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1.  Relationship Between Antihypertensive Medications and Cognitive Impairment: Part I. Review of Human Studies and Clinical Trials 
Purpose of review
There is an established association between hypertension and increased risk of poor cognitive performance and dementia including Alzheimer’s disease; however, associations between antihypertensive medications (AHMs) and dementia risk are less consistent. An increased interest in AHM has resulted in expanding publications; however, none of the recent reviews are comprehensive. Our extensive review includes 15 observational and randomized controlled trials (RCTs) published over the last 5 years, assessing the relationship between AHM and cognitive impairment.
Recent findings
All classes of AHM showed similar result patterns in human studies with the majority of study results reporting point estimates below one and only a small number of studies (N = 15) reporting statistically significant results in favor of a specific class.
Summary
Only a small number of studies reported statistically significant results in favor of a specific class of AHM. Methodological limitations of the studies prevent definitive conclusions. Further work is now needed to evaluate the class of AHM and cognitive outcomes in future RCTs, with a particular focus on the drugs with the promising results in both animals and human observational studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s11906-016-0674-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s11906-016-0674-1
PMCID: PMC4975763  PMID: 27492370
Antihypertensive medication; Cognitive decline; Dementia; Alzheimer’s disease
2.  Relationship Between Antihypertensive Medications and Cognitive Impairment: Part II. Review of Physiology and Animal Studies 
Purpose of Review
There is an established association between hypertension and increased risk of poor cognitive performance and dementia including Alzheimer’s disease; however, associations between antihypertensive medications (AHM) and dementia risk are less clear. An increased interest in AHM has resulted in expanding publications; however, none of the recent reviews provide comprehensive review. Our extensive review includes 24 mechanistic animal and human studies published over the last 5 years assessing relationship between AHM and cognitive function.
Recent Findings
All classes of AHM showed similar result patterns in animal studies. The mechanism by which AHM exert their effect was extensively studied by evaluating well-established pathways of AD disease process, including amyloid beta (Aβ), vascular, oxidative stress and inflammation pathways, but only few studies evaluated the blood pressure lowering effect on the AD disease process.
Summary
Methodological limitations of the studies prevent comprehensive conclusions prior to further work evaluating AHM in animals and larger human observational studies, and selecting those with promising results for future RCTs.
doi:10.1007/s11906-016-0673-2
PMCID: PMC4988998  PMID: 27492369
Antihypertensive medication; Cognitive decline; Dementia; Alzheimer’s disease
3.  Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse 
Neuropsychopharmacology  2015;40(9):2185-2197.
Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose–response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell—consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement.
doi:10.1038/npp.2015.62
PMCID: PMC4613608  PMID: 25754762
4.  Antihypertensive drugs decrease risk of Alzheimer disease 
Neurology  2013;81(10):896-903.
Objectives:
The aim of this study was to determine whether use of diuretics, angiotensin-1 receptor blockers (ARB), angiotensin-converting enzyme inhibitors (ACE-I), calcium channel blockers (CCB), or β-blockers (BB) was associated with a reduced risk of Alzheimer disease (AD) dementia in participants with normal cognition or mild cognitive impairment (MCI).
Methods:
Secondary longitudinal data analysis of the Ginkgo Evaluation of Memory Study in older adults at least 75 years of age with normal cognition (n = 1,928) or MCI (n = 320) over a median 6.1-year period using Cox proportional hazard models after adjusting for confounders.
Results:
Diuretic use was reported by 15.6%, ARB 6.1%, ACE-I 15.1%, CCB 14.8%, and BB 20.5%. Of the 2,248 participants, 290 (13%) developed AD dementia. Hazard ratio for incident AD dementia among participants with normal cognition was 0.51 in diuretic (95% confidence interval [CI] 0.31–0.82), 0.31 in ARB (95% CI 0.14–0.68), 0.50 in ACE-I (95% CI 0.29–0.83), 0.62 in CCB (95% CI 0.35–1.09), and 0.58 in BB (95% CI 0.36–0.93) users and was not significantly altered when mean systolic blood pressure was above 140 mm Hg. In participants with MCI, only diuretic use was associated with decreased risk (hazard ratio = 0.38, 95% CI 0.20–0.73).
Conclusions:
Diuretic, ARB, and ACE-I use was, in addition to and/or independently of mean systolic blood pressure, associated with reduced risk of AD dementia in participants with normal cognition, while only diuretic use was associated with reduced risk in participants with MCI.
doi:10.1212/WNL.0b013e3182a35228
PMCID: PMC3885216  PMID: 23911756
5.  Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys 
Addiction biology  2012;18(1):30-39.
Although substantial research effort has focused on developing pharmacological treatments for cocaine abuse, no effective medications have been developed. Recent studies show that enzymes that metabolize cocaine in the periphery, forestalling its entry into the brain, can prevent cocaine toxicity and its behavioral effects in rodents. Here we report on effects of one such enzyme (Albu-CocH) on the pharmacokinetic and behavioral effects of cocaine in squirrel monkeys. Albu-CocH was developed from successive mutations of human butyrylcholinesterase (BChE) and has 1000-fold greater catalytic activity against cocaine than naturally occurring BChE. Pharmacokinetic studies showed that Albu-CocH (5 mg/kg) had a half-life of 56.6 hours in squirrel monkeys. In these studies, plasma levels of cocaine following i.v. 1 mg/kg cocaine were reduced two hours after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine methyl ester were increased. These effects were still evident 72 hrs following Albu-CocH administration. In behavioral experiments in monkeys, pretreatment with 5 mg/kg Albu-CocH dramatically decreased self-administration of a reinforcing dose of i.v. cocaine (30 μg/kg/injection) for over 24 hours. Pretreatment with 5 mg/kg Albu-CocH also attenuated the reinstatement of extinguished cocaine self-administration by an i.v. priming injection of cocaine (0.1 or 0.3 mg/kg) and, in separate studies, attenuated the discriminative stimulus effects of cocaine. The ability of Albu-CocH to attenuate the abuse-related effects of cocaine in squirrel monkeys indicates that further investigation of BChE mutants as potential treatment for cocaine abuse and toxicity is warranted.
doi:10.1111/j.1369-1600.2011.00424.x
PMCID: PMC3337883  PMID: 22264200
cocaine; hydrolase; self-administration; reinstatement; discrimination; squirrel monkeys
6.  Serum ceramides increase the risk of Alzheimer disease 
Neurology  2012;79(7):633-641.
Objectives:
Previous studies have shown that high serum ceramides are associated with memory impairment and hippocampal volume loss, but have not examined dementia as an outcome. The aim of this study was to examine whether serum ceramides and sphingomyelins (SM) were associated with an increased risk of all-cause dementia and Alzheimer disease (AD).
Methods:
Participants included 99 women without dementia aged 70–79, with baseline serum SM and ceramides, enrolled in a longitudinal population-based study and followed for up to 6 visits over 9 years. Baseline lipids, in tertiles, were examined in relation to all-cause dementia and AD using discrete time Cox proportional survival analysis. Lipids were analyzed using electrospray ionization tandem mass spectrometry.
Results:
Twenty-seven (27.3%) of the 99 women developed incident dementia. Of these, 18 (66.7%) were diagnosed with probable AD. Higher baseline serum ceramides, but not SM, were associated with an increased risk of AD; these relationships were stronger than with all-cause dementia. Compared to the lowest tertile, the middle and highest tertiles of ceramide d18:1–C16:0 were associated with a 10-fold (95% confidence interval [CI] 1.2–85.1) and 7.6-fold increased risk of AD (95% CI 0.9–62.1), respectively. The highest tertiles of ceramide d18:1–C24:0 (hazard ratio [HR] = 5.1, 95% CI 1.1–23.6) and lactosylceramide (HR = 9.8, 95% CI 1.2–80.1) were also associated with risk of AD. Total and high-density lipoprotein cholesterol and triglycerides were not associated with dementia or AD.
Conclusions:
Results from this preliminary study suggest that particular species of serum ceramides are associated with incident AD and warrant continued examination in larger studies.
doi:10.1212/WNL.0b013e318264e380
PMCID: PMC3414665  PMID: 22815558
7.  Statins, Risk of Dementia and Cognitive Function: Secondary Analysis of the Ginkgo Evaluation of Memory Study (GEMS) 
Goal
To examine whether lipid lowering medications (LLMs) and especially statin drugs can delay cognitive decline and dementia onset in individuals with and without Mild Cognitive Impairment (MCI) at baseline.
Methods
Longitudinal, observational study of 3,069 cognitively healthy elderly, ages 75 years and older, who were enrolled in the Ginkgo Evaluation of Memory Study. Primary outcome measure was the time to adjudicated all-cause dementia and Alzheimer dementia (AD). Secondary outcome measure was the change in global cognitive function over time measured by 3MSE and ADAS-cog scores.
Findings
Among participants without MCI at baseline current use of statins was consistently associated with a reduced risk of all cause dementia (HR 0. 79, 95% confidence interval, 0.65–0.96, p=0.021) and AD (HR 0.57, 95% confidence interval, 0.39–0.85, p= 0.005). In participants who initiated statin therapy lipophilic statins tended to reduce dementia risk more than nonlipophilic agents. In contrast there was no significant association between LLM use (including statins), dementia onset or cognitive decline in individuals with baseline MCI. However, in individuals without MCI at baseline there was a trend for a neuroprotective effect of statins on cognitive decline.
Conclusions
Statins may slow the rate of cognitive decline and delay the onset of AD and all cause dementia in cognitively healthy elderly individuals whereas individuals with MCI may not have comparable cognitive protection from these agents. However, the results from this observational study need to be interpreted with caution and will require confirmation by randomized clinical trials stratifying treatment groups based on MCI status at baseline.
doi:10.1016/j.jstrokecerebrovasdis.2010.11.002
PMCID: PMC3140577  PMID: 21236699
Cognitive function; 3HMG-ACoA reductase inhibitors; Mild Cognitive Impairment; dementia
8.  An amyloid β42-dependent deficit in anandamide mobilization is associated with cognitive dysfunction in Alzheimer’s disease 
Neurobiology of Aging  2011;33(8):1522-1532.
