Neuropsychopharmacology (2005) 30, S143-S209 © 2005 Nature Publishing Group All rights reserved 0893-133X/05 www.neuropsychopharmacology.org S143 Tuesday, December 13, 2005 the context of cocaine delivery can alter the neurochemical responses to Poster Session II - Tuesday the drug. In addition, increasing evidence suggests that stress can also in- fluence COC reinforcement through extrahypothalamic brain regions. The present study was designed to determine differences in the neuro- 1. Diffusion Tensor Imaging in Cocaine Dependence: Evidence for chemical and neuroendocrine responses to COC during response-con- Reduced Myelin in the Anterior Corpus Callosum tingent and response-independent COC administration in rats. F. Gerard Moeller*, Khader M Hassan, Joel L Steinberg, Ignacio Methods: Male Wistar rats were divided into triads of 3 rats each: Valdes, Larry Kramer, Ponnada A Narayana and Alan C Swann one rat was selected as the self-administration (SA) rat, while the Psychiatry and Behavioral Sciences, Univ. of Texas Health Sci. Center other two rats were designated as the yoked-cocaine (YC) and yoked- at Houston, Houston, TX, USA saline (YS) rats, respectively. Rats were implanted with jugular Sponsor: Alan Swann catheters and a microdialysis guide cannula aimed at the medial pre- frontal cortex (MPC). SA rats were trained to self-administer cocaine Background: Fractional anisotropy (FA) as measured by diffusion (0.25 mg/kg/inf) under a fixed-ratio 2 schedule of reinforcement; 20- tensor imaging (DTI) is becoming increasingly used as a measure min samples were collected 2 hrs prior to, during and after the SA of subtle white matter pathology in psychiatric populations. How- session. ever, diffusion anisotropy is affected both by the state of myelin Results: DA and norepinephrine (NE) concentrations in the micro- and axonal structure and therefore lacks pathologic specificity. Ev- dialysates from the MPC were significantly elevated in SA and YC idence has been accumulating that the individual eigenvalues, groups during the SA session. Similar results were observed for DA which represent diffusion along the fiber track (λ 1) or perpendi- in the amygdala. The increases in DA and NE levels in the MPC cular to the fiber track (λ2), provide enhanced pathologic speci- during the session were greater in the YC group compared to the SA ficity compared to anisotropic and mean diffusivity indices. The group. Moreover, the duration of the DA response in the MPC was purpose of this study was to compare cocaine dependent subjects greater in the YC group vs. the SA group. We did not find significant with non-drug using controls using individual DTI eigenvalues. differences in DA levels between the SA and YC groups in the amyg- Methods: Eighteen cocaine dependent subjects and 18 healthy controls dala. To determine the effects of self-administered COC on corti- underwent full brain Diffusion tensor imaging (DTI) acquired with a dif- costerone (CORT), the hormone was measured in the MPC using in fusion sensitized dual spin echo prepared echoplanar imaging (SE-EPI) vivo microdialysis. Dialysates were analyzed for CORT by radioim- sequence, on a 1.5 T General Electric echospeed CNV MRI scanner using munoassay (RIA). Baseline MPC CORT was low and stable in all a standard quadrature RF Head Coil. The diffusion tensor encoding groups prior to the start of the SA session and remained stable scheme was based on the uniformly distributed and balanced rotation- throughout the entire experiment in the YS rats, suggesting that the ally invariant Icosa21 tensor encoding set. Fast spin echo proton density procedure itself was not stressful. MPC CORT was significantly ele- and T2 weighted images were acquired from the same location as DTI. vated in the microdialysates from the SA rats during SA (269% in- DTI post processing was performed using the Automated Image Regis- crease), while MPC CORT was increased 553% above baseline in tration (AIR) package. The distortion corrected images were decoded the YC rats. MPC CORT was significantly higher in the YC com- using a least squares singular value decomposition approach to estimate pared to the SA rats. Plasma CORT and ACTH were higher in YC the diffusion tensor elements. The corpus callosum was the focus of this group than in the SA and YS groups prior to the beginning of the analysis, which was divided into 7 segments based on the previous work SA sessions. by Witelson (1989) in order to compare regions of the corpus callosum Discussion: It has been suggested that one of the numerous mole- and thereby examine fiber tracts linked to different cortical regions. All 7 cules involved in stress response pathways is P-gp (glycoprotein) or segments of the corpus callosum were compared between cocaine users MDR1 efflux transporter. MDR1a is found in vascular endothelial and controls for using a Mixed Model ANOVA for λ1 and λ2. cells and is active at the blood-brain barrier, whereas MDR1b is Results: Results showed a significant increase in λ2inthegenu of the