Effects of prolonged and maintenance strength training on force production, walking, and balance in aging women and men.

To examine effects of 21-week twice/week strength training (ST) period followed by an additional 21-week twice or once/week ST period on force production, walking and balance in aging people. Seventy-two women (58 ± 7 years; W) and 63 (58 ± 6 years) men (M) were randomized for the first 21-week ST period: STW and STM, control (C) CW and CM. Training participants were randomized for the second 21-week ST period: once/week STWx1 and STMx1, twice/week STWx2 and STMx2. LegPress, isometric leg extension rate of force development (RFD), walking time, and balance. First 21-week ST period: leg press, RFD, balance, and walking improved significantly in STW and STM. Second 21-week ST period: leg press first increased in STMx1 and STMx2, and then decreased to the level of 21 weeks in STMx2 and remained unchanged in STWx2 and decreased in STWx1 and STMx1. Walking and balance improved significantly in STWx1 and STWx2. A progressive 21-week ST period twice/week in aging people can lead to large improvements in maximal strength, walking time, and balance in both genders. A further strength training period with the same amount of training may maintain the strength gains, whereas balance and walking may be maintained with less training.

Effect of age on the association between body fat percentage and maximal walking speed.

OBJECTIVE: To study the effect of age on the association between body fat percentage and maximal walking speed in older people. DESIGN AND PARTICIPANTS: Cross-sectional analysis of data collected in the Finnish population-based Health 2000 Survey involving 916 men and 1 222 women aged 55 years and older with complete data on body composition and a walking speed test. METHODS: Body fat percentage was assessed using bioelectrical impedance analysis and maximal walking speed based on a timed walking test over a distance of 6.1 meters. Linear regression models were used to study the effect of age on association between body fat percentage and maximal walking speed. RESULTS: The association between body fat percentage quartiles and maximal walking speed differed significantly between persons of different ages (p for age interaction = 0.027). In the age-stratified analyses, the association between body fat percentage and maximal walking speed remained significant among 60-69-year olds and 70-79-year-olds, but disappeared among 55-59-year-olds and 80-year and older after adjustment for potential covariates. Body fat percentage explained 11% of the variation in maximal walking speed among 55-59-year-olds, 21% among 60-69-year-olds, 17% among 70-79-year-olds and 11% among 80-year and older. CONCLUSION: Association between body fat percentage and maximal walking speed was strongest between the ages of 60 and 79 years. The results suggest that the effects of excess body fatness are especially harmful for physical functioning among adults in their sixties and seventies and they could benefit from interventions.

Muscle mass and strength, body composition and dietary intake in master strength athletes vs untrained men of different ages.

AIM: The aim of this study was to compare muscle strength and thickness, body composition and dietary intake between master strength athletes and controls. METHODS: Cross-sectional comparison between: 1) young control men (25.7+/-3.4 y; n=10); 2) middle-aged master athletes (52.1+/-4.7 y; n=9); 3) middle-aged control men (51.9+/-3.1 y; n=11); 4) older master athletes (71.8+/-3.8 y; n=8); and 5) older control men (70.6+/-3.3 y; n=10). Athletes had been strength trained for 22.8+/-14.9 y. Maximal isometric strength of the leg extensors was measured with a leg dynamometer, body composition by skin folds, muscle thickness of the vastus lateralis with an ultrasound scanner and dietary intake by food diaries for 4 days. RESULTS: Athletes had more lean body mass than age-matched controls (P<0.001-0.05) and young controls more than older controls (P<0.01). No group differences were observed in the thickness of vastus lateralis. Athletes showed higher absolute strength and strength per vastus lateralis thickness ratio than all control groups (P<0.01-0.001). Body mass adjusted dietary intake did not differ between the strength trained and control men. Dietary intake did not correlate with strength, muscle thickness and lean body mass. CONCLUSION: The present older men with a long-term history of strength training showed greater muscle strength and strength per muscle thickness ratio than the untrained controls. The data support the usefulness of continuous strength training to preserve muscle strength in older men.

Dietary intake, serum hormones, muscle mass and strength during strength training in 49 - 73-year-old men.