The endocannabinoids and their attending CB1 cannabinoid receptors have been implicated in the control of cognition, but their possible roles in dementias are still unclear. In the present study, we used liquid chromatography/mass spectrometry to conduct an endocannabinoid-targeted lipidomic analysis of post mortem brain samples from 38 Alzheimer’s disease (AD) patients and 17 control subjects, matched for age and post mortem interval. The analysis revealed that midfrontal and temporal cortex tissue from AD patients contains, relative to control subjects, significantly lower levels of the endocannabinoid anandamide and its precursor 1-stearoyl, 2-docosahexaenoyl-sn-glycero-phosphoethanolamine-N-arachidonoyl (NArPE). No such difference was observed with the endocannabinoid 2-arachidonoyl-sn-glycerol or 15 additional lipid species. In AD patients, but not in control subjects, statistically detectable positive correlations were found between (a) anandamide content in midfrontal cortex and scores of the Kendrick’s digit copying test (P=0.004, r=0.81; n=10), which measures speed of information processing; and (b) anandamide content in temporal cortex and scores of the Boston naming test (P=0.027, r=0.52; n=18), which assesses language facility. Furthermore, anandamide and NArPE levels in midfrontal cortex of the study subjects inversely correlated with levels of the neurotoxic amyloid peptide, Aβ42, while showing no association with Aβ40 levels, amyloid plaque load or tau protein phosphorylation. Finally, high endogenous levels of Aβ42 in APPSWE/Neuro-2a cells directly reduced anandamide and NArPE concentrations in cells lysates. The results suggest that an Aβ42-dependent impairment in brain anandamide mobilization contributes to cognitive dysfunction in AD.
doi:10.1016/j.neurobiolaging.2011.03.012
PMCID: PMC3154439  PMID: 21546126
endocannabinoid; anandamide; amyloid β42; cognitive dysfunction; Alzheimer’s disease; human brain; lipidomics
9.  Novel Use of a Lipid-Lowering Fibrate Medication to Prevent Nicotine Reward and Relapse: Preclinical Findings 
Neuropsychopharmacology  2012;37(8):1838-1847.
Experimental drugs that activate α-type peroxisome proliferator-activated receptors (PPARα) have recently been shown to reduce the rewarding effects of nicotine in animals, but these drugs have not been approved for human use. The fibrates are a class of PPARα-activating medications that are widely prescribed to improve lipid profiles and prevent cardiovascular disease, but these drugs have not been tested in animal models of nicotine reward. Here, we examine the effects of clofibrate, a representative of the fibrate class, on reward-related behavioral, electrophysiological, and neurochemical effects of nicotine in rats and squirrel monkeys. Clofibrate prevented the acquisition of nicotine-taking behavior in naive animals, substantially decreased nicotine taking in experienced animals, and counteracted the relapse-inducing effects of re-exposure to nicotine or nicotine-associated cues after a period of abstinence. In the central nervous system, clofibrate blocked nicotine's effects on neuronal firing in the ventral tegmental area and on dopamine release in the nucleus accumbens shell. All of these results suggest that fibrate medications might promote smoking cessation. The fact that fibrates are already approved for human use could expedite clinical trials and subsequent implementation of fibrates as a treatment for tobacco dependence, especially in smokers with abnormal lipid profiles.
doi:10.1038/npp.2012.31
PMCID: PMC3376316  PMID: 22453137
nicotine; reward; relapse; dopamine signaling; PPARα; fibrate; Addiction & Substance Abuse; Animal models; Biological Psychiatry; dopamine signaling; nicotine; PPARalpha; relapse; reward
10.  Combined effects of THC and caffeine on working memory in rats 
British Journal of Pharmacology  2012;165(8):2529-2538.
BACKGROUND AND PURPOSE
Cannabis and caffeine are two of the most widely used psychoactive substances. Δ9-Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, induces deficits in short-term memory. Caffeine, a non-selective adenosine receptor antagonist, attenuates some memory deficits, but there have been few studies addressing the effects of caffeine and THC in combination. Here, we evaluate the effects of these drugs using a rodent model of working memory.
EXPERIMENTAL APPROACH
Rats were given THC (0, 1 and 3 mg·kg−1, i.p.) along with caffeine (0, 1, 3 and 10 mg·kg−1, i.p.), the selective adenosine A1-receptor antagonist CPT (0, 3 and 10 mg·kg−1) or the selective adenosine A2A-receptor antagonist SCH58261 (0 and 5 mg·kg−1) and were tested with a delayed non-matching-to-position procedure in which behaviour during the delay was automatically recorded as a model of memory rehearsal.
KEY RESULTS
THC alone produced memory deficits at 3 mg·kg−1. The initial exposure to caffeine (10 mg·kg−1) disrupted the established pattern of rehearsal-like behaviour, but tolerance developed rapidly to this effect. CPT and SCH58261 alone had no significant effects on rehearsal or memory. When a subthreshold dose of THC (1 mg·kg−1) was combined with caffeine (10 mg·kg−1) or CPT (10 mg·kg−1), memory performance was significantly impaired, even though performance of the rehearsal-like pattern was not significantly altered.
CONCLUSION AND IMPLICATIONS
Caffeine did not counteract memory deficits induced by THC but actually exacerbated them. These results are consistent with recent findings that adenosine A1 receptors modulate cannabinoid signalling in the hippocampus.
LINKED ARTICLES
This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7
doi:10.1111/j.1476-5381.2011.01554.x
PMCID: PMC3423236  PMID: 21699509
delayed spatial matching; mediating response; rehearsal; marijuana; adenosine receptor antagonist; caffeine; THC
11.  Reinforcing and neurochemical effects of cannabinoid CB1 receptor agonists, but not cocaine, are altered by an adenosine A2A receptor antagonist 
Addiction biology  2010;16(3):405-415.
