Competing Motivations: Proactive Response Inhibition Toward Addiction-Related Stimuli in Quitting-Motivated Individuals.

We examined whether addiction-related cues impact proactive inhibition (the restraint of actions in preparation for stopping) in individuals who are motivated to quit gambling or cannabis use. In Study 1, treatment-seeking individuals with cannabis use disorder and matched controls performed a stop-signal task that required them to inhibit categorizing cannabis or neutral pictures, and within varying levels of stop-signal probability. In Study 2, two groups of individuals, who applied to a voluntary self-exclusion program toward gambling, performed the stop-task following relaxation or gambling craving induction, with results compared to non-gamblers. Study 1 showed that despite being less efficient in proactive inhibition, individuals with cannabis use disorder exhibited heightened proactive inhibition toward cannabis cues. In Study 2, proactive inhibition toward gambling cues was heightened in gamblers after craving, but the degree of proactive adjustment decreased as a function of induced changes in gambling-related motivation. Present findings demonstrate that exposure to addiction-related cues can modulate proactive inhibition in individuals who are motivated to restrict their addictive behaviors.

Neural activity during attentional conflict predicts reduction in tinnitus perception following rTMS.

BACKGROUND: Subjective idiopathic tinnitus is an intrusive, distracting, and potentially disabling disorder characterized by phantom perception of sounds. Although tinnitus has no approved pharmacologic treatment, recent evidence supports the use of repetitive transcranial magnetic stimulation (rTMS) to alleviate tinnitus symptoms. OBJECTIVE/HYPOTHESIS: Repetitive TMS delivered over the middle superior temporal gyrus (STG) may alter ratings of tinnitus awareness and annoyance more than loudness due to change in attentional processing. STG has reciprocal connections to regions of the prefrontal cortex that mediate attention. To probe the hypothesized influence of STG stimulation on attention, a subset of patients with tinnitus enrolled in an rTMS clinical trial [n = 12, 9 male, mean (sd) age = 49 (15) years] underwent an attentional conflict task before and after rTMS treatment in a repeated-measures functional magnetic resonance imaging (fMRI) study. METHODS: The Multi-Source Interference Task (MSIT), a Stroop-based visual attentional conflict fMRI task, was used to map participants' neural processing of attentional conflict prior to rTMS intervention (Baseline) and after three rTMS intervention arms: Sham, 1 Hz, and 10 Hz (four sessions per arm, 1800 pulses per session, delivered @110% of the motor threshold over the posterior superior temporal gyrus). RESULTS: All measures of tinnitus severity (awareness, loudness, and annoyance) improved with 1 Hz rTMS intervention; however, the greatest and most robust changes were observed for ratings of tinnitus awareness (mean 16% reduction in severity from Baseline, p < 0.01). The MSIT elicited a similar pattern of neural activation among tinnitus participants at Baseline compared to an independent sample of 43 healthy comparison adults (r = 0.801, p = 0.001). Linear regression with bootstrap resampling showed that greater recruitment of bilateral prefrontal and bilateral parietal regions by MSIT at Baseline corresponded with poorer treatment response. Individual regions' activities explained 37-67% variance in participant treatment response, with left dorsolateral prefrontal cortex's MSIT activity at Baseline explaining the greatest reduction in tinnitus awareness following 1 Hz stimulation. Although left dorsolateral prefrontal cortex activity at Baseline also predicted reduction in tinnitus loudness and annoyance (∼50% variance explained), these symptoms were more strongly predicted by right middle occipital cortex (∼70% variance explained) - suggesting that the neural predictors of symptom-specific treatment outcomes may be dissociable. CONCLUSION: These candidate neural reactivity markers of treatment response have potential clinical value in identifying tinnitus sufferers who would or would not therapeutically benefit from rTMS intervention.

Changes in functional connectivity of the amygdala during cognitive reappraisal predict symptom reduction during trauma-focused cognitive-behavioral therapy among adolescent girls with post-traumatic stress disorder.

BACKGROUND: While trauma-focused cognitive-behavioral therapy (TF-CBT) is the 'gold standard' treatment for pediatric post-traumatic stress disorder (PTSD), little is known about the neural mechanisms by which TF-CBT produces clinical benefit. Here, we test the hypothesis that PTSD symptom reduction during TF-CBT among adolescent girls with PTSD is associated with changes in patterns of brain functional connectivity (FC) with the amygdala during cognitive reappraisal. METHOD: Adolescent girls with PTSD related to physical or sexual assault (n = 34) were enrolled in TF-CBT, delivered in an approximately 12-session format, in an open trial. Before and after treatment, they were engaged in a cognitive reappraisal task, probing neural mechanisms of explicit emotion regulation, during 3 T functional magnetic resonance imaging. RESULTS: Among adolescent girls completing TF-CBT with usable pre- and post-treatment scans (n = 20), improvements in self-reported emotion from pre- to post-treatment were positively related to improvements in PTSD symptoms. Adolescent girls with greater post-treatment symptom reduction were also able to suppress amygdala-insula FC while re-appraising, which was not evident in girls with less symptom reduction. Pre- to post-treatment changes in right amygdala to left insula FC that scaled with PTSD symptom reduction also scaled with improvements in emotion regulation. CONCLUSIONS: These preliminary results suggest the neurocircuitry mechanisms through which TF-CBT produces clinical outcomes, providing putative brain targets for augmenting TF-CBT response.

Differential functional connectivity within an emotion regulation neural network among individuals resilient and susceptible to the depressogenic effects of early life stress.

BACKGROUND: Early life stress (ELS) is a significant risk factor for depression. The effects of ELS exposure on neural network organization have not been differentiated from the effect of depression. Furthermore, many individuals exposed to ELS do not develop depression, yet the network organization patterns differentiating resiliency versus susceptibility to the depressogenic effects of ELS are not clear. METHOD: Women aged 18-44 years with either a history of ELS and no history of depression (n = 7), a history of ELS and current or past depression (n = 19), or a history of neither ELS nor depression (n = 12) underwent a resting-state 3-T functional magnetic resonance imaging (fMRI) scan. An emotion regulation brain network consisting of 21 nodes was described using graph analyses and compared between groups. RESULTS: Group differences in network topology involved decreased global connectivity and hub-like properties for the right ventrolateral prefrontal cortex (vlPFC) and decreased local network connectivity for the dorsal anterior cingulate cortex (dACC) among resilient individuals. Decreased local connectivity and increased hub-like properties of the left amygdala, decreased hub-like properties of the dACC and decreased local connectivity of the left vlPFC were observed among susceptible individuals. Regression analyses suggested that the severity of ELS (measured by self-report) correlated negatively with global connectivity and hub-like qualities for the left dorsolateral PFC (dlPFC). CONCLUSIONS: These preliminary results suggest functional neural connectivity patterns specific to ELS exposure and resiliency versus susceptibility to the depressogenic effects of ELS exposure.

Clinical milestones predict symptom remission over 6-month and choice of treatment of patients with major depressive disorder (MDD).

BACKGROUND: It is uncertain as to what short-term outcomes predict long-term treatment compliance and outcomes in patients with MDD. AIMS: To determine what treatment milestones predict symptom remission with long-term treatment with antidepressant medication. METHOD: Pooled analysