Hypertension differentially impacts cognition in men and women in early midlife.

The current study aimed to understand how sex differences in the timing of hypertension onset contribute to early midlife risk for cognitive decline that may differ by sex and whether sex-dependent advantages in normotensive populations are influenced by the presence of hypertension. One hundred and ninety-five adults aged 45-55 from the New England Family Study underwent neuropsychological testing to assess attention, executive function, and memory. Physician-diagnosed hypertension status was self-reported via questionnaire. Mid-adulthood hypertension was associated with worse performance on measures of attention and memory, but the cognitive domains impacted varied by sex. Hypertension was associated with only attention in men, whereas in women it was associated with attention and associative and working memory. Sex differences in midlife cognitive performance found in normotensive adults were attenuated in those with hypertension. Our results underscore the importance of accounting for sex when assessing the impact of hypertension on midlife cognition that could be indicative of later decline and risk for cognitive impairment and dementia, given hypertension is an independent risk factor.

Effects of long-term cocaine self-administration on brain resting-state functional connectivity in nonhuman primates.

Long-term cocaine use is associated with a variety of neural and behavioral deficits that impact daily function. This study was conducted to examine the effects of chronic cocaine self-administration on resting-state functional connectivity of the dorsal anterior cingulate (dACC) and putamen-two brain regions involved in cognitive function and motoric behavior-identified in a whole brain analysis. Six adult male squirrel monkeys self-administered cocaine (0.32 mg/kg/inj) over 140 sessions. Six additional monkeys that had not received any drug treatment for ~1.5 years served as drug-free controls. Resting-state fMRI imaging sessions at 9.4 Tesla were conducted under isoflurane anesthesia. Functional connectivity maps were derived using seed regions placed in the left dACC or putamen. Results show that cocaine maintained robust self-administration with an average total intake of 367 mg/kg (range: 299-424 mg/kg). In the cocaine group, functional connectivity between the dACC seed and regions primarily involved in motoric behavior was weaker, whereas connectivity between the dACC seed and areas implicated in reward and cognitive processing was stronger. In the putamen seed, weaker widespread connectivity was found between the putamen and other motor regions as well as with prefrontal areas that regulate higher-order executive function; stronger connectivity was found with reward-related regions. dACC connectivity was associated with total cocaine intake. These data indicate that functional connectivity between regions involved in motor, reward, and cognitive processing differed between subjects with recent histories of cocaine self-administration and controls; in dACC, connectivity appears to be related to cumulative cocaine dosage during chronic exposure.

Effects of acute treatments with the serotonin 2A antagonist M100907 alone or in combination with the serotonin 2C agonist WAY163909 on methamphetamine self-administration in rhesus monkeys.

BACKGROUND: Serotonin 5-HT2A receptor antagonists and 5-HT2C receptor agonists have been proposed as important candidates for the development of pharmacotherapies for psychostimulant abuse, with evidence suggesting that those receptors may act together to control behavior. However, the role of 5-HT2A receptors on the reinforcing effects of psychostimulant drugs has not been fully elucidated. METHODS: In the present study, we investigated the effects of the selective 5HT2A receptor antagonist M100907 alone or in combination with the selective 5HT2C agonist WAY 163909 on intravenous methamphetamine self-administration in rhesus macaques (N = 3). Methamphetamine self-administration (0.01-0.03 mg/kg/inf) was evaluated under a fixed-ratio 20-schedule of reinforcement, and acute pretreatments were conducted 1 h (M100907) or 45 min (WAY 163,909) prior to the beginning of self-administration sessions at the EDMax dose of methamphetamine once stability criteria were met. RESULTS: Pretreatment with M100907 (0.03-0.3 mg/kg, i.m.) dose-dependently attenuated methamphetamine self-administration, with the highest dose significantly decreasing response rates compared to vehicle. Combined administration of ineffective doses of M100907 and WAY 163,909 had no effects on methamphetamine self-administration. CONCLUSIONS: Our study indicates that acute selective 5-HT2A receptor blockade decreases peak methamphetamine intake in nonhuman primates. Combination approaches with sub-threshold doses of 5-HT2A receptor antagonists and 5-HT2C receptor agonists, on the other hand, do not seem to be effective in decreasing methamphetamine reinforcement. Further studies are needed in order to investigate the effects of chronic treatments with M100 on complete METH SA dose-response curves.

Acute effects of 3,4-methylenedioxymethamphetamine (MDMA) and R(-) MDMA on actigraphy-based daytime activity and sleep parameters in rhesus monkeys.

3,4-Methylenedioxymethamphetamine (MDMA) affects monoaminergic pathways that play a critical role in sleep-wake cycles. Dopaminergic mechanisms are thought to mediate the sleep-disrupting effects of stimulant drugs. However, the mechanisms underlying the effects of MDMA on sleep-wake cycles and the effects of R(-) MDMA, a stereoisomer that lacks dopaminergic activity, on sleep remain unknown. The aim of the present study was to investigate the effects of racemic MDMA and R(-) MDMA on daytime activity and sleep-like parameters evaluated with actigraphy in adult rhesus macaques (Macaca mulatta, n = 6). Actiwatch monitors were attached to the monkeys' collars and actigraphy recording was conducted during baseline conditions and after the administration of acute intramuscular injections of saline (vehicle), racemic MDMA (0.3, 1.0, or 1.7 mg/kg), or R(-) MDMA (0.3, 1.0, or 1.7 mg/kg) at 9 or 16 h (3 h before "lights off"). Morning treatments had no effects on sleep-like parameters. Racemic MDMA decreased general daytime activity during the first hour after injection and increased daytime activity at 3 hr posttreatment. Although afternoon administration of racemic MDMA increased sleep latency, it improved other sleep parameters, decreasing wake time after sleep onset (WASO) and increasing sleep efficiency for subjects with low baseline sleep efficiency. Afternoon treatment with R(-) MDMA improved sleep measures, increasing sleep efficiency and decreasing sleep latency and WASO, while having no effects on daytime activity. The stimulant and sleep-disrupting effects of racemic MDMA are likely mediated by dopaminergic and noradrenergic mechanisms, while serotonergic pathways appear to be involved in the sleep-promoting effects of MDMA. (PsycINFO Database Record