Several recent studies suggest functional and molecular interactions between striatal adenosine A2A and cannabinoid CB1 receptors. Here we demonstrate that A2A receptors selectively modulate reinforcing effects of cannabinoids. We studied effects of A2A receptor blockade on the reinforcing effects of delta-9-tetrahydrocannabinol (THC) and the endogenous CB1 receptor ligand anandamide under a fixed-ratio (FR) schedule of intravenous drug injection in squirrel monkeys. A low dose of the selective adenosine A2A receptor antagonist MSX-3 (1 mg/kg) caused downward shifts of THC and anandamide dose-response curves. In contrast, a higher dose of MSX-3 (3 mg/kg) shifted THC and anandamide dose-response curves to the left. MSX-3 did not modify cocaine or food-pellet self-administration. Also, MSX-3 neither promoted reinstatement of extinguished drug-seeking behavior nor altered reinstatement of drug-seeking behavior by non-contingent priming injections of THC. Finally, using in-vivo microdialysis in freely-moving rats, a behaviorally active dose of MSX-3 significantly counteracted THC-induced, but not cocaine-induced, increases in extracellular dopamine levels in the nucleus accumbens shell. The significant and selective results obtained with the lower dose of MSX-3 suggest that adenosine A2A antagonists acting preferentially at presynaptic A2A receptors might selectively reduce reinforcing effects of cannabinoids that lead to their abuse. However, the appearance of potentiating rather than suppressing effects on cannabinoid reinforcement at the higher dose of MSX-3 would likely preclude the use of such a compound as a medication for cannabis abuse. Adenosine A2A antagonists with more selectivity for presynaptic versus postsynaptic receptors could be potential medications for treatment of cannabis abuse.
doi:10.1111/j.1369-1600.2010.00258.x
PMCID: PMC3115444  PMID: 21054689
Adenosine A2A receptor; anandamide; dopamine; reinforcement; reinstatement; THC
12.  Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors 
Biological psychiatry  2011;69(7):633-641.
Background
Recent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. FAAH inhibition increases levels of several endogenous substances in the brain, including the endocannabinoid anandamide and the non-cannabinoid fatty-acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which are ligands for alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). Here, we evaluated whether directly-acting PPAR-α agonists can modulate reward-related effects of nicotine.
Methods
We combined behavioral, neurochemical and electrophysiological approaches to evaluate effects of the PPAR-α agonists WY14643 and methOEA (a long-lasting form of OEA) on: (1) nicotine self-administration in rats and squirrel monkeys; (2) reinstatement of nicotine-seeking behavior in rats and monkeys; (3) nicotine discrimination in rats; (4) nicotine-induced electrophysiological activity of VTA dopamine neurons in anesthetized rats; and (5) nicotine-induced elevation of dopamine levels in the nucleus accumbens shell of freely-moving rats.
Results
PPAR-α agonists dose-dependently decreased nicotine self-administration and nicotine-induced reinstatement in rats and monkeys, but did not alter food- or cocaine-reinforced operant behavior or the interoceptive effects of nicotine. PPAR-α agonists also dose-dependently decreased nicotine-induced excitation of dopamine neurons in the ventral tegmental area (VTA) and nicotine-induced elevations of dopamine levels in the nucleus accumbens shell of rats. The ability of WY14643 and methOEA to counteract the behavioral, electrophysiological, and neurochemical effects of nicotine was reversed by the PPAR-α antagonist MK886.
Conclusions
These findings indicate that PPAR-α might provide a valuable new target for anti-smoking medications.
doi:10.1016/j.biopsych.2010.07.009
PMCID: PMC2994947  PMID: 20801430
Nicotine; PPAR-α; reinstatement; reward; OEA; PEA; FAAH
13.  Automatic recording of mediating behavior in delayed matching- and nonmatching-to-position procedures in rats 
Psychopharmacology  2010;214(2):495-504.
Rationale
Delayed matching-to-position and nonmatching-to-position procedures are widely used to model working memory in rodents. Mediating behavior—which enhances performance but is not explicitly required by the task—is generally considered an obstacle to the measurement of memory, but often occurs despite attempts to prevent it. The ubiquitous nature of mediating behavior suggests it might be analogous to rehearsal, an important component of learning and memory in humans.
Objectives
The aim was to study an easily recordable, rehearsal-like mediating response in rats under baseline conditions and after treatment with amnestic drugs [scopolamine (0.1–0.3 mg/kg) and delta-9-tetrahydrocannabinol (THC; 1–5.6 mg/kg)].
Methods
Lighted nosepoke holes were used to present position cues and record delayed matching or nonmatching responses. Performance of a distractor task was required to prevent simply waiting at the correct choice, but the nosepoke holes were left accessible during the delay.
Results
Each rat trained with the nonmatching task exhibited one of two mediating “strategies” that increased the odds of a correct choice: responding in the to-be-correct hole during the delay or responding in the opposite hole during the delay. Rats trained with the matching task all showed the former strategy. Treatment with scopolamine disrupted performance of the mediating response. Scopolamine and THC both decreased the effectiveness of the mediating response, increasing errors even on trials when the “appropriate” mediating behavior did occur.
