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5038 • The Journal of Neuroscience, April 2, 2014 • 34(14):5038 –5043
Nipping Cue Reactivity in the Bud: Baclofen Prevents Limbic
Activation Elicited by Subliminal Drug Cues

Kimberly A. Young,1 Teresa R. Franklin,1 David C.S. Roberts,2 Kanchana Jagannathan,1 Jesse J. Suh,1,3
Reagan R. Wetherill,1 Ze Wang,1 Kyle M. Kampman,1 Charles P. O'Brien,1,3 and Anna Rose Childress1,3
1Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, 2Department of Physiology and
Pharmacology, School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157, and 3Philadelphia VA Medical Center, Philadelphia,
Pennsylvania 19104
Relapse is a widely recognized and difficult to treat feature of the addictions. Substantial evidence implicates cue-triggered activation of
the mesolimbic dopamine system as an important contributing factor. Even drug cues presented outside of conscious awareness (i.e.,
subliminally) produce robust activation within this circuitry, indicating the sensitivity and vulnerability of the brain to potentially
problematic reward signals. Because pharmacological agents that prevent these early cue-induced responses could play an important role
in relapse prevention, we examined whether baclofen—a GABA receptor agonist that reduces mesolimbic dopamine release and

conditioned drug responses in laboratory animals— could inhibit mesolimbic activation elicited by subliminal cocaine cues in cocaine-
dependent individuals. Twenty cocaine-dependent participants were randomized to receive baclofen (60 mg/d; 20 mg t.i.d.) or placebo.
Event-related BOLD fMRI and a backward-masking paradigm were used to examine the effects of baclofen on subliminal cocaine (vs
neutral) cues. Sexual and aversive cues were included to examine specificity. We observed that baclofen-treated participants displayed
significantly less activation in response to subliminal cocaine (vs neutral) cues, but not sexual or aversive (vs neutral) cues, than
placebo-treated participants in a large interconnected bilateral cluster spanning the ventral striatum, ventral pallidum, amygdala,
midbrain, and orbitofrontal cortex (voxel threshold p
0.005; cluster corrected at p 0.05). These results suggest that baclofen may
inhibit the earliest type of drug cue-induced motivational processing—that which occurs outside of awareness— before it evolves into a
less manageable state.

Key words: addiction; baclofen; cocaine; cues; fMRI; subliminal
that follow In humans, Drugs of abuse and conditioned drug cues (e.g., stimuli repeat- such cue-induced responses are often associated with self- edly associated with prior drug use/delivery) reliably elicit neural reported drug desire activation (see meta-analyses; and are therefore well positioned as prime and dopamine (DA) release targets for relapse prevention.
Mesolimbic activation can even occur to drug cues presented dorsal striatal and mesolimbic brain regions, including the ven- entirely outside of awareness. Using fast event-related BOLD tral striatum (VS) and amygdala (AMY). In laboratory animals, fMRI and a backward-masking paradigm, our laboratory dem- these cue-induced neurochemical responses and their down- onstrated that subliminally presented drug cues increased neural stream effects (e.g., DA receptor activation) are required for the activity in the VS, AMY, ventral pallidum (VP), and orbitofrontal robust and persistent drug-seeking and drug-taking behaviors cortex (OFC) of drug-addicted individuals . Pharmacological agents that preventthese early responses to drug cues could play an important role Received Nov. 27, 2013; revised Feb. 27, 2014; accepted March 6, 2014.
in the treatment of addiction—potentially preventing drug Author contributions: A.R.C. designed research; K.M.K. and A.R.C. performed research; K.A.Y., K.J., Z.W., and cue-induced motivation from developing into a larger and more A.R.C. analyzed data; K.A.Y., T.F., D.C.S.R., J.J.S., R.R.W., C.P.O., and A.R.C. wrote the paper.
The authors declare no competing financial interests.
difficult to manage state. However, the ability of medications to This work was supported by National Institutes of Health Grants T32 DA029974, R01 DA010241, and P50 inhibit such early brain responses has not been demonstrated.
