Effects of Tart Cherry Juice on Biomarkers of Inflammation and Oxidative Stress in Older Adults.

Inflammation and oxidative stress are important factors in the development of cardiovascular disease and atherosclerosis. The findings of our previous study suggest that 12 weeks consumption of tart cherry juice lowers the levels of systolic blood pressure (BP) and low-density lipoprotein (LDL) cholesterol in older adults. The present study investigated the effects of tart cherry juice on blood biomarkers of inflammation and oxidative stress. In this randomized-controlled clinical trial, a total of 37 men and women between the ages of 65⁻80 were randomly assigned to consume 480 mL of tart cherry juice or control drink daily for 12 weeks. Several blood biomarkers of inflammation and oxidative stress were assessed at baseline and after 12 weeks intervention. After the 12 weeks intervention, tart cherry juice significantly increased the plasma levels of DNA repair activity of 8-oxoguanine glycosylase (p < 0.0001) and lowered (p = 0.03) the mean c-reactive protein (CRP) level compared to the control group. There was a significant group effect observed for plasma CRP (p = 0.03) and malondialdehyde (MDA) (p = 0.03), and a borderline significant group effect observed for plasma oxidized low-density lipoprotein (OxLDL) (p = 0.07). Within group analysis showed that the plasma levels of CRP, MDA, and OxLDL decreased numerically by 25%, 3%, and 11%, respectively after 12 weeks of tart cherry juice consumption compared with corresponding baseline values. The present study suggests that the ability of tart cherry juice to reduce systolic BP and LDL cholesterol, in part, may be due to its anti-oxidative and anti-inflammatory properties. Larger and longer follow-up studies are needed to confirm these findings.

The influence of high intensity exercise and the Val66Met polymorphism on circulating BDNF and locomotor learning.

Brain-derived neurotrophic factor (BDNF) has been directly related to exercise-enhanced motor performance in the neurologically injured animal model; however literature concerning the role of BDNF in the enhancement of motor learning in the human population is limited. Previous studies in healthy subjects have examined the relationship between intensity of an acute bout of exercise, increases in peripheral BDNF and motor learning of a simple isometric upper extremity task. The current study examined the role of high intensity exercise on upregulation of peripheral BDNF levels as well as the role of high intensity exercise in mediation of motor learning and retention of a novel locomotor task in neurologically intact adults. In addition, the impact of a single nucleotide polymorphism in the BDNF gene (Val66Met) in moderating the relationship between exercise and motor learning was explored. It was hypothesized that participation in high intensity exercise prior to practicing a novel walking task (split-belt treadmill walking) would elicit increases in peripheral BDNF as well as promote an increased rate and magnitude of within session learning and retention on a second day of exposure to the walking task. Within session learning and retention would be moderated by the presence or absence of Val66Met polymorphism. Fifty-four neurologically intact participants participated in two sessions of split-belt treadmill walking. Step length and limb phase were measured to assess learning of spatial and temporal parameters of walking. Serum BDNF was collected prior to and immediately following either high intensity exercise or 5min of quiet rest. The results demonstrated that high intensity exercise provides limited additional benefit to learning of a novel locomotor pattern in neurologically intact adults, despite increases in circulating BDNF. In addition, presence of a single nucleotide polymorphism on the BDNF gene did not moderate the magnitude of serum BDNF increases with high intensity exercise, nor did it moderate the relationship between high intensity exercise and locomotor learning.

Stimulation of 5-HT1B receptors decreases cocaine- and sucrose-seeking behavior.

Serotonin systems have been implicated in incentive motivation for cocaine, yet little is known about the role of 5-HT(1B) receptors in these processes. We used the extinction/reinstatement model to examine the effects of the 5-HT(1B/1A) receptor agonist, RU24969, on reinstatement of extinguished cocaine-seeking behavior. Rats trained to self-administer cocaine subsequently underwent extinction. They were then tested twice for cue and cocaine-primed reinstatement of extinguished cocaine-seeking behavior, receiving saline pretreatment 1 day and their assigned dose of RU24969 (0.3, 1.0, 3.0 mg/kg) the other day. Rats were later trained on a schedule of sucrose reinforcement in novel chambers and then tested for effects of RU24969 on cue reinstatement of sucrose-seeking behavior and locomotion. RU24969 decreased cue and cocaine reinstatement of cocaine-seeking behavior and cue reinstatement of sucrose-seeking behavior. Locomotion was increased only at the highest RU24969 dose (3 mg/kg). A subsequent experiment demonstrated that the effects of RU24969 (1 mg/kg) on extinguished cocaine-seeking behavior were reversed by the 5-HT(1B) antagonist GR127935 (3 mg/kg). These findings suggest that the effects of RU24969 on cue and cocaine reinstatement of cocaine-seeking behavior are 5-HT(1B) receptor-mediated. Overall, the results suggest that stimulation of 5-HT(1B) receptors may produce a general decrease in motivation.

Differential roles of 5-HT receptor subtypes in cue and cocaine reinstatement of cocaine-seeking behavior in rats.