Effects of dietary intake on serum hormones, muscle cross-sectional area (CSA) and strength during strength training were studied in two groups of men: 1) strength training + nutritional counseling (n = 22, 59.1 +/- 6.1 yrs), and 2) strength training (n = 23, 58.5 +/- 7.1 yrs). Both groups performed strength training twice a week for 21 weeks. Counseling increased carbohydrate (p < 0.01) and fiber intake (p < 0.001) and polyunsaturated/saturated fat-ratio (p < 0.05) and decreased fat intake (p < 0.01). Muscle strength and CSA increased by 16 - 20 % and by 5.4 - 5.9 % in both groups (p < 0.001). Changes in protein content of diet correlated with the changes in the acute postexercise concentrations of total (r = 0.64, p < 0.01) and free testosterone (r = 0.54, p < 0.05) after training in the counseling group. Moreover, changes in the free testosterone responses to heavy-resistance exercise correlated with the increases in the muscle CSA (r = 0.52, p < 0.05) in the counseling group. Serum basal testosterone/sex hormone-binding globulin-ratios correlated with the body mass normalized energy (kJ/kg: r = 0.54, p < 0.001), protein (g/kg: r = 0.42, p < 0.01) and fat (g/kg: r = 0.51, p < 0.01) intake in all participants during the training. The data indicate that protein and fat intake may influence serum testosterone concentrations and that the changes in exercise-induced testosterone responses may contribute to muscle mass development during strength training.

Effects of strength training and reduced training on functional performance and metabolic health indicators in middle-aged men.

Changes in muscular fitness and metabolic health indicators were examined in 22 men (57.9 +/- 6.6 years, BMI 24.5 +/- 2.6 kg/m (2)) and 21 control men (58.2 +/- 6.1 years, BMI 25.4 +/- 2.8 kg/m (2)) during two consecutive 21-week periods: 1) whole body progressive strength training (ST: twice a week), and 2) continued reduced training (CRT: 3 ST sessions/2 weeks, n = 17 + 17). After the 21-week ST period, maximal strength of leg extensors increased in the ST group by 19.6 +/- 7.6 % vs. 2.8 +/- 4.4 % (p < 0.001) and also 10-m walking time and 10-step stair-climbing time shortened by - 17.2 +/- 7.6 % vs. 4.1 +/- 3.9 % (p < 0.01) and by - 8.2 +/- 6.8 % vs. - 3.0 +/- 6.8 % (p < 0.05) compared to the controls. Systolic blood pressure (BP) decreased in the ST group by - 4.4 +/- 6.7 % vs. 1.3 +/- 9.5 % (p < 0.05) compared to the controls after the ST period. Muscle strength as well as walking and stair-climbing times remained the same during the CRT. However, the changes in diastolic BP (- 8.9 +/- 8.7 % vs. - 1.0 +/- 6.6 %, p < 0.05) and fasting blood glucose concentrations (0.1 +/- 0.4 mmol/L vs. 0.3 +/- 0.4 mmol/L, p < 0.05) differed between the ST and control groups after the whole 42-week study period. Strength training has positive health effects in aging men by increasing maximal strength and functional performance and by decreasing resting blood pressure and high-intensity reduced strength training can maintain these health benefits.

Pharmacological characterization and CNS effects of a novel highly selective alpha2C-adrenoceptor antagonist JP-1302.