DA12756, and the Commonwealth of Pennsylvania CURE Addiction Center of Excellence. We thank the research and The GABAB receptor agonist, baclofen, and other GABA- clinical staff and nurses at the Center for Studies of Addictions, for their expert assistance throughout the study, the modulating agents attenuate drug- and/or drug cue-induced me- technical staff at the University of Pennsylvania Center for Functional Neuroimaging, and Yin Li, for assistance withimage processing. We also thank the National Institute on Drug Abuse for providing the study medication.
solimbic neural activation DA release Correspondence should be addressed to Anna Rose Childress, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, 3900 Chestnut Street, Philadelphia, PA 19104. E-mail: in laboratory animals. Although the findings of clinical Copyright 2014 the authors studies have been more mixed, baclofen has been found to reduce

Young et al. • Baclofen Prevents Drug Cue-Induced Limbic Activity J. Neurosci., April 2, 2014 • 34(14):5038 –5043 • 5039
drug desire and/or use in cocaine-, methamphetamine-, opiate-, nicotine-, and alcohol-dependent populations (for review, seeIn the current study, we examined whetherbaclofen could reduce the neural response to subliminal cocaine cues in cocaine-dependent individuals. Given its effects on DAneurotransmission in rodents, and on drug desire and use in humans, we hypothesized that baclofen would inhibit activationto subliminal drug cues in mesolimbic brain regions that receive (i.e., VS, VP, AMY, OFC) or provide (i.e., midbrain) DAergic input. To investigate the specificity of baclofen's effects, we alsoexamined whether baclofen altered the mesolimbic response to other cues of motivational significance (e.g., sexual and aversive Participants were 23 treatment-seeking, cocaine-dependent men, be-tween 18 and 55 years of age, who met DSM-IV criteria for cocainedependence, described smoking as their primary route of cocaine/crackadministration, reported using cocaine on at least 8 of the 30 d before Figure 1.
Representative trial from the backward-masked cue task. In each trial, participants screening, and were available for a 7- to 10-d inpatient stay (data from 7 were presented with the following visual stimuli in immediate succession: crosshair (500 ms); participants were included in a prior report, No target stimulus (33 ms); masking stimulus (467 ms); crosshair (1000 ms). Target images were participants reported current use of a medication affecting central dopa- presented from one of four categories [i.e., cocaine (shown), neutral, sexual, and aversive].
minergic neurotransmission or a history of psychosis, seizures, or or-ganic brain syndrome unrelated to cocaine use, and no participants werephysically dependent on alcohol or sedative hypnotics. Exclusion criteria a very brief target stimulus (e.g., 20 –33 ms), with an SOA ⬍40 ms, has included clinically significant cardiovascular, hematologic, hepatic, re- been demonstrated to effectively prevent conscious visual processing of nal, neurological, or endocrine abnormalities; history of head trauma or emotional targets Im- injury; and contraindications for MRI. Participants were recruited portantly, we previously demonstrated, using a forced choice categoriza- through advertisements in local media and flyers posted throughout the tion task, that these backward-masking procedures prevent the Philadelphia metropolitan area. All participants provided written in- conscious perception of these same target stimuli in cocaine-dependent formed consent and underwent a psychiatric and medical screening be- men Target stimuli consisted of cocaine (use and fore enrollment. This study adhered to the Declaration of Helsinki and preparation), sexual (heterosexual erotic scenes), aversive (disfigured/ was approved by the University of Pennsylvania Institutional Review mutilated bodies), and neutral (outdoor/office objects) images (24 im- ages per category; for details, see and werepresented quasi-randomly, each without replacement until all stimuli Study design were shown (96 trials). Masking stimuli consisted of 48 additional Following enrollment, participants were admitted to a supervised drug- neutral images and were presented randomly without replacement free residential setting and were randomized to receive baclofen (60 until all stimuli were shown and were then presented randomly again.
mg/d; 20 mg t.i.d.; n ⫽ 11) or placebo (n ⫽ 12) using a double-blind This entire process was immediately repeated in a second 96 trial design (Murty Pharmaceuticals). The dose of baclofen was gradually cycle. To optimize the efficiency of the event-related design, 48 null titrated up to 60 mg between treatment days 1 and 6. On treatment days stimuli (i.e., fixation crosses) of 2000 ms duration were quasi- 7–9, while taking the full dose of study medication, participants com- randomly displayed between trials in each cycle, as guided by OptSeq pleted the backward-masking paradigm as the first task in a BOLD fMRI scanning session. Other brain and behavioral measures were subse-quently acquired and will be the focus of other reports.