Conclusions
The procedures and data analysis approach used here provide an objective, automated means of measuring mediating behavior, which might be useful as an animal model of memory rehearsal.
doi:10.1007/s00213-010-2057-7
PMCID: PMC3050121  PMID: 21086118
Delayed spatial matching; Mediating response; Working memory; Rehearsal; Scopolamine; THC
14.  Evaluation of the Effect of Systolic Blood Pressure and Pulse Pressure on Cognitive Function: The Women's Health and Aging Study II 
PLoS ONE  2011;6(12):e27976.
Background
Evidence suggests that elevated systolic blood pressure (SBP) and pulse pressure (PP) in midlife is associated with increased risk for cognitive impairment later in life. There is mixed evidence regarding the effects of late life elevated SBP or PP on cognitive function, and limited information on the role of female gender.
Methods/Principal Findings
Effects of SBPand PPon cognitive abilities at baseline and over a 9-year period were evaluated in 337 non-demented community-dwelling female participants over age 70 in the Women's Health and Aging Study II using logistic and Cox proportional hazards regression analyses. Participants aged 76–80 years with SBP≥160 mmHg or PP≥84 mmHg showed increased incidence of impairment on Trail Making Test-Part B (TMT, Part B), a measure of executive function, over time when compared to the control group that included participants with normal and pre-hypertensive SBP (<120 and 120–139 mmHg) or participants with low PP (<68 mmHg) (HR = 5.05 [95%CI = 1.42, 18.04], [HR = 5.12 [95%CI = 1.11; 23.62], respectively). Participants aged 70–75 years with PP≥71 mmHg had at least a two-fold higher incidence of impairment on HVLT-I, a measure of verbal learning, over time when compared to participants with low PP (<68 mmHg) (HR = 2.44 [95%CI = 1.11, 5.39]).
Conclusions/Significance
Our data suggest that elevated SBP or PP in older non-demented women increases risk for late-life cognitive impairment and that PP could be used when assessing the risk for impairment in cognitive abilities. These results warrant further, larger studies to evaluate possible effects of elevated blood pressure in normal cognitive aging.
doi:10.1371/journal.pone.0027976
PMCID: PMC3235094  PMID: 22174760
15.  The endogenous cannabinoid 2-arachidonoylglycerol is intravenously self-administered by squirrel monkeys 
Two endogenous ligands for cannabinoid CB1 receptors, anandamide and 2-arachidonoylglycerol (2-AG), have been identified and characterized. 2-AG is the most prevalent endogenous cannabinoid ligand in the brain and electrophysiological studies suggest 2-AG, rather than anandamide, is the true natural ligand for cannabinoid receptors and the key endocannabinoid involved in retrograde signaling in the brain. Here, we evaluated intravenously administered 2-AG for reinforcing effects in non-human primates. Squirrel monkeys that previously self-administered anandamide or nicotine under a fixed-ratio schedule with a 60-s timeout after each injection had their self-administration behavior extinguished by vehicle substitution and were then given the opportunity to self-administer 2-AG. Intravenous 2-AG was a very effective reinforcer of drug-taking behavior, maintaining higher numbers of self-administered injections per session and higher rates of responding than vehicle across a wide range of doses. To assess involvement of CB1 receptors in the reinforcing effects of 2-AG, we pre-treated monkeys with the cannabinoid CB1-receptor inverse agonist/antagonist rimonabant. Rimonabant produced persistent blockade of 2-AG self-administration without affecting responding maintained by food under similar conditions. Thus, 2-AG was actively self-administered by monkeys with or without a history of cannabinoid self-administration and 2-AG’s reinforcing effects were mediated by CB1 receptors. Self-administration of 2-AG by squirrel monkeys provides a valuable procedure for studying abuse liability of medications that interfere with 2-AG signaling within the brain and for investigating mechanisms involved in the reinforcing effects of endocannabinoids.
doi:10.1523/JNEUROSCI.6058-10.2011
PMCID: PMC3123903  PMID: 21562266
16.  Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors 
Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide (mAEA), the hydrolysis resistant analogue of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-α triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-α in the brain, and provide a potential new target for the treatment of nicotine addiction.
doi:10.1523/JNEUROSCI.3221-08.2008
PMCID: PMC3169176  PMID: 19091987
dopamine neurons; nicotine; electrophysiology; endocannabinoids; fatty acid amide hydrolase; patch-clamp; peroxisome proliferator-activated receptor
17.  Effects of fatty acid amide hydrolase inhibition on neuronal responses to nicotine, cocaine and morphine in the nucleus accumbens shell and ventral tegmental area: involvement of PPAR-α nuclear receptors 
Addiction biology  2010;15(3):277-288.