BACKGROUND AND PURPOSE: Pharmacological validation of novel functions for the alpha2A-, alpha2B-, and alpha2C-adrenoceptor (AR) subtypes has been hampered by the limited specificity and subtype-selectivity of available ligands. The current study describes a novel highly selective alpha2C-adrenoceptor antagonist, JP-1302 (acridin-9-yl-[4-(4-methylpiperazin-1-yl)-phenyl]amine). EXPERIMENTAL APPROACH: Standard in vitro binding and antagonism assays were employed to demonstrate the alpha2C-AR specificity of JP-1302. In addition, JP-1302 was tested in the forced swimming test (FST) and the prepulse-inhibition of startle reflex (PPI) model because mice with genetically altered alpha2C-adrenoceptors have previously been shown to exhibit different reactivity in these tests when compared to wild-type controls. KEY RESULTS: JP-1302 displayed antagonism potencies (KB values) of 1,500, 2,200 and 16 nM at the human alpha2A-, alpha2B-, and alpha2C-adrenoceptor subtypes, respectively. JP-1302 produced antidepressant and antipsychotic-like effects, i.e. it effectively reduced immobility in the FST and reversed the phencyclidine-induced PPI deficit. Unlike the alpha2-subtype non-selective antagonist atipamezole, JP-1302 was not able to antagonize alpha2-agonist-induced sedation (measured as inhibition of spontaneous locomotor activity), hypothermia, alpha2-agonist-induced mydriasis or inhibition of vas deferens contractions, effects that have been generally attributed to the alpha2A-adrenoceptor subtype. In contrast to JP-1302, atipamezole did not antagonize the PCP-induced prepulse-inhibition deficit. CONCLUSIONS AND IMPLICATIONS: The results provide further support for the hypothesis that specific antagonism of the alpha2C-adrenoceptor may have therapeutic potential as a novel mechanism for the treatment of neuropsychiatric disorders.

Serum, cheek cell and breast milk fatty acid compositions in infants with atopic and non-atopic eczema.

BACKGROUND: The major theory implicating diet with allergic diseases is associated with altered food consumption and subsequent changes in fatty acid composition. OBJECTIVE: To investigate fatty acid compositions among infants with atopic and non-atopic eczema and healthy infants and to evaluate the expediency of non-invasive cheek cell phospholipid fatty acid composition as a marker in patients with eczema. METHODS: Diagnosis of eczema in infants was confirmed clinically and by positive (atopic eczema, n=6) or negative (non-atopic eczema, n=6) skin prick testing in comparison with controls (n=19). The fatty acid compositions of infant cheek cell and serum phospholipids and breast milk total lipids were analysed by gas chromatography. RESULTS: The distinction between atopic and non-atopic eczema was manifested in cheek cell phospholipids as linoleic acid (14.69 (13.67-15.53)% of total fatty acids; the median (interquartile range)), the sum of n-6 fatty acids (19.94 (19.06-20.53)%) and the sum of polyunsaturated fatty acids (22.70 (21.31-23.28)%) were higher in infants with atopic eczema compared with non-atopic eczema (12.69 (10.87-13.93); 17.72 (15.63-18.91) and 19.90 (17.64-21.06), respectively; P<0.05) and controls (12.50 (12.16-13.42); 18.19 (17.43-18.70) and 20.32 (19.32-21.03), respectively; P<0.05). Serum phospholipid gamma-linolenic acid was lower in both atopic and non-atopic eczema compared with controls (P<0.05) and additionally eicosapentaenoic acid was higher in atopic eczema compared with controls (P<0.05). CONCLUSION: These preliminary results suggest differences in fatty acid compositions between the two types of eczema, calling for further evaluation in a larger setting. The two types of eczema may be regulated by different immunological processes, and fatty acids may have a more profound role in the atopic type.

Relationship between diet and serum anabolic hormone responses to heavy-resistance exercise in men.

Relationship between dietary intake and serum anabolic hormone concentrations of testosterone (T), free testosterone (FT), and growth hormone were examined at rest as well as after the heavy-resistance exercise (HRE) in 8 strength athletes (SA) and 10 physically active non-athletes (NA). In the first part of the study serum basal anabolic hormone concentrations and dietary intake were examined in the total group of subjects. In the second part of the study a subgroup of 5 SA and 5 NA performed the high volume and high intensity HRE. Dietary intake was registered by dietary diaries for 4 days preceding the loading day. Significant correlations were observed between serum basal T and fat (E%: r = 0.55, p < 0.05, g/kg: r = 0.65, p < 0.01) and protein intake (E%: r = - 0.77, p < 0.001, g/kg: r = - 0.68, p < 0.01) in the total group of subjects. However, when the two groups were examined separately the significant relationships between serum basal T and dietary fat and protein could be noticed in SA only (fat g/kg: SA r = 0.77, p < 0.05; in NA r = 0.44, n.s., protein g/kg: SA r = - 0.84, p < 0.05; in NA r = 0.27, n.s.). Both serum T and FT responses to HRE were correlated with fat (E%: r = 0.85, p < 0.01 and r = 0.73, p < 0.05, g/kg: r = 0.72, p < 0.05 and r = 0.77, p < 0.01) and protein (E%: r = - 0.81, p < 0.01 and r = - 0.69, p < 0.05, g/kg: r = - 0.86, p < 0.01 and r = - 0.65, p < 0.05). The results suggest the possible role of diet leading to alterations in serum T and FT during prolonged strength training, and that diets with insufficient fat and/or excessive protein may compromise the anabolic hormonal environment over a training program.