fMRI acquisitionOn the day of the BOLD scan, participants provided a urine sample to Interviews and questionnaires verify a cocaine-free state, and adverse events were assessed. Imaging data The Mini International Neuropsychiatric Interview was used to deter- were acquired using a 3T whole-body scanner (Siemens AG) equipped mine whether subjects met DSM-IV criteria for cocaine dependence or with a standard 8-channel receive-only array head coil, at the Hospital of other Axis 1 psychiatric disorders Drug and alco- the University of Pennsylvania. After participants were positioned in the hol use history was assessed with the Addiction Severity Index scanner, a 5 min high-resolution three-dimensional T1-weighted General intelligence (IQ) was estimated using the Wechsler MPRAGE structural scan [repetition time (TR) 1620 ms; echo time (TE) Abbreviated Scale of Intelligence 3.87 ms; 160 slices; slice thickness 1 mm; matrix 192 ⫻ 256; flip angle 15°]was acquired, which was used for coregistration and normalization.
fMRI backward-masked cue task and stimuli Functional images were acquired with a T2*-weighted gradient-echo EPI We used a backward-masking paradigm with a fast event-related fMRI sequence with the following parameters: TR 2000 ms; TE 30 ms; 33 design to measure neural responses to subliminally presented target interleaved slices; slice thickness 3 mm without any gap between adjacent stimuli, as described in detail previously A par- slices; FOV 192 mm; matrix 64 ⫻ 64; flip angle 80°.
ticular strength of this paradigm is that stimuli can be presented withoutthe potential confounds (e.g., shame, embarrassment, regret) that can Data analysis occur to consciously presented stimuli. Briefly, this passive viewing task Two subjects withdrew from the study before participating in the fMRI consisted of 192 trials and lasted ⬃8.5 min. Each trial lasted 2000 ms and session and incomplete fMRI data were acquired on one subject due to consisted of the display of the following visual stimuli in sequence: 500 technical difficulties. Thus, 20 participants (n ⫽ 10 baclofen; n ⫽ 10 ms fixation cross, 33 ms target stimulus, 467 ms masking stimulus; and placebo) contributed utilizable fMRI data and were included in analysis.
1000 ms fixation cross Thus, the stimulus-onset-asynchrony Group differences in age, years of education, estimated IQ, and prior (SOA) between target and mask was 33 ms. This design was chosen drug use were assessed with independent-samples t tests using SPSS because the presentation of a longer masking stimulus immediately after (Version 19).
5040 • J. Neurosci., April 2, 2014 • 34(14):5038 –5043
Young et al. • Baclofen Prevents Drug Cue-Induced Limbic Activity Table 1. Participant characteristics
Placebo (n ⫽ 10) Baclofen (n ⫽ 10) Treatment and cue condition interact to mediate neural activationThe 2 ⫻ 3 ANOVA revealed a significant interaction between Basic demographics treatment group (baclofen vs placebo) and cue condition (co- Age (years) 关mean (SEM)兴 caine vs neutral, sex vs neutral, and aversive vs neutral) on neural Education (years) 关mean (SEM)兴 activation (F 4.02; p ⬍ 0.05). This interaction effect was Estimated IQ (WASI) 关mean (SEM)兴 reflected in a large interconnected cluster of voxels that encom- passed all our regions of a priori interest (VS, VP, AMY, OFC, and Prior drug use 关mean (SEM)兴 Baclofen blunts the mesolimbic response to subliminal cocaine cues Cocaine use (years) The second-level planned t tests demonstrated that neural ac- Cocaine use (days in past 30) Alcohol use (years) tivation in response to subliminal cocaine (vs neutral) cues Alcohol use (days in past 30) was significantly lower in baclofen-treated than placebo- Marijuana use (years) treated participants in each of our a priori mesolimbic regions Marijuana use (days in past 30) 2.87; voxel threshold p ⬍ 0.005, cluster corrected at p ⬍ 0.05). This effect was visualized as an interconnectedcluster of 2576 contiguous voxels bilaterally spanning the VS,VP, AMY, OFC, and midbrain ). Peak voxels for each Image preprocessing. fMRI data were preprocessed using Statistical a priori and non-a priori region within this cluster are re- Parametric Mapping (SPM8; Wellcome Department of Cognitive Neu- ported in There were no brain regions in which the rology, London, UK) in the Matlab environ- response to cocaine cues was greater in baclofen-treated than ment. Functional images from each participant were slice-time corrected placebo-treated participants. Additionally, no differences and realigned to correct for within-volume movement. Significant prin- were found between baclofen- and placebo-treated partici- ciple motion components derived from singular vector decomposition pants in the response to either sexual or aversive (vs neutral) were removed and data were then filtered, spatially smoothed using a 9mm 3 full-width half-maximum Gaussian kernel, and normalized to cues in any brain regions at the cluster-corrected threshold standard Montreal Neurological Institute (MNI) space.
