Neurobiology of Substance Abuse and Addiction

National Institute On Alcohol Abuse And Alcoholism

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Abstract

DECREASED DOPAMINE (DA) BRAIN REACTIVITY IN MARIJUANA ABUSERS. Here we compared the responses to methylphenidate (MP) in 24 controls and 24 marijuana abusers to probe the reactivity of the brain to DA stimulation (measured with PET/11Craclopride). Marijuana abusers showed markedly blunted behavioral (high, drug effects, anxiety, restlessness), cardiovascular (pulse rate, diastolic pressure) and brain DA responses (reduced decreases in distribution volumes, though normal reductions in non-displaceable binding potential or BPND) to MP. In ventral striatum or VS (key brain reward region), MP-induced reductions in DA reactivity were inversely correlated with negative emotionality and in VS these were correlated with addiction severity and craving. STRIATAL DA D2 RECEPTORS (D2R) COUNTERBALANCE OF VENTRAL STRIATAL ACTIVATION IS BLUNTED IN CANNABIS ABUSERS. Here, we hypothesized the coupling between striatal D2R and activation responses in VS would be disrupted in cannabis abusers. In controls, we showed that fMRI activation in VS to a simple reaction task was accounted by an opposing balance between D2R (measured with PET/11Craclopride) in caudate, which decreased activation, and that in VS, which increased activation, and was associated with successful performance accounting for 50% of the variance. In contrast for abusers the strong association between D2R and VS activation was not significant even when their performance was normal indicating disruption of neurovascular coupling. BMI MODULATES CALORIE-DEPENDENT DA CHANGES IN ACCUMBENS FROM GLUCOSE INTAKE. DA mediates rewarding effects of food. We tested the hypothesis that DA response to calorie intake (independent of palatability) in VS is attenuated with increases in weight. PET/11Craclopride was used to measure DA changes triggered by calorie intake by contrasting the effects of an artificial sweetener (sucralose) to glucose to assess their association with BMI in 19 participants (BMI range 21-35). DA changes in VS triggered by calorie intake (contrast glucose - sucralose) were significantly correlated with BMI (r&#8202;=&#8202;0.68) indicating opposite responses in lean than in obese individuals; in lean (BMI <25) it increased DA and in obese it decreased DA. This might contribute to excessive food intake in obesity to compensate for the deficit between expected and actual responses. EFFECT OF COMBINED NALTREXONE AND BUPROPION THERAPY (NB32) ON THE BRAIN'S REACTIVITY TO FOOD CUES. The mechanism for the weight loss observed with NB32 is not fully understood. We assessed changes in brain reactivity to food cues before and after NB32 treatment. Forty women (31.1+/-8.1 years; BMI: 32.5+/-3.9) received 4 weeks of NB32 or placebo. fMRI responses to a food video contrasted with a neutral video were assessed before and after treatment. NB32 attenuated activation in hypothalamus to food cues (P<0.01) and enhanced activation in regions involved in inhibitory control (anterior cingulate), internal awareness (superior frontal, insula, superior parietal) and memory (hippocampal), which might underlie its therapeutic benefits. FUNCTIONAL CONNECTIVITY (FC) OF SUBSTANTIA NIGRA (SN) AND VENTRAL TEGMENTAL AREA (VTA): MATURATION DURING ADOLESCENCE AND EFFECTS OF ADHD. Here, we demonstrate in 402 healthy children/adolescents (12+/-3 years) and 704 healthy young adults (23+/-5 years) that the FC of DA pathways matures significantly from childhood to adulthood and is different for healthy children and ADHD (N=203; 12+/-3 years). This transition is characterized by age-related increases in connectivity of VTA with limbic regions and with the DMN and by decreases in connectivity of the SN with motor and medial temporal cortices. MAPPING SMALL-WORLD PROPERTIES THROUGH DEVELOPMENT IN THE HUMAN BRAIN: DISRUPTION