Behavioral and neurochemical characterization of alpha(2A)-adrenergic receptor knockout mice.

Genetic manipulation of mice now provides new tools to evaluate the biological functions of the alpha(2)-adrenergic receptor (alpha(2)-AR) subtypes (alpha(2A), alpha(2B), and alpha(2C)). To investigate the role of the alpha(2A)-AR in the modulation of mouse primary behavioral characteristics and brain neurochemistry, mice with targeted inactivation of the gene for the alpha(2A)-AR were compared with wild-type C57BL/6 control animals. First, a comprehensive behavioral screen was employed to provide a detailed characterization of basic neurologic functions. Thereafter, the mice were analyzed in three models of anxiety, i.e. the elevated-plus maze test, the marble burying test and the open field test. The diurnal activity pattern of the mice was assessed in a 24-h locomotor activity test. Furthermore, receptor autoradiography of the brain was performed using the subtype-non-selective alpha(2)-AR antagonist radioligand [(3)H]RS-79948-197. Lack of the alpha(2A)-AR was associated with alterations in autonomic functions, including increased heart rate and piloerection. The mutant mice also exhibited impaired motor coordination skills, increased anxiety-like behavior and an abnormal diurnal activity pattern. In addition, neurochemical analysis of monoamine neurotransmitters revealed a considerable increase in brain norepinephrine turnover in mice lacking alpha(2A)-AR. Our results provide further support for the crucial role of the alpha(2A)-AR in modulating brain noradrenergic neurotransmission and many aspects of mouse behavior and physiology.

Spatial working memory improvement by an alpha2-adrenoceptor agonist dexmedetomidine is not mediated through alpha2C-adrenoceptor.

1. Aged alpha2C-adrenoceptor knockout and wild type mice were used to investigate whether alpha2C-adrenoceptors are involved in mediating the beneficial effects of alpha2-adrenoceptor agonist, dexmedetomidine, on spatial working memory. 2. A win-stay task in the radial arm maze was used to dissociate the effects of dexmedetomidine on working vs. reference memory. In addition, the animals were tested in simple response habit learning in the T-maze. 3. Knockout mice made more working memory errors after the change of the baited arm in radial arm maze, but after training reached again as accurate level of performance as wild type controls. Dexmedetomidine 5 and 10 microg/kg alleviated the increase in spatial working memory errors after the change of the baited arm in knockout mice. Knockout and wild type mice performed equally well in T-maze, and dexmedetomidine had no effect on this simple response learning. 4. The present results indicate that alpha2-adrenoceptor agonists have a selective effect on spatial working memory not only in monkeys but also in mice. Further, this study confirms our earlier finding that the presence of alpha2C-adrenoceptors is not necessary for the spatial working memory enhancing effect of alpha2-adrenoceptor agonists.

Evaluation of the alpha2C-adrenoceptor as a neuropsychiatric drug target studies in transgenic mouse models.

The functional characterization of the three distinct alpha2-adrenoceptor (Q2-AR) subtypes was for long hampered by the inavailability of subtype-selective pharmacological probes. Recent studies with gene-targeted mice have revealed that the alpha2A-AR has a major role in the mediation of many prominent effects of subtype non-selective alpha2-AR agonists, i.e. sedation, analgesia, hypothermia, sympatho-inhibition, and reduction of blood pressure. We have now employed several neuropsychopharmacological test models to investigate the effects mediated by the alpha2C-AR subtype and this receptor's potential as a CNS drug target. The studies employed two genetically engineered mouse strains, having either a targeted inactivation of the alpha2C-AR gene (alpha2C-KO) or over-expressing the alpha2C-AR (alpha2C-OE). Lack of alpha2C-AR expression was associated with increased amphetamine-induced locomotor activity, startle reactivity, aggression, and activity in the forced swimming test; prepulse inhibition of the startle reflex was attenuated. Opposite changes were observed in the alpha2C-OE mice. The results suggest that the alpha2C-AR subtype has a distinct inhibitory role in the processing of sensory information and in the control of motor and emotion-related activities in the CNS. It is therefore possible that alpha2C-AR-selective drugs may have therapeutic value in the treatment of various neuropsychiatric disorders.