The endocannabinoid system regulates neurotransmission in brain regions relevant to neurobiological and behavioral actions of addicting drugs. We recently demonstrated that inhibition by URB597 of fatty acid amide hydrolase (FAAH), the main enzyme which degrades the endogenous cannabinoid N-acylethanolamine (NAE) anandamide and the endogenous non-cannabinoid NAEs oleoylethanolamide and palmitoylethanolamide, blocks nicotine-induced excitation of ventral tegmental area (VTA) dopamine (DA) neurons and DA release in the shell of the nucleus accumbens (ShNAc), as well as nicotine-induced drug self-administration, conditioned place preference and relapse in rats. Here, we studied whether effects of FAAH inhibition on nicotine-induced changes in activity of VTA DA neurons were specific for nicotine or extended to two drugs of abuse acting through different mechanisms, cocaine and morphine. We also evaluated whether FAAH inhibition affects nicotine-, cocaine- or morphine-induced actions in the ShNAc. Experiments involved single unit electrophysiological recordings from DA neurons in the VTA and medium spiny neurons in the ShNAc in anaesthetized rats. We found that URB597 blocked effects of nicotine and cocaine in the ShNAc through activation of both surface cannabinoid CB1-receptors and alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). URB597 did not alter the effects of either cocaine or morphine on VTA DA neurons. These results show that the blockade of nicotine-induced excitation of VTA DA neurons, which we previously described, is selective for nicotine and indicate novel mechanisms recruited to regulate the effects of addicting drugs within the ShNAc of the brain reward system.
doi:10.1111/j.1369-1600.2010.00222.x
PMCID: PMC3167063  PMID: 20477753
cocaine; dopamine neurons; electrophysiology; nicotine; nucleus accumbens; peroxisome proliferator-activated receptor-α
18.  Peroxisome proliferator-activated receptors-alpha modulate dopamine cell activity through nicotinic receptors 
Biological psychiatry  2010;68(3):256-264.
Background
Modulation of midbrain dopamine neurons by nicotinic acetylcholine receptors (nAChRs) plays an important role in behavior, cognition, motivation and reward. Specifically, nAChRs containing β2 subunits (β2-nAChRs) switch dopamine cells from a resting to an excited state. However, how β2-nAChRs can be modulated and thereby dopamine firing activity be affected is still elusive. Because changes in dopamine cell activity are reflected in the dynamics of micro-circuits generating altered responses to stimuli/inputs, factors regulating their state are fundamental. Among these, endogenous ligands to the nuclear receptor-transcription factor peroxisome proliferator-activated receptors type-alpha (PPARα) have been recently found to suppress nicotine-induced responses of dopamine neurons.
Methods
We used both in vitro and in vivo electrophysiological techniques together with behavioral analysis to investigate on the effects of modulation of PPARα in Sprague Dawley rat and C57BLJ/6 mouse dopamine neurons, and their interactions with β2-nAChRs. To this aim, we took advantage of a selective re-expression of β2-nAChR exclusively in dopamine cells by stereotaxically injecting a lentiviral vector in the mouse ventral tegmental area.
Results
We found that activation of PPARα decreases in vitro both dopamine cell activity and ventral tegmental area net output through negative modulation of β2-nAChRs. Additionally, PPARα activation in vivo reduces both the number of spontaneously active dopamine neurons and nicotine-induced increased locomotion.
Conclusions
Our combined findings suggest PPARα ligands as important negative modulators of β2-nAChRs on dopamine neurons. Thus, PPARα ligands might prove beneficial in treating those disorders where dopamine dysfunction plays a prominent role, such as schizophrenia and nicotine addiction.
doi:10.1016/j.biopsych.2010.04.016
PMCID: PMC2907468  PMID: 20570248
acetylcholine; dopamine neuron; nicotine; patch-clamp; peroxisome proliferator-activated receptor; ventral tegmental area
19.  Effects of Endocannabinoid System Modulation on Cognitive and Emotional Behavior 
Cannabis has long been known to produce cognitive and emotional effects. Research has shown that cannabinoid drugs produce these effects by driving the brain’s endogenous cannabinoid system and that this system plays a modulatory role in many cognitive and emotional processes. This review focuses on the effects of endocannabinoid system modulation in animal models of cognition (learning and memory) and emotion (anxiety and depression). We review studies in which natural or synthetic cannabinoid agonists were administered to directly stimulate cannabinoid receptors or, conversely, where cannabinoid antagonists were administered to inhibit the activity of cannabinoid receptors. In addition, studies are reviewed that involved genetic disruption of cannabinoid receptors or genetic or pharmacological manipulation of the endocannabinoid-degrading enzyme, fatty acid amide hydrolase (FAAH). Endocannabinoids affect the function of many neurotransmitter systems, some of which play opposing roles. The diversity of cannabinoid roles and the complexity of task-dependent activation of neuronal circuits may lead to the effects of endocannabinoid system modulation being strongly dependent on environmental conditions. Recent findings are reviewed that raise the possibility that endocannabinoid signaling may change the impact of environmental influences on emotional and cognitive behavior rather than selectively affecting any specific behavior.
doi:10.3389/fnbeh.2011.00057
PMCID: PMC3171696  PMID: 21949506
endocannabinoids; cognition; anxiety; depression; learning; memory; animal models
20.  Effect of ginkgo biloba on blood pressure and incidence of hypertension in elderly men and women 
American journal of hypertension  2010;23(5):528-533.
Background
Accumulating evidence suggests that ginkgo biloba is cardioprotective, in part, through its vasodilatory and antihypertensive properties. However, definitive data on its blood pressure-lowering effects in humans is lacking.
Methods
We determined the effects of ginkgo biloba extract (240 mg/day) on blood pressure and incident hypertension in 3,069 participants (mean age, 79 yrs; 46% female; 96% White) from the Ginkgo Evaluation of Memory study. We also examined whether the treatment effects are modified by baseline hypertension status.