IN SCHIZOPHRENIA. Evidence from imaging studies suggests that the human brain has a small-world network topology that might be disrupted in certain brain disorders. However, current methodology is based on global graph theory measures, such as clustering, C, characteristic path length, L, and small-worldness, S, that lack spatial specificity and are insufficient to identify regional brain abnormalities. Here we propose novel ultra-fast methodology for mapping local properties of brain network topology such as local C, L and S (lC, lL and lS) in the human brain at 3-mm isotropic resolution from 'resting-state' magnetic resonance imaging data. Children/adolescents had stronger lFCD, higher lC and longer lL in most cortical regions and thalamus than 74 healthy adults, consistent with pruning of functional connectivity during maturation. In contrast, lFCD, lC and lL were weaker in thalamus and midbrain, and lL was shorter in frontal cortical regions and cerebellum for 69 schizophrenia patients suggesting exaggerated pruning in schizophrenia. IMAGE-GUIDED SYNTHESIS REVEALS POTENT BLOOD-BRAIN BARRIER (BBB) PERMEABLE HISTONE DEACETYLASE INHIBITORS (HDAC). Here we report the development and evaluation of highly potent and BBB permeable HDAC inhibitors for CNS applications by radiolabeling a series of compounds based on the benzamide HDAC inhibitor, MS-275. BBB penetration was optimized by rapid carbon-11 (C-11) labeling and PET imaging in the baboon and using imaging derived data on BBB penetration from each compound to feed back into the design. 17 compounds were evaluated. A key element conferring BBB penetration was a basic benzylic amine. These derivatives exhibited 1-100 nM inhibitory activity against HDAC1 and HDAC2. Three of the C-11 labeled aminomethyl benzamide derivatives showed high BBB penetration (&#8764;0.015%ID/cc) and regional binding heterogeneity. This approach afforded a strategy for developing highly potent and BBB permeable HDAC inhibitors. RADIONUCLIDE LABELING AND EVALUATION OF CANDIDATE RADIOLIGANDS FOR PET IMAGING OF HDACs IN BRAIN. There is a need to develop PET radioligands for HDAC. 6-((18)FFluoroacetamido)-1-hexanoicanilide ((18)FFAHA) was recently developed as a HDAC substrate and shows moderate BBB permeability and specific signal (by metabolic trapping/or deacetylation) but rapid metabolism. Here, we report the radiosynthesis of two C-11 labeled radiotracers (substrate and inhibitor-based radioligand) for HDAC and their evaluation in non-human primate brain. PET studies showed very low brain uptake and rapid metabolism of both labeled compounds but revealed a surprising enhancement of brain penetration by F for H substitution when comparing one of these to (18)FFAHA. Further structural refinement is needed for the development of brain-penetrant, metabolically stable HDAC radiotracers. WHOLE-BODY PK OF HDAC INHIBITOR DRUGS, BUTYRIC ACID, VALPROIC ACID AND 4-PHENYLBUTYRIC ACID MEASURED BY PET. The fatty acids, n-butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid (VPA, 2-propylpentanoic acid) have been used in the treatment of varius diseases. The recognition that these drugs inhibit HDACs has renewed interest in their biodistribution and PK. Here we synthesized their C-11 labeled analogues and performed dynamic PET in baboons. (11)CBA was metabolized rapidly (only 20% of parent compound at 5 min PI) whereas for VPA and PBA 98% and 85% of the radioactivity were the unmetabolized compound at 30 min PI respectively. The brain uptake of the three compounds was very low (<0.006%ID/cc, BA>VPA>PBA), consistent with the need for very high doses for therapeutic efficacy. The organ biodistribution between drugs differed; (11)CBA showed high uptake in spleen and pancreas, (11)CPBA showed high uptake in liver and heart AND (11)CVPA had exceptionally high heart uptake. Their unique biodistribution may be of relevance in understanding their therapeutic and side effect profiles.