Overexpression of alpha2C-adrenoceptors impairs water maze navigation.

We investigated the role of overexpression of alpha2C-adrenoceptors in water maze navigation in mice transgenically manipulated to have a threefold overexpression of the alpha2C-adrenoreceptors. Alpha2C-adrenoreceptors overexpressing mice swam more in the peripheral annulus of the pool and did not find the hidden escape platform as well as the wild type control mice. A subtype-nonselective alpha2-adrenoreceptor antagonist, atipamezole (ATI, 1000 microg/kg, s.c.), fully reversed the deficit in platform finding and search strategy in overexpressing mice. Noradrenaline depletion (-95%) induced by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) did not impair platform finding of wild type or overexpressing mice. The DSP-4 lesion slightly increased swimming in the peripheral annulus in wild type mice, but not in overexpressing mice. The DSP-4 lesion produced a dissociable effect on the action of atipamezole to improve platform finding and search strategy in overexpressing mice: atipamezole did not alleviate the platform finding deficit in DSP-4 lesioned overexpressing mice, but normalized their abnormal search strategy. These results suggest that the abnormal search pattern and deficit in the accuracy of platform finding are mediated by constitutive activity of overexpressed alpha2C-adrenoreceptors.

Genetic alteration of the alpha2-adrenoceptor subtype c in mice affects the development of behavioral despair and stress-induced increases in plasma corticosterone levels.

alpha2-Adrenoceptors (alpha2-AR) modulate many central nervous system functions, such as regulation of sympathetic tone, vigilance, attention, and reactivity to environmental stressors. Three alpha2-AR subtypes (alpha2A, alpha2B, and alpha2C) with distinct tissue-distribution patterns are known to exist, but the functional significance of each subtype is not clear. Since specific, alpha2-AR subtype-selective pharmacological probes are not available, mice with genetically altered alpha2C-AR expression were studied in order to investigate the possible involvement of the alpha2C-AR in physiological and behavioral responses to acute and repeated stress. A modified version of Porsolt's forced swimming test was used to assess the possible effects of altered alpha2C-AR expression on the development of behavioral despair. alpha2C-Overexpression increased and the lack of alpha2C-AR (alpha2C-KO) decreased the immobility of mice in the forced swimming test, ie alpha2C-AR expression appeared to promote the development of behavioral despair. In addition, alpha2C-KO was associated with attenuated elevation of plasma corticosterone after different stressors, and overexpression of alpha2C-ARs was linked with increased corticosterone levels after repeated stress. Moreover, the brain dopamine and serotonin balance, but not norepinephrine turnover, was dependent on alpha2C-AR expression, and the expression of c-fos and junB mRNA was increased in alpha2C-KO mice. Since alpha2C-KO produced stress-protective effects, and alpha2C-AR overexpression seemed to promote the development of changes related to depression, it is suggested that a yet-to-be developed subtype-selective alpha2C-AR antagonist might have therapeutic value in the treatment of stress-related neuropsychiatric disorders.

Alpha2C-adrenoceptor overexpression disrupts execution of spatial and non-spatial search patterns.

We investigated the role of alpha2C-adrenoceptors in the modulation of spatial and non-spatial navigation behaviour. Alpha2C-adrenoceptor overexpressing mice developed an ineffective thigmotaxic search pattern characterized by swimming close to the pool walls during both spatial and non-spatial water maze training. A subtype-non-selective alpha2-adrenoceptor antagonist, atipamezole (1000 microg/kg, s.c.), fully reversed this impairment in their search strategy. Withdrawal of atipamezole at the end of spatial training resulted in an immediate disruption of the search pattern in alpha2C-adrenoceptor overexpressing mice. The swimming pattern of alpha2C-adrenoceptor overexpressing mice during a five day free swimming period was normal, when no cognitive component was required. Diazepam (0.3 and 1.0 mg/kg, i.p.), neither improved the accuracy in finding the platform nor decreased thigmotaxis. These results suggest that alpha2C-adrenoceptors may modulate the execution of complex navigation patterns.

