehypertensives and hypertensives by ambulatory blood pressure (BP) levels. A total of 124 consecutive children and adolescents aged 5 to 18 years were analysed. Patients underwent 24 h ambulatory blood pressure monitoring (ABPM) and echocardiography. Hypertensive and prehypertensive subjects had significantly higher LVMI than normotensives (36.8 +/- 8.4 g/m(2.7) and 34.1 +/- 3.4 g/m(2.7) vs. 29.5 +/- 8.3 g/m(2.7), P < 0.01 and P < 0.05, respectively). In multivariate analysis predictors for LVMI were body mass index (BMI) z score and hypertension (R-squared = 0.31). LVMI values in hypertensive subjects were significantly higher than those of normotensives even after adjustment for age, sex and BMI z score. The prevalence of LVH was significantly higher in the prehypertensive compared to normotensive subjects, and was equal to that of the hypertensive subjects. Hypertension and prehypertension in children and adolescents were associated with pathologically elevated LVMI values. If confirmed in a larger group prehypertensive children may be at risk for target organ damage similar to the condition of established hypertension.

Characterization of methylphenidate self-administration and reinstatement in the rat.

RATIONALE: Methylphenidate, which is used to treat attention deficit/hyperactivity disorder, increases extracellular dopamine by inhibiting the dopamine transporter. Methylphenidate has an abuse potential, and there are increasing reports of recreational use of methylphenidate. Little work has examined methylphenidate self-administration in rodent models. OBJECTIVES: This work characterized intravenous methylphenidate self-administration in rats, determined whether dopamine mediates its reinforcing effects and examined the influence of route of administration on the ability of methylphenidate to reinstate extinguished drug-seeking behaviour. MATERIALS AND METHODS: Rats were trained to self-administer methylphenidate (0.25 mg per infusion) via an intravenous catheter according to a fixed ratio 1 (FR1) or progressive ratio (PR) schedule. The effects of manipulating the dose of methylphenidate and of treatment with the dopamine D1 receptor antagonist SCH23390 or the dopamine D2 receptor antagonist eticlopride (both at 0.01 and 0.03 mg/kg) were examined. Finally, the ability of noncontingent administrations of methylphenidate (intraperitoneal [IP] or gavage) to reinstate extinguished drug-seeking behaviour was examined. RESULTS: Rats readily self-administered methylphenidate dose dependently on FR1 and PR schedules. Treatment with SCH23390 or eticlopride increased the number methylphenidate infusions taken by rats on the FR1 schedule and reduced breaking points on the PR schedule. Following extinction of drug-seeking behaviour, methylphenidate reinstated responding and was more effective at doing so when administered IP. CONCLUSION: These results demonstrate that intravenous methylphenidate is a reinforcer and that its reinforcing efficacy is related to increased dopamine activity at D1 and D2 receptors. Methylphenidate reinstates drug-seeking behaviour; the route of administration modifies this response suggesting that pharmacokinetic factors are important in determining methylphenidate-induced reinstatement.

Neurotoxic lesions of the medial prefrontal cortex or medial striatum impair multiple-location place learning in the water task: evidence for neural structures with complementary roles in behavioural flexibility.

This series of experiments assessed the effects of neurotoxic damage to either the medial prefrontal cortex or the medial striatum on the acquisition of multiple-location place learning in the water task. During training, normal subjects learn to search for a new hidden platform location at the beginning of each training session and to continue to swim to that location until the end of training during that session. By the end of training, normal subjects show one-trail place learning in which they find the new location on the first trial and swim directly to that location on the second swim. Rats with damage to either the medial prefrontal cortex or dorso-medial striatum showed deficits in learning to swim to the new location each day. These deficits were interpreted as impairments in behavioural flexibility. The lesion-induced impairment was not caused by perseverative errors but was manifested in an inability to rapidly acquire a new spatial position in conflict with the previous position. Interestingly, the subjects from both lesion groups were able to show normal place learning and memory after repeated training within a session. The results were interpreted as suggestive of a complementary role of these neural structures in behavioural flexibility.

Target organ damage in "white coat hypertension" and "masked hypertension".

BACKGROUND: In this study we investigated (i) the prevalence of white coat hypertension (WCH) and masked hypertension (MH) in patients who had never been treated earlier with antihypertensive medication, and (ii) the association of these conditions with target organ damage. METHODS: A total of 1,535 consecutive patients underwent office blood pressure (BP) measurements, 24-h ambulatory BP monitoring (ABPM), echocardiography, and ultrasonography of the carotid arteries. Subjects who showed normotension or hypertension on the basis of both office and ambulatory BP (ABP) measurement were characterized as having confirmed normotension or confirmed hypertension, respectively. WCH was defined as office hypertension with ambulatory normotension, and MH as office normotension with ambulatory hypertension. RESULTS: WCH was found in 17.9% and MH in 14.5% of the subjects. The prevalence of WCH was significantly higher in subjects with obesity, while the prevalence of MH was significantly higher in normal-weight subjects. The confirmed hypertensive subjects as well as the masked hypertensive subjects had significantly higher left ventricular mass (LVM) (corrected for body surface area) and carotid intima media thickness (cIMT) than the confirmed normotensive subjects did (108.9 +/- 30.6, 107.1 +/- 29.1 vs. 101.4 +/- 29.9 g/m(2) and 0.68 +/- 0.16, 0.68 +/- 0.21 vs. 0.63 +/- 0.15 mm, respectively, P < 0.005). White coat hypertensive subjects did not have a significantly higher LVM index than confirmed normotensive subjects (101.5 +/- 25.9 vs. 101.4 +/- 29.9 g/m(2)); they tended to have higher cIMT than the confirmed normotensive subjects, but the difference was not statistically significant (0.67 +/- 0.15 vs. 0.63 +/- 0.15 mm). CONCLUSIONS: WCH and MH are common conditions in patients who visit hypertension outpatient clinics. Confirmed hypertension and MH are accompanied by increased LVM index and cIMT, even after adjusting for other risk factors.

A sensitizing regimen of amphetamine that disrupts attentional set-shifting does not disrupt working or long-term memory.

Exposure to an intermittent, escalating dose of amphetamine induces a sensitized state that, both behaviourally and neurochemically, mirrors several features linked to the positive symptoms of schizophrenia. Increasingly it is being realized that cognitive deficits are a core component of schizophrenia; therefore we sought to assess the effects of inducing an amphetamine-sensitized state on memory (working and long-term) and cognitive flexibility, two cognitive domains impaired in schizophrenia. Rats were exposed to a sensitizing regimen of amphetamine (1-5 mg/kg; three times per week for 5 weeks; escalating at 1mg/kg per week) or saline. In experiment 1, animals were tested on an operant delayed non-match to position task (working memory). Experiment 2 used a standard fixed-platform location water maze task (long-term memory), while experiment 3 used a variable-platform location water maze task (long-term memory and working memory). Amphetamine-sensitized animals were not impaired on any of these tasks. In experiment 4, animals were assessed on a strategy selection task in which they were first required to learn to locate a food reward using a particular learning strategy (place or response) then to learn to shift to an alternate learning strategy (response or place). Amphetamine-sensitized animals were not impaired on this task. In the final experiment animals were found to be impaired in performance of the extra-dimensional shift component of an attentional set-shifting task. These results suggest that while amphetamine sensitization does not produce memory impairments similar to those seen in schizophrenia, it does produce strong impairments in set-shifting, suggesting changes in prefrontal function similar to those seen in schizophrenia.

The 5-HT2C receptor agonist Ro60-0175 reduces cocaine self-administration and reinstatement induced by the stressor yohimbine, and contextual cues.