used for these t tests, indicating the specificity of baclofen's Statistical analysis. All statistical imaging analyses were performed in effects on the neural response to cocaine cues.
standard space using SPM8. For each subject, a general linear model Because previous reports have indicated that baclofen might using a canonical hemodynamic response basis function with temporal have smaller effects on the response to non-drug, relative to drug, and dispersion derivatives was used to model the regressors of interest, reinforcers we further examined the re- creating three first-level contrasts (cocaine vs neutral, sex vs neutral, and sponse to sexual and aversive (vs neutral) cues at two additional, aversive vs neutral). A 2 ⫻ 3 ANOVA was used to examine the effects of more relaxed, thresholds (i.e., p ⬍ 0.005 and p ⬍ 0.01, each with treatment group (baclofen vs placebo) and the three cue conditions (co- a minimum extent of 10 contiguous voxels, uncorrected) to ex- caine vs neutral, sex vs neutral, and aversive vs neutral) on neural activa- amine baclofen's "degree of specificity." The more stringent of tion. Three planned second-level t tests were then used to compare the these two thresholds was chosen since it provides an acceptable effects of baclofen vs placebo on each cue condition. To control for Type balance between type I and type II error rates in fMRI data 1 error in these second-level analyses, we selected a multiple-comparison The less stringent thresh- cluster-corrected combined threshold of p ⬍ 0.05, which was determined old reflects our focus on 5 a priori regions of interest ( p ⬍ 0.05/5 by Monte-Carlo simulations to correspond to a voxel threshold of p ⬍ tests ⫽ p ⬍ 0.01). At p ⬍ 0.005, baclofen-treated, relative to 0.005 and a cluster size of ⬎513 voxels (cocaine vs neutral), ⬎445 voxels(sex vs neutral), or ⬎370 voxels (aversive vs neutral; 3dClustSim soft- placebo-treated, participants had lower responses to sexual cues ware; It is worth noting that our second-level in the midbrain (peak coordinate: 6, ⫺20, ⫺18; t ⫽ ⫺3.45) and t tests were conducted as unbiased whole-brain analyses; we did not the ventral pallidum (peak coordinate: ⫺16, ⫺4, ⫺4; t ⫽ ⫺4.03).
constrain these analyses to voxels that showed a significant interaction At p ⬍ 0.01, responses were additionally reduced in the ventral effect in the 2 ⫻ 3 ANOVA. This analytic approach prevents the problem striatum (peak coordinate: ⫺12, 2, ⫺8; t ⫽ ⫺2.68) and orbito- of inflated statistical significance (i.e., "double-dipping") that can occur frontal cortex (peak coordinate: 40, 20, ⫺20; t ⫽ ⫺2.78) of when a statistically selected subset of data is used in secondary analyses baclofen-treated participants. For aversive cues, at p ⬍ 0.005, Regions of activation were identified manu- there were still no differences in the neural response between ally using the Harvard-Oxford probabilistic anatomical atlas within the baclofen- and placebo-treated groups. However, at the most re- FMRIB Software Library (FSL). Although all regions of activation are laxed threshold of p ⬍ 0.01, baclofen-treated participants had reported, we limit our discussion to effects found in our regions of a lower responses to aversive cues in the midbrain (peak coordi- priori interest.
nate: ⫺4, ⫺16, ⫺16; t ⫽ ⫺2.82).