The 5-HT indirect agonist, d-fenfluramine, attenuates cue reinstatement of extinguished cocaine-seeking behavior. To investigate the role of 5-HT receptor subtypes in this effect, we examined whether the attenuation is reversed by either a 5-HT(1A), 5-HT(2A/C), or 5-HT(2C) receptor antagonist. We also examined the effects of the antagonists alone on both cue and cocaine-primed reinstatement. Rats that had been trained to press a lever for cocaine (0.75 mg/kg/0.1 ml, i.v.) paired with light and tone cues underwent daily extinction sessions during which responding had no consequences. We then examined the effects of WAY 100635 (0-1.0 mg/kg, s.c.), ketanserin (0-10.0 mg/kg, i.p.), or SB 242,084 (0-1.0 mg/kg, i.p.) with and without d-fenfluramine (1.0 mg/kg, i.p.) pretreatment on cue reinstatement. Subsequently, we examined the effects of the antagonists on cocaine-primed (7.5 or 15.0 mg/kg, i.p.) reinstatement. The 5-HT(1A) antagonist, WAY 100635, failed to alter cue reinstatement, but attenuated cocaine reinstatement. Conversely, the 5-HT(2A/C) antagonist, ketanserin, attenuated cue reinstatement, but failed to alter cocaine reinstatement. The 5-HT(2C)-selective antagonist, SB 242,084, did not alter cue or cocaine reinstatement, but was the only drug that reversed the d-fenfluramine-induced attenuation of cue reinstatement. The findings suggest that stimulation of 5-HT(1A) receptors plays a critical role in cocaine-primed, but not cue, reinstatement. Furthermore, 5-HT(2A) and 5-HT(2C) receptors may play oppositional roles in cue reinstatement. The SB 242,084 reversal of the d-fenfluramine attenuation suggests that stimulation of 5-HT(2C) receptors inhibits cue reinstatement, whereas the ketanserin-induced attenuation of cue reinstatement suggests that decreased stimulation of 5-HT(2A) receptors inhibits this behavior.

D1-receptor drugs and cocaine-seeking behavior: investigation of receptor mediation and behavioral disruption in rats.

RATIONALE: Dopamine D1-receptor antagonists and agonists both attenuate cocaine-seeking behavior (i.e., operant responding in the absence of cocaine reinforcement) elicited by a cocaine prime or cocaine-paired stimuli. It remains unclear whether these effects are D1-receptor mediated. OBJECTIVES: The present study tested whether a D1 antagonist (SCH-23390) would reverse the attenuating effects of a D1 agonist (SKF-81297) on cocaine-seeking behavior and whether behavioral disruption is involved in these effects. METHODS: Rats trained to press a lever for cocaine reinforcement with light and tone cues paired with each infusion underwent daily extinction sessions during which responding had no scheduled consequences (i.e., neither cocaine nor the cocaine-paired stimulus complex was available). After responding diminished, the effects of the D1 antagonist on the dose-response functions of the D1 agonist for reinstatement of cocaine-seeking behavior by response-contingent cue presentations or cocaine priming were examined. A separate experiment assessed the effects of the agonist on the dose-response function of the antagonist for cue reinstatement. Stereotyped behavior and activity were also measured during each test session. RESULTS: The attenuating effects of SKF-81297 on cocaine-seeking behavior during cocaine-primed reinstatement were reversed by co-administration of SCH-23390. However, no evidence for reversal of the attenuation during cue reinstatement was found even though agonist-induced stereotypy and antagonist-induced hypoactivity were reversed by co-administration of the two drugs during the same test session. CONCLUSIONS: The findings suggest that the attenuating effects of D1-receptor drugs on cocaine-seeking behavior during cocaine reinstatement are mediated by dopamine D1 receptors; however, it remains unclear whether the effects of these drugs on cocaine-seeking behavior during cue reinstatement are D1-receptor mediated. Nevertheless, it is evident that the attenuation of cocaine-seeking behavior by these drugs is not simply due to behavioral disruption.

Blockade or stimulation of D1 dopamine receptors attenuates cue reinstatement of extinguished cocaine-seeking behavior in rats.

RATIONALE: D(1) dopamine receptor antagonists and agonists attenuate cocaine reinstatement of cocaine-seeking behavior (i.e., responding in the absence of cocaine reinforcement). OBJECTIVES: The present study investigated the effects of a D(1) antagonist (SCH-23390), partial agonist (SKF-38393), and full agonist (SKF-81297) on reinstatement of cocaine-seeking behavior elicited by presentation of cocaine-paired cues. METHODS: Rats that had been trained to self-administer cocaine with a light/tone stimulus complex paired with each infusion underwent extinction across days. After responding diminished, rats were given response-contingent access to the cocaine-paired stimulus complex. The effects of SCH-23390 (0-10.0 microg/kg), SKF-38393 (0-3.0 mg/kg), and SKF-81297 (0-3.0 mg/kg) on cue reinstatement of cocaine-seeking behavior were examined. The ability of the two D(1) agonists to independently reinstate cocaine-seeking behavior and the effects of SKF-81297 on cocaine reinstatement were also examined. To investigate the possibility of behavioral interference, the effects of SKF-38393 and SKF-81297 on grooming and stereotypy were assessed. RESULTS: SCH-23390 and SKF-81297, but not SKF-38393, attenuated cue reinstatement. However, while SKF-81297 dose-dependently increased response latency, SCH-23390 did not. SKF-81297 also independently reinstated responding at the two lowest doses tested while SKF-38393 had no effect. Furthermore, SKF-81297 decreased cocaine reinstatement and increased response latency only at the highest dose. Finally, stereotypy was observed at all doses of SKF-81297 that also decreased responding, although the patterns of changes in these behaviors did not completely correspond. CONCLUSIONS: While the antagonist and full agonist produced similar effects on cocaine-seeking behavior, only the agonist increased response latency, suggesting that different processes mediate the effects of these drugs.