Kevin M. Perry

Striatal D2/D3 receptor availability is inversely correlated with cannabis consumption in chronic marijuana users

BACKGROUND Although the incidence of cannabis abuse/dependence in Americans is rising, the neurobiology of cannabis addiction is not well understood. Imaging studies have demonstrated deficits in striatal D(2)/D(3) receptor availability in several substance-dependent populations. However, this has not been studied in currently using chronic cannabis users. OBJECTIVE The purpose of this study was to compare striatal D(2)/D(3) receptor availability between currently using chronic cannabis users and healthy controls. METHODS Eighteen right-handed males age 18-34 were studied. Ten subjects were chronic cannabis users; eight were demographically matched controls. Subjects underwent a [(11)C]raclopride (RAC) PET scan. Striatal RAC binding potential (BP(ND)) was calculated on a voxel-wise basis. Prior to scanning, urine samples were obtained from cannabis users for quantification of urine Δ-9-tetrahydrocannabinol (THC) and THC metabolites (11-nor-Δ-9-THC-9-carboxylic acid; THC-COOH and 11-hydroxy-THC;OH-THC). RESULTS There were no differences in D(2)/D(3) receptor availability between cannabis users and controls. Voxel-wise analyses revealed that RAC BP(ND) values were negatively associated with both urine levels of cannabis metabolites and self-report of recent cannabis consumption. CONCLUSIONS In this sample, current cannabis use was not associated with deficits in striatal D(2)/D(3) receptor availability. There was an inverse relationship between chronic cannabis use and striatal RAC BP(ND). Additional studies are needed to identify the neurochemical consequences of chronic cannabis use on the dopamine system.

Impaired Cardiometabolic Responses to Glucagon-Like Peptide 1 in Obesity and Type 2 Diabetes Mellitus

Glucagon-like peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7–36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1-mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling.

Test–retest variability of [11C]raclopride-binding potential in nontreatment-seeking alcoholics

Knowledge of the reproducibility of striatal [11C]raclopride (RAC) binding is important for studies that use RAC PET paradigms to estimate changes in striatal dopamine (DA) during pharmacological and cognitive challenges. To our knowledge, no baseline test–retest data exist for nontreatment‐seeking alcoholics (NTS). We determined the test–retest reproducibility of baseline RAC binding potential (BPND) in 12 male NTS subjects. Subjects were scanned twice with single‐bolus RAC PET on separate days. Striatal RAC BP (BPND) for left and right dorsal caudate, dorsal putamen, and ventral striatum was estimated using the Multilinear Reference Tissue Method (MRTM) and Logan Graphical Analysis (LGA) with a reference region. Test–retest variability (TRV), % change in BPND between scan days, and the intraclass correlation coefficient (ICC) were used as metrics of reproducibility. For MRTM, TRV for striatal RAC binding in NTS subjects was ±6.5% and ±7.1% for LGA. Average striatal ICCs were 0.94 for both methods (P < 0.0001). Striatal BPND values were similar to those reported previously for detoxified alcoholics. The results demonstrate that baseline striatal RAC binding is highly reproducible in NTS subjects, with a low variance similar to that reported for healthy control subjects. Synapse, 2011.

Role of Endogenous ET‐1 in the Regulation of Myocardial Blood Flow in Lean and Obese Humans

Endothelin is an important determinant of peripheral vascular tone, and increased endogenous endothelin activity contributes to peripheral vascular dysfunction in human obesity. The contributions of endothelin to the regulation of coronary vascular tone in health in humans have not been well studied. We hypothesized that the contribution of endothelin to the regulation of myocardial perfusion would be augmented in human obesity. Using [NH3]ammonia positron emission tomography (PET), we measured myocardial perfusion under resting and adenosine‐stimulated conditions on two separate days, with and without concurrent exposure to BQ123, an antagonist of type A endothelin receptors (1 µmol/min IV beginning 90 min before measurement). We studied 10 lean and 9 obese subjects without hypertension, hyperlipidemia, or diabetes mellitus. We observed a BQ123‐induced increase in resting myocardial perfusion of ∼40%, not different between lean and obese subjects (BQ123‐induced increase in flow: lean 0.12 ± 0.20, obese 0.32 ± 0.51 ml/g/min, P = 0.02 BQ123 effect, P = 0.27 comparing response across groups). Although basal flow rates varied by region of the myocardium, the BQ123 effect was seen in all regions. BMI and cholesterol were significantly related to BQ123‐induced increases in basal tone in multivariable analysis. There was no baseline difference in the adenosine‐stimulated increase in blood flow between lean and obese subjects, and BQ123 failed to augment these responses in either group. These observations suggest that endothelin is an important contributor to the regulation of myocardial perfusion under resting conditions in healthy lean and obese humans, with increased contributions in proportion to increasing obesity.

Reliability of striatal [11C]raclopride binding in smokers wearing transdermal nicotine patches

PurposeIn studies where [11C]raclopride (RAC) positron emission tomography (PET) is used to assess changes in striatal dopamine, it is important to control for cognitive states, such as drug craving, that could alter dopamine levels. In cigarette smokers, transdermal nicotine patches (TNP) can control nicotine craving, but the effects of nicotine patches on RAC binding are unknown. Thus, we sought to determine the test-retest reliability of RAC binding in the presence of nicotine patches.MethodsEleven male smokers were scanned twice with RAC on separate days while wearing TNP.ResultsAcross the striatum, test-retest variability was 7.63 ± 5.88; percent change in binding potential was 1.11 ± 9.83; and the intraclass correlation coefficient was 0.91 (p < 0.0001).ConclusionBaseline RAC binding is highly reproducible in smokers wearing nicotine patches. This suggests that TNP are an acceptable method for controlling cigarette craving during studies that utilize RAC to examine changes in dopamine.