Cocaine, sexual, and aversive cues elicit mesolimbic activation As a basic confirmation that our cues elicited activation in our Demographic and clinical results
brain regions of interest, we examined the neural response to Basic demographic and substance use characteristics are pre- cocaine, sexual, and aversive cues (vs neutral cues) in the placebo sented in There were no differences between groups in group. For these illustrative single-group analyses, we used the age, years of education, estimated IQ, race, or prior cocaine, al- relaxed threshold of p ⬍ 0.01, k ⬎ 10, uncorrected. Cocaine cues cohol, or marijuana use. The majority of participants reported no induced activation in the bilateral VS (peak coordinate left: ⫺18, adverse events on BOLD scan day. Of the participants who did, 6, ⫺14; t ⫽ 4.56; peak coordinate right: 14, 2, ⫺14; t ⫽ 4.65), VP the most common adverse event reported was drowsiness (pla- (peak coordinate left: ⫺26, ⫺14, ⫺6; t ⫽ 4.02; peak coordinate cebo, n ⫽ 2; baclofen, n ⫽ 1). Scan-day urine samples from all right: 12, 0, ⫺6; t ⫽ 4.67), AMY (peak coordinate left: ⫺18, 0, participants were negative for recent cocaine use.
⫺18; t ⫽ 3.18; peak coordinate right: 16, 0, ⫺16; t ⫽ 4.01), OFC

Young et al. • Baclofen Prevents Drug Cue-Induced Limbic Activity J. Neurosci., April 2, 2014 • 34(14):5038 –5043 • 5041
Figure 2.
Neural activation to backward-masked cocaine (vs neutral) cues in baclofen- and placebo-treated cocaine-dependent men. A, Baclofen-treated compared with placebo-treated
participants demonstrated significantly less neural activation in a large interconnected cluster bilaterally spanning the ventral striatum, ventral pallidum, amygdala, midbrain, and orbitofrontal
cortex (voxel threshold p ⬍ 0.005; cluster corrected at p ⬍ 0.05). The image on the left shows the significant cluster of reduced activation rendered in 3D (crosshairs are centered on the left ventral
striatum. S, Superior; I, inferior; A, anterior; R, right; L, left). Cross-sectional coronal and axial images of ventral striatum, amygdala, and midbrain are displayed on the right. B, Placebo-treated
participants demonstrated increased neural activation in response to cocaine (vs neutral) cues in the ventral striatum, ventral pallidum, amygdala, and orbitofrontal cortex (left); neural activation
to cocaine cues was absent in baclofen-treated participants (right; data displayed at p ⬍ 0.01, k ⬎ 10, uncorrected). For cross-sectional images, data are displayed neurologically (left is left) and
the color bars represent T values.
Table 2. Regions of reduced activation in response to subliminal cocaine cues in
activation in the AMY (peak coordinate: 14, ⫺8, ⫺18; t ⫽ 3.89) baclofen-treated compared with placebo-treated participants
and midbrain (peak coordinate: 8, ⫺10, ⫺14; t ⫽ 3.62) was noted in response to aversive cues.
The current study tested the hypothesis that baclofen, a GABA Nucleus accumbens receptor agonist, inhibits the neural response to drug cues pre- sented outside of awareness. We demonstrate that participants treated with baclofen display significantly less activation in a large interconnected cluster spanning the VS, VP, AMY, OFC, and midbrain in response to subliminal cocaine cues than those Orbitofrontal cortex treated with placebo. These results replicate our previous find- ings that subliminal drug cues elicit mesolimbic activation and suggest that baclofen Non-a priori regions may prevent this effect, providing the first demonstration that the brain response to subliminal drug cues can be pharmacologically Inferior frontal gyrus inhibited. Further, we demonstrate no significant differences be- tween baclofen- and placebo-treated participants in the neural response to sexual or aversive cues, indicating that the effects of baclofen on cue-induced mesolimbic activation were specific to Superior temporal gyrus the drug cues. Given the well accepted role of the mesolimbic MNI coordinates and T-values of local maxima are shown for each region within the significant cluster (voxel reward circuit in drug reward and motivation, our findings indi- threshold p ⬍ 0.005; cluster-corrected p ⬍ 0.05). L, Left; R, right.