found mainly in astrocytes and microglia. We tested the hypothesis anterior corpus callosum in cocaine dependent subjects compared to that MDR1 genes respond differentially to SA vs. YC administra- controls. Within cocaine dependent subjects there was a significant tion. We found that levels of the MDR1a, but not MDR1b, tran- positive correlation between years of cocaine use and λ2. There was no scripts were higher in each of the SA animals compared to its re- significant difference between groups for λ 1. spective YC control. We are currently replicating and extending Discussion: Twoprior studies found reductions in FA in cocaine de- these preliminary findings and, if upheld, these data may suggest pendent subjects on DTI (Lim et al., 2002, Moeller et al., 2005). How- the possibility that the MDR1a gene contributes to the reduced ever, based on reduced FA value, it is difficult to determine whether de- toxicity in SA relative to YC rats. These results suggest that the con- myelination or axonal injury is responsible for the fiber tract damage. text in which cocaine is administered can alter the neurochemical Based on prior animal and human studies suggesting that demyelination and neuroendocrine responses to cocaine. Furthermore, CORT in increases diffusion normal to the direction of fiber tracts λ2with mini- the MPC may mediate neurobiological responses involved in COC mal effect on λ1 our findings are consistent with a reduction in myelin in reinforcement. the anterior corpus callosum in cocaine dependent subjects. These re- sults will be discussed in light of other studies showing evidence of frontal-subcortical dysfunction in cocaine dependent subjects. 3. Decreased Corticolimbic Responset To Monetary Reward in Cocaine Addiction: Association with Motivation and Self-Control Rita Z Goldstein*, Dardo Tomasi, Nelly Alia-Klein, Lisa A Cottone, 2. Effects of Self-Administered and Passive Cocaine Infusions on Lei Zhang, Thomas Maloney, Frank Telang, Elisabeth C Caparelli, Dopamine, Norepinephrine and Corticosterone Concentrations in James M Swanson and Nora D Volkow the Medial Prefrontal Cortex Nicholas E Goeders*, Gennady N Smagin, Marie F Lanfranco, Medical Research, Brookhaven National Laboratory, Upton, NY, USA Patricia K Seitz, Mary L Thomas, Kathryn A Cunningham and Vitaly Sponsor: James Swanson S Palamarchouk Background: Our objective was to study the role of the corticolimbic Pharmacology, Toxicology & Neuroscience, LSU Health Sciences reward circuit in sensitivity to reward/motivation and inhibitory con- Center, Shreveport, LA, USA trol in cocaine addiction. Background: Cocaine (COC) reinforcement is widely accepted to be Methods: Sixteen cocaine users and 12 healthy controls performed a mediated via the mesocorticolimbic dopamine (DA) system. However, delayed forced-choice task under three blocked monetary value ACNP 2005 Annual Meeting S144 conditions (high money=45 cents, low money=1 cent, no HPA axis hormones. Because nalbuphine has both mu and kappa ac- money=0) while brain activation was measured with BOLD fMRI. tivity, its endocrine effects are not predictable from data on the effects State measures of motivation on this incentive fMRI task were as- of mu or kappa opioids alone. sessed objectively by speed (reaction time) and accuracy of re- Methods: We examined the effects of two analgesic doses of nalbuphine sponses (percent correct), and on a subjective level as self-reported on prolactin, ACTH and cortisol in 10 healthy male volunteers with a engagement in this task. Inhibitory control was assessed by trait es- history of current cocaine abuse (DSM-IV, 305.6). Subjects provided timates from a personality questionnaire (Tellegen’s Multidimen- informed consent for participation in these studies. Nalbuphine (5 sional Personality Questionnaire, MPQ, Self Control scale) and by mg/70 kg, IV) was administered to 7 men and 10 mg/70 kg, IV was ad- state estimates from a conflict task (Fan’s Attention Network Task, ministered to 3 men. Blood samples were collected 30 and 5 min before ANT, Conflict scale). nalbuphine infusion, and 13 blood samples were collected at 10, 17, 19, Results: The manipulated independent variable (monetary value) 23, 27, 31, 35, 40, 45, 60, 75, 105, 135 min after nalbuphine administra- produced a differential pattern of neural response (fMRI signal tion. Heart rate and blood pressure were monitored and subjective ef- change) in healthy controls: there was a trend in the orbitofrontal fects of nalbuphine were measured on a Visual Analog Scale (VAS). cortex (OFC) to respond in a graded fashion (45>1>0), the ante- Results: Significant nalbuphine dose-related increases in prolactin rior cingulate gyrus (ACG) and cerebellum responded to the two occurred within 17 min (P=.04). Peak prolactin levels of 22.1 ± 7.1 conditions of monetary value equally (45=1>0), and the mesen- ng/ml and 54.1 ± 11.3 ng/ml were measured at 60 min after low and cephalon responded to the highest available reward only high dose nalbuphine administration, respectively.