Results
At baseline 54% of the study participants were hypertensive, 28% were pre-hypertensive, and 17% were normotensive. Over a median follow-up of 6.1 years, there were similar changes in blood pressure and pulse pressure in the ginkgo biloba and placebo groups. Although baseline hypertension status did not modify the antihypertensive effects of ginkgo biloba, it did influence the changes in blood pressure variables observed during follow-up, with decreases in hypertensives, increases in normotensives, and no changes in pre-hypertensives. Among participants who were not on antihypertensive medications at baseline, there was no difference between treatment groups in medication use over time, as the OR (95% CI) for being a never-user in the ginkgo biloba group was 0.75 (0.48–1.16). The rate of incident hypertension also did not differ between participants assigned to ginkgo biloba vs. placebo (HR, 0.99, 95% CI, 0.84–1.15).
Conclusions
Our data indicate that ginkgo biloba does not reduce blood pressure or the incidence of hypertension in elderly men and women.
doi:10.1038/ajh.2010.14
PMCID: PMC2989407  PMID: 20168306
gingko biloba; blood pressure; hypertension; elderly
21.  Angiotensin Converting Enzyme Inhibitors and Cognitive Decline in Older Adults with Hypertension: Results from the Cardiovascular Health Study 
Archives of internal medicine  2009;169(13):1195-1202.
Background
Hypertension (HTN) is a risk factor for dementia and animal studies suggest that centrally active (cross the blood brain barrier) angiotensin converting enzyme (ACE) inhibitors may protect against dementia beyond HTN control.
Methods
Participants in the Cardiovascular Health Study cognition substudy (mean age 75 yrs) with treated HTN and no diagnosis of heart failure (n= 1054) were followed for a median of 6 years to determine whether cumulative exposure to ACE inhibitors (as a class and by central activity), compared to other antihypertensive agents, was associated with lower risk of incident dementia, cognitive decline (by the modified mini mental state exam, 3MSE), or incident disability in instrumental activities of daily living (IADL).
Results
Among 414 participants exposed to ACE inhibitors and 640 not, there were 158 cases of incident dementia. Compared to other anti-HTN drugs, there was no association between exposure to all ACE inhibitors and risk of dementia (HR 1.01, 95% CI 0.88–1.15), difference in 3MSE scores (−0.32 points/yr, p=0.15), or odds of IADL disability (OR (95% CI) 1.06 (0.99–1.14). Adjusted results were similar. However, centrally active ACE inhibitors were associated with 65% less decline in 3MSE scores per year of exposure (p= 0.01) and non-centrally active ACE inhibitors were associated with greater risk of incident dementia (adjusted HR 1.20 (1.00–1.43) per year of exposure) and greater odds of IADL disability (adjusted OR 1.16 (1.03–1.30) per year of exposure) compared to other anti-HTN drugs.
Conclusions
While ACE inhibitors as a class do not appear to be independently associated with dementia risk or cognitive decline in older hypertensive adults, there may be within class differences in regards to these outcomes. These results should be confirmed with an RCT of a centrally active ACE inhibitor in the prevention of cognitive decline and dementia.
doi:10.1001/archinternmed.2009.175
PMCID: PMC2881686  PMID: 19597068
22.  Anandamide-induced behavioral disruption through a vanilloid-dependent mechanism in rats 
Psychopharmacology  2008;203(3):529-538.
Rationale
Endocannabinoids are involved in a variety of behavioral and physiological processes that are just beginning to be understood. In the 5-choice serial reaction-time task, exogenous cannabinoids have been found to alter attention, but endocannabinoids such as anandamide have not been studied.
Objectives
We used this task to evaluate the effects of anandamide in rats. Since anandamide is a ligand for not only cannabinoid receptors, but also transient receptor potential vanilloid 1 (TRPV1) receptors, and as recently suggested, peroxisome proliferator-activated nuclear receptor-α (PPARα), we also determined whether anandamide’s effects in this task were mediated by each of these receptors.
Methods
Whenever one of five holes was illuminated for 2 s, a food pellet was delivered if a response occurred in that hole during the light or within 2 s after the light.
Results
Anandamide increased omission errors and decreased responding during inter-trial intervals. These effects were blocked by the TRPV1 antagonist capsazepine, but not by the cannabinoid-receptor antagonist rimonabant or the PPARα antagonist MK886. Testing with open-field activity and food consumption procedures in the same rats suggested that the disruption of operant responding observed in the attention task was not due to motor depression, anxiety, decreased appetite, or an inability to find and consume food pellets.
Conclusions
The vanilloid-dependent behavioral disruption induced by anandamide was specific to the operant attention task. These effects of anandamide resemble effects of systemically-administered dopamine antagonists and might reflect changes in vanilloid-mediated dopamine transmission.
doi:10.1007/s00213-008-1399-x
PMCID: PMC2695254  PMID: 19015836
endocannabinoid; 5-choice serial reaction time task (5-CSRRT); open-field activity; transient receptor potential vanilloid 1 receptor (TRPV1); peroxisome proliferator-activated receptor (PPAR); anxiety; feeding
23.  Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates 
Biological psychiatry  2008;64(11):930-937.
Background
CB1 cannabinoid receptors in the brain are known to participate in the regulation of reward-based behaviors, however, the contribution of each of the endocannabinoid transmitters, anandamide and 2-arachidonoylglycerol (2-AG), to these behaviors remains undefined. To address this question, we assessed the effects of URB597, a selective anandamide deactivation inhibitor, as a reinforcer of drug-seeking and drug-taking behavior in squirrel monkeys.