cate that one potential mechanism by which baclofen could havea therapeutic benefit in addiction is by "nipping in the bud" the (peak coordinate left: ⫺22, 18, ⫺16; t ⫽ 7.74; peak coordinate early motivational processing in response to drug cues—prevent- right: 32, 24, ⫺18; t ⫽ 4.45), and midbrain (peak coordinate: ⫺6, ing the earliest onset of drug cue-induced motivation before it ⫺18, ⫺14; t ⫽ 3.08) of placebo (but not baclofen)-treated par- ever reaches a state of conscious desire.
ticipants, as expected ). Sexual and aversive cues also The effects of baclofen on drug cue-induced limbic activation induced mesolimbic activation in placebo-treated participants: are consistent with previously published observations in humans.
activation in the VP (peak coordinate: ⫺16, ⫺6, ⫺2; t ⫽ 4.32), For example, in preliminary work in our laboratory using posi- AMY (peak coordinate: ⫺20, ⫺6, ⫺10; t ⫽ 2.9) midbrain (peak tron emission tomography (PET) with O 15-H2O, we examined coordinate: ⫺8, ⫺20, ⫺12; t ⫽ 3.2), and bilateral OFC (peak cocaine cue-induced limbic activation in a small sample of coordinate left: ⫺34, 36, ⫺20; t ⫽ 4.05; peak coordinate right: 40, cocaine-dependent men taking baclofen (10 –20 mg b.i.d. for 20, ⫺20; t ⫽ 3.09) was noted in response to sexual cues, and 7–10 d; these patients did not display the 5042 • J. Neurosci., April 2, 2014 • 34(14):5038 –5043
Young et al. • Baclofen Prevents Drug Cue-Induced Limbic Activity characteristic limbic activation to visible cocaine cues noted pre- these initial findings, it will be important to replicate them in a viously in unmedicated patients Our lab- larger sample and in other populations. Second, although we oratory has also shown that baclofen can even modulate the same demonstrate that a baclofen dose of 60 mg/d is sufficient to pre- circuitry at rest, since acute (20 mg) or long-term (80 mg/d; 20 vent limbic activation to cues presented outside awareness, it is mg q.i.d. for 21 d) treatment reduced resting cerebral blood flow possible that higher doses may be required for the full clinical in various limbic structures, including the VS, AMY, and/or me- benefit of baclofen to be realized Finally, we dial OFC Together, these results examined the impact of baclofen versus placebo at a single time support the hypothesis that baclofen may modulate neural activ- point. This design feature was chosen to ensure that we assessed ity in the human brain in regions involved in drug-motivated the impact of baclofen on the very first exposure to cocaine cues, while avoiding the unknown and potentially confounding effects A large body of research has demonstrated that drugs and of prior, unreinforced exposure (e.g., extinction). This design their conditioned cues elicit DA release in the VS and AMY depends heavily on randomization as a statistical control for po- tential differences in baseline cue reactivity. Fortunately, as Further, systemic administration of baclofen, and other shown in there were no significant differences in GABA-modulating agents, attenuates both drug-induced (e.g., demographic or drug use variables between the baclofen- and cocaine, nicotine, morphine; and drug cue- placebo-treated groups, minimizing the possibility that base- induced DA release—presumably by line differences influenced the current findings.
activating GABAB receptors located on DA neurons in the ventral The results of this study have intriguing implications for the tegmental area of the midbrain. Given that baclofen modulates treatment of addiction. The field of relapse prevention has fo- mesolimbic DA release in rodents, it is possible that the effects of cused almost exclusively on strategies to counter conscious drug baclofen on subliminal cue-induced activation noted here are motivation—and relapse rates remain stubbornly high. How- related to baclofen-induced alterations in DA release. In support ever, motivational processes and goal pursuit can be generated— of this idea, DA release in response to visible drug cues occurs and even operate— entirely outside of awareness quite rapidly (i.e., ⬍100 ms; and could there- Our findings provide the first evi- fore mediate neural activation in response to subliminal drug dence that a pharmacotherapy can impact unconscious drug mo- cues. Further, medications that directly alter dopaminergic neu- tivational processing in humans. These findings highlight a novel rotransmission (e.g., haloperidol, levodopa) have recently been mechanism by which pharmacotherapies, alone or in combina- found to modulate mesolimbic activation induced by sublimi- tion with existing psychosocial treatments, can prevent the earli- nally presented rewarding (e.g., sexual) stimuli est brain responses to drug cues and thus may provide a critical Although it is therefore likely that baclofen's modulation of me- form of relapse protection for cue-vulnerable individuals.
solimbic DA mediates the effects noted here, further explorationusing techniques such as PET will be required to directly examinethe neurochemical mechanisms involved.