Role of alpha2C-adrenoceptor subtype in spatial working memory as revealed by mice with targeted disruption of the alpha2C-adrenoceptor gene.

The role of the alpha2C-adrenoceptor subtype in mediating the beneficial effect of alpha2-adrenoceptor agonists on spatial working memory was studied in adult mice with targeted inactivation of the alpha2C-receptor gene (KO) and their wild-type controls (WT). A delayed alternation task was run in a T-maze with mixed delays varying from 20 s to 120 s. Dexmedetomidine, a specific but subtype nonselective alpha2-adrenoceptor agonist, dose-dependently decreased the total number of errors. The effect was strongest at the dose of 5 microg/kg (s.c.), and was observed similarly in KO and WT mice. KO mice performed inferior to WT mice due to a higher number of perseverative errors. Dexmedetomidine slowed initiation of the motor response in the start phase at lower doses in WT mice than in KO mice but no such difference was observed in the return phase of the task, suggesting involvement of alpha2C-adrenoceptors in the cognitive aspect of response preparation or in response sequence initiation. According to these findings, enhancement of spatial working memory is best achieved with alpha2-adrenoceptor agonists which have neither agonistic nor antagonistic effects at the alpha2C-adrenoceptor subtype.

Alpha2C-adrenoceptor-overexpressing mice are impaired in executing nonspatial and spatial escape strategies.

Drugs acting via alpha2-adrenoceptors modulate cognitive functions mediated via frontostriatothalamic feedback loops. The alpha2C-adrenoceptor subtype is expressed in the basal ganglia, hippocampus, and neocortex, areas that are involved in memory and other cognitive functions. alpha2C-Overexpressing (OE) mice were impaired in spatial or nonspatial water maze (WM) tests, and alpha2 antagonist treatment fully reversed the WM escape defect in OE mice. However, alpha2C-overexpression did not influence open field and passive avoidance behaviors or cortical EEG arousal or the actions of alpha2 agonist or antagonist drugs on these functions. Our results suggest that alpha2C-adrenoceptors can modulate navigation to a hidden or visible escape platform, whereas many other actions of alpha2-adrenergic agents, such as sedation, are not mediated via alpha2C-adrenoceptors. Therefore, alpha2-agonists lacking alpha2C-AR affinity or alpha2C-AR subtype-selective alpha2 antagonists could modulate functioning of frontostriatothalamic feedback loops more effectively than the current subtype-nonselective drugs.

D-amphetamine and L-5-hydroxytryptophan-induced behaviours in mice with genetically-altered expression of the alpha2C-adrenergic receptor subtype.

Three human and mouse genes encoding alpha2-adrenoceptor subtypes (alpha2A, alpha2B, and alpha2C) have been cloned. The alpha2C-adrenoceptor is the most abundant alpha2-adrenoceptor subtype in the striatum and modulates metabolism of both dopamine and serotonin. To investigate the possible involvement of the alpha2C-adrenoceptor subtype in behaviours regulated by dopamine and serotonin, two strains of genetically-engineered mice were examined. One had a targeted inactivation of the alpha2C-adrenoceptor gene, and the other had tissue-specific over-expression of alpha2C-adrenoceptors. The locomotor activity of the mice was evaluated after stimulation with D-amphetamine, and the behavioural serotonin syndrome and head twitches were investigated after L-5-hydroxytryptophan treatment. In addition, the effects of D-amphetamine and L-5-hydroxytryptophan were studied after pretreatment with dexmedetomidine, a subtype-nonselective alpha2-adrenoceptor agonist. The lack of alpha2C-adrenoceptor expression increased and the over-expression of alpha2C-adrenoceptors decreased the response to D-amphetamine stimulation. The effect of alpha2C-adrenoceptor gene inactivation was more prominent in D-amphetamine-treated males than in females. Dexmedetomidine inhibited D-amphetamine-induced hyperlocomotion and the L-5-hydroxytryptophan-induced serotonin syndrome, but the inhibition was attenuated in mice lacking alpha2C-adrenoceptors. However, the head twitches induced by L-5-hydroxytryptophan were effectively inhibited by dexmedetomidine in all studied mice, which suggests that alpha2A-adrenoceptors mediate the inhibition of the head twitch response. The results lend further support to the proposed existence of functionally distinct alpha2-adrenoceptor subtypes that can serve as new and specific therapeutic targets in various neuropsychiatric diseases.