Methods
We investigated the reinforcing effects of the fatty acid amide hydrolase (FAAH) inhibitor URB597 in monkeys trained to intravenously self-administer Δ9-tetrahydrocannabinol (THC), anandamide or cocaine, and quantified brain endocannabinoid levels using liquid chromatography/mass spectrometry. We measured brain FAAH activity using an ex vivo enzyme assay.
Results
URB597 (0.3 mg/kg, intravenous) blocked FAAH activity and increased anandamide levels throughout the monkey brain. This effect was accompanied by a marked compensatory decrease in 2-AG levels. Monkeys did not self-administer URB597 and the drug did not promote reinstatement of extinguished drug-seeking behavior previously maintained by THC, anandamide, or cocaine. Pretreatment with URB597 did not modify self-administration of THC or cocaine even though, as expected, it significantly potentiated anandamide self-administration.
Conclusions
In the monkey brain, the FAAH inhibitor URB597 increases anandamide levels while causing a compensatory down-regulation in 2-AG levels. These effects are accompanied by a striking lack of reinforcing properties, which distinguishes URB597 from direct-acting cannabinoid agonists such as THC. Our results reveal an unexpected functional heterogeneity within the endocannabinoid signaling system, and suggest that FAAH inhibitors might be used therapeutically without risk of abuse or triggering of relapse to drug abuse.
doi:10.1016/j.biopsych.2008.08.008
PMCID: PMC2701259  PMID: 18814866
Anandamide; FAAH; self-administration; reinstatement; URB597; 2-arachidonoylglycerol
24.  Inhibition of anandamide hydrolysis by URB597 reverses abuse-related behavioral and neurochemical effects of nicotine in rats 
Emerging evidence suggests that the rewarding, abuse-related effects of nicotine are modulated by the endocannabinoid system of the brain. For example, pharmacological blockade or genetic deletion of cannabinoid CB1 receptors can reduce or eliminate many abuse-related behavioral and neurochemical effects of nicotine. Furthermore, doses of Δ9-tetrahydrocannabinol (THC) and nicotine that are ineffective when given alone can induce conditioned place preference when given together. These previous studies have used systemically-administered CB1-receptor agonists and antagonists and gene deletion techniques, which affect cannabinoid CB1 receptors throughout the brain. A more functionally selective way to alter endocannabinoid activity is to inhibit fatty acid amide hydrolase (FAAH), thereby magnifying and prolonging the effects of only the endocannabinoid anandamide (AEA) when and where it is synthesized and released on demand. Here we combined behavioral and neurochemical approaches to evaluate whether the FAAH inhibitor cyclohexyl carbamic acid 3’-carbamoyl-3-yl ester (URB597) could alter the abuse-related effects of nicotine in rats. We found that URB597, at a dose (0.3 mg/kg) that had no behavioral effects by itself, prevented development of nicotine-induced conditioned place preference (CPP) and acquisition of nicotine self-administration. URB597 also reduced nicotine-induced reinstatement in both CPP and self-administration models of relapse. Furthermore, in vivo microdialysis showed that URB597 reduced nicotine-induced dopamine elevations in the nucleus accumbens shell, the terminal area of the brain’s mesolimbic reward system. These findings suggest that FAAH inhibition can counteract the addictive properties of nicotine and that FAAH may serve as a new target for development of medications for treatment of tobacco dependence.
doi:10.1124/jpet.108.142224
PMCID: PMC2663803  PMID: 18725543
25.  Albuminuria and Dementia in the Elderly: A Community Study 
Background
Dementia is associated with microvascular disease of the retina. In this study we examine if cognitive status (normal cognition, mild cognitive impairment and dementia) is associated with albuminuria, a microvascular disorder of the kidney.
Study Design
Cross sectional analysis.
Setting and Participants
2316 participants from the Cardiovascular Health Cognition Study who underwent a brain MRI and testing for albuminuria.
Predictor
Doubling of albuminuria.
Outcome
Dementia defined according to neuropsychological and clinical evaluation.
Measurements
Multinomial logistic modeling was used to estimate the odds ratio and 95% confidence intervals of dementia and mild cognitive impairment with doubling of albuminuria as compared to the odds with normal cognition.
Results
283 (12.2%) participants had dementia, 344 (14.9%) had mild cognitive impairment, and 1689 (72.9%) had normal cognition. As compared to participants with normal cognition, a doubling of albuminuria was associated with increased odds of dementia (OR 1.22, 95% CI, 1.15, 1.29). Adjustment for prevalent cardiovascular disease and cardiovascular risk factors, lipid levels, C reactive protein, estimated GFR, and apolipoprotein E-4 genotype attenuated this association, but it remained statistically significant (OR 1.12, 95% CI, 1.03, 1.22). Mild cognitive impairment was associated with albuminuria on unadjusted analysis, but not with adjustment for other factors.
Limitations
Results are cross sectional; causality cannot be imputed.
Conclusions
The odds of dementia are increased in the presence of albuminuria. These findings suggest a role of shared susceptibility for microvascular disease in the brain and kidney in older adults.
doi:10.1053/j.ajkd.2007.12.044
PMCID: PMC2607238  PMID: 18468749
albuminuria; elderly; dementia; mild cognitive impairment; MRI brain

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