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Luteinizing hormone reduces the activity of the npr2 guanylyl cyclase in mouse ovarian follicles, contributing to the cyclic gmp decrease that promotes resumption of meiosis in oocytes

Contents lists available at Developmental Biology journal homepage: Luteinizing hormone reduces the activity of the NPR2 guanylyl cyclasein mouse ovarian follicles, contributing to the cyclic GMP decrease thatpromotes resumption of meiosis in oocytes Jerid W. Robinson ,1, Meijia Zhang , Leia C. Shuhaibar , Rachael P. Norris , Andreas Geerts Frank Wunder , John J. Eppig , Lincoln R. Potter nn, Laurinda A. Jaffe n

Microsoft word - anexo 6.doc

 Bienvenido Unidad de Endotelio, Riesgo Cardiovascular y Salud Cardiometabólica Bienvenido al Servicio de la Unidad de Endotelio, Riesgo Cardiovascular y Salud Cardiometabólica. La Unidad Endotelio dependiente del Servicio de Medicina Interna del Hospital Ramón y Cajal, fue concebida en el año 1998, el mismo año en el que fueron concedidos los premios Nóbel de Medicina a los principales investigadores sobre el endotelio, considerado en la medicina actual el barómetro de la enfermedad cardiovascular. Actualmente la Unidad se compone de un grupo multidisciplinar de profesionales, integrada por médicos, enfermeras, nutricionistas, genetistas, biólogos, bioquímicos e ingenieros. Perspectiva histórica En 1980 fue fundada la "Unidad de Diabetes", pionera en su género en España dentro de los Servicios de Medicina Interna y a la que se le fueron incorporando patologías monográficas como la "hipertensión arterial", "dislipemia" y "obesidad", no sólo en el plano asistencial sino también en el de la investigación, participando en multitud de ensayos clínicos, hasta configurarse en 1990 una estructura de "Unidad de Riesgo Cardiovascular" que fue de las primeras en asentarse como tal en nuestro país. Como consecuencia de los cambios experimentados en la patología cardiovascular aterosclerótica y sobre todo como consecuencia del protagonismo creciente del endotelio como "capa funcionalmente activa" y no solo como "capa de revestimiento" en 1998 se presenta un proyecto de cambio a Unidad de Patología Endotelial que se puso en marcha en el año 2000. Sus inicios fueron lentos pero firmes y fructíferos, practicándose desde entonces una medicina moderna en todos sus matices: preventiva, predictiva, participativa, personalizada y traslacional. El comienzo La Unidad de Endotelio, Riesgo Cardiovascular y Salud Cardiometabólica del Hospital Ramón y Cajal, antigua Unidad de Patología Endotelial, fue fundada en el año 2000 como una "sección funcional" del Servicio de Medicina Interna por los entonces responsables del Servicio y del Hospital, bajo el auspicio de la Consejería de Sanidad de la Comunidad de Madrid. Dicha unidad fue a su vez la evolución natural de unidades previas del Servicio de Medicina Interna, servicio que como citado previamente siempre ha mantenido una línea cardiometabólica cuando todavía, ni siquiera, se había acuñado el término. Nuestra trayectoria hasta la actualidad En 2008 la Consejería apuesta de una forma decidida por la Unidad y culmina en unas nuevas instalaciones con un amplio surtido de novedades tecnológicas y bioquímicas para un mejor diagnóstico y manejo del enfermo vascular, claramente diferenciador de las Unidades de Riesgo Vascular de otros Hospitales de la Comunidad de Madrid. La Unidad fue dotada de recursos humanos y materiales en función del número de pacientes incorporados en aquella fecha (400). Las previsiones se quedaron cortas y hoy la Unidad de Endotelio, Riesgo Cardiovascular y Salud Cardiometabólica sobrepasa los 2000 pacientes con una tasa de seguimiento a los 5 años superior al 95%.