Adrenergic alpha2C-receptors modulate the acoustic startle reflex, prepulse inhibition, and aggression in mice.

Studies on animal models of stress, anxiety, aggression, and sensorimotor gating have linked specific monoamine neurotransmitter abnormalities to the cognitive and behavioral disturbances associated with many affective neuropsychiatric disorders. Although alpha2-adrenoceptors (alpha2-ARs) have been suggested to have a modulatory role in these disorders, the specific roles of each alpha2-AR subtype (alpha2A, alpha2B, and alpha2C) are largely unknown. The restricted availability of relevant animal models and the lack of subtype-selective alpha2-AR drugs have precluded detailed studies in this area. Therefore, transgenic mice were used to study the possible role of the alpha2C-AR subtype in two well established behavioral paradigms: prepulse inhibition (PPI) of the startle reflex and isolation-induced aggression. The alpha2C-AR-altered mice appear grossly normal, but subtle changes have been observed in their brain dopamine (DA) and serotonin (5-HT) metabolism. In this study, the mice with targeted inactivation of the gene encoding alpha2C-ARs (alpha2C-KO) had enhanced startle responses, diminished PPI, and shortened attack latency in the isolation-aggression test, whereas tissue-specific overexpression of alpha2C-ARs (alpha2C-OE) was associated with opposite effects. Correlation analyses suggested that both the magnitude of the startle response and its relative PPI (PPI%) were modulated by the mutations. In addition, the differences in PPI, observed between drug-naive alpha2C-OE mice and their wild-type controls, were abolished by treatment with a subtype nonselective alpha2-agonist and antagonist. Thus, drugs acting via alpha2C-ARs might have therapeutic value in disorders associated with enhanced startle responses and sensorimotor gating deficits, such as schizophrenia, attention deficit disorder, post-traumatic stress disorder, and drug withdrawal.

Genetic alteration of alpha 2C-adrenoceptor expression in mice: influence on locomotor, hypothermic, and neurochemical effects of dexmedetomidine, a subtype-nonselective alpha 2-adrenoceptor agonist.

alpha 2-Adrenergic receptors (alpha 2-ARs) regulate many physiological functions and are targets for clinically important antihypertensive and anesthetic agents. Three human and mouse genes encoding alpha 2-AR subtypes (alpha 2A, alpha 2B, and alpha 2C) have been cloned. We investigated the involvement of the alpha 2C-AR in alpha 2-adrenergic pharmacology by applying molecular genetic techniques to alter the expression of alpha 2C-AR in mice. The effects of dexmedetomidine, a subtype-nonselective alpha 2-AR agonist, on monoamine turnover in brain and on locomotor activity were similar in mice with targeted inactivation of the alpha 2C-AR gene and in their controls, but the hypothermic effect of the alpha 2-AR agonist was significantly attenuated by the receptor gene inactivation. Correspondingly, another strain of transgenic mice with 3-fold overexpression of alpha 2C-AR in striatum and other brain regions expressing alpha 2C-AR showed normal reductions in brain monoamine metabolism and locomotor activity after dexmedetomidine, but their hypothermic response to the alpha 2C-AR agonists was significantly accentuated. The hypothermic effect of alpha 2-AR agonists thus seems to be mediated in part by alpha 2C-AR. Some small but statistically significant differences between the strains were also noted in brain dopamine metabolism. Lack of alpha 2C-AR expression was linked with reduced levels of homovanillic acid in brain, and mice with increased alpha 2C-AR expression had elevated concentrations of the dopamine metabolite compared with their controls.