Previously, we showed that the 5-HT2C receptor agonist Ro60-0175 reduces cocaine self-administration, and the ability of cocaine to reinstate responding after extinction of drug-seeking behavior. The present experiments extended these findings further by determining whether the effects of Ro60-0175 on self-administration were sustained with repeated treatment, and whether Ro60-0175 altered reinstatement induced by the pharmacological stressor yohimbine, or by the context in which self-administration occurred. In Experiment 1, Ro60-0175 (1 mg/kg, s.c.) reduced cocaine (0.25 mg/infusion) self-administration maintained by a progressive ratio schedule. This reduction was sustained over eight daily injections. In Experiment 2, rats self-administered cocaine in daily 2 h sessions for 15 days on a FR1 schedule. Following extinction, yohimbine (1 mg/kg, i.p.) reinstated responding, and this effect was reduced dose dependently by Ro60-0175 (0.3-3 mg/kg, s.c.). In Experiment 3, rats were trained to respond for cocaine on a FR1 schedule in a distinct environmental context (A); responding was then extinguished in a different context (B). Reinstatement tests occurred in either context A or B. Responding was reinstated only when rats were tested in the original self-administration context (A). This reinstatement was reduced dose dependently by Ro60-0175. All effects of Ro60-0175 were blocked by the 5-HT2C receptor antagonist SB242084. Thus, Ro60-0175, acting via 5-HT2C receptors, reduces cocaine self-administration and cocaine-seeking triggered by a stressor and by drug-associated cues. The effects of Ro60-0175 do not exhibit tolerance within the 8-day test period. These results indicate that selective 5-HT2C receptor agonists may be a useful pharmacological strategy for treatment of drug abuse.

Hypertension and hypothyroidism: results from an ambulatory blood pressure monitoring study.

OBJECTIVE: To examine differences between hypothyroid patients and healthy volunteers in 24-h ambulatory blood pressure parameters. METHODS: The study population consisted of 100 individuals who were recently diagnosed for hypothyroidism. These patients had never been treated before with antihypertensive treatment or received drugs for hypothyroidism. All participants underwent 24-h ambulatory blood pressure monitoring. The control group consisted of 100 healthy volunteers matched one to one for gender and age with the hypothyroid participants. RESULTS: Clinic systolic and diastolic blood pressures were significantly higher in patients with hypothyroidism compared with volunteers. The mean 24-h systolic blood pressure and 24-h pulse pressure were significantly higher in patients with hypothyroidism compared with volunteers. The 24-h systolic blood pressure variability was also significantly higher in patients with hypothyroidism. Fasting serum cholesterol tended to be higher in patients with hypothyroidism compared with volunteers but the difference was not statistically significant, while fasting serum triglycerides were significantly higher. Body mass index was also significantly higher in patients with hypothyroidism. CONCLUSIONS: These findings indicate that hypothyroidism may be an important predictor of higher mean 24-h systolic blood pressure, 24-h pulse pressure and 24-h systolic blood pressure variability, parameters of ambulatory blood pressure monitoring that have been previously associated with higher cardiovascular target organ damage.

Gestational methylazoxymethanol acetate treatment impairs select cognitive functions: parallels to schizophrenia.

Gestational methylazoxymethanol acetate (MAM) exposure has been suggested to produce neural and behavioral abnormalities similar to those seen in schizophrenia. In order to assess MAM treatment as a model of schizophrenia, pregnant female rats were injected with MAM (22 mg/kg) on gestational day 17 and their offspring were assessed in adulthood on a series of cognitive tasks. The first experiment involved an attentional set-shifting task, a rodent analog of the Wisconsin card sort task. In experiment 2, animals were tested on the 5-choice serial reaction time task, a rodent analog of the continuous performance task. In the final experiment animals were assessed on a differential reinforcement of low rate of responding 20 s schedule of reinforcement (DRL-20), a task that is sensitive to changes in inhibitory control. In the first experiment, MAM-treated animals required a greater number of trials than controls to successfully learn an extradimensional shift on the set-shifting task, and had difficulties in learning to reverse a previously acquired discrimination. In contrast, MAM-treated animals showed little impairment on the 5-choice task, aside from a modest but consistent increase in premature responding. Finally, MAM exposed animals showed substantial impairments in DRL performance. Post-mortem analysis of brain tissue showed significant decreases in tissue weight in the hippocampus, parietal cortex, prefrontal cortex, and dorsal striatum of MAM-treated animals. These results support the notion that MAM treatment may simulate some aspects of schizophrenic cognition.

A sensitizing regimen of amphetamine impairs visual attention in the 5-choice serial reaction time test: reversal by a D1 receptor agonist injected into the medial prefrontal cortex.

Exposure to repeated, intermittent, escalating doses of amphetamine in rats disrupts information processing in several tasks. Some of these deficits, notably impaired attentional set shifting, may reflect altered prefrontal cortex function. This study examined the effects of repeated treatment with amphetamine on performance in the 5-choice serial reaction time test. This test measures sustained visual attention, a behavior that is known to require the prefrontal cortex. Rats were trained to respond to a brief light stimulus presented randomly in one of five spatial locations, with 100 trials per session. Once performance had stabilized rats were treated with escalating doses of amphetamine (three injections per week for 5 weeks at 1-5 mg/kg per week); testing was continued on nondrug days, and for several weeks of withdrawal. During the amphetamine-treatment and withdrawal phases accuracy of responding was unaffected, but errors of omission increased. Lengthening the stimulus duration abolished this effect. Reducing the stimulus duration also reduced response accuracy and this effect was more marked in amphetamine-treated rats. Both reduced accuracy, and increased omissions, seen in amphetamine-treated rats were reversed by injecting the D1 receptor agonist SKF38393 into the medial prefrontal cortex. This treatment also prevented the decline in accuracy in control animals that resulted from reducing the stimulus duration. These results, indicating that exposure to amphetamine induces a long-lasting deficit in visual attention, add to a growing list of deficits suggesting that amphetamine-sensitized state may model the cognitive deficit state in schizophrenia. The reversal of these deficits by a D1 receptor agonist provides further evidence that prefrontal D1 dopamine receptors are involved in cognition, and may be a potential target for treatment of impaired cognition in schizophrenia.

Sensitization to amphetamine, but not PCP, impairs attentional set shifting: reversal by a D1 receptor agonist injected into the medial prefrontal cortex.

RATIONALE: Repeated exposure to psychomotor stimulants can lead to sensitization to their effects, and sensitization has been implicated in the pathophysiology of schizophrenia and drug abuse. These disorders are characterized by cognitive deficits, particularly in prefrontally mediated executive function. OBJECTIVE: The present experiments were conducted to investigate the effects of sensitizing regimens of amphetamine and phencyclidine (PCP) on attentional set shifting. METHODS: Rats received injections of amphetamine, PCP or saline three times per week for 5 weeks. Four weeks later, rats were trained to dig for food in one of two bowls, each bowl having an odour and a texture. Only one dimension (odour or texture) correctly predicted which bowl was baited. Rats were then tested on a series of discriminations including those requiring an intra-dimensional shift (IDS), an extra-dimensional shift (EDS) or a reversal of previously relevant and irrelevant stimuli. RESULTS: Rats sensitized to amphetamine performed normally on the IDS, but were impaired on the EDS, as well as on reversal discriminations. PCP-sensitized rats were unaffected on any of the discriminations. In amphetamine-sensitized rats the deficit at the EDS stage was reversed by infusion of the D(1) receptor agonist SKF38393 into the medial prefrontal cortex (mPFC). CONCLUSIONS: Results show that the amphetamine-sensitized state impairs prefrontally mediated attentional set shifting. This is consistent with cognitive deficits in schizophrenia and addiction, and with the evidence that amphetamine sensitization is accompanied by functional changes in the mPFC. These results further add to a growing literature showing that activating D(1) receptors in the mPFC improves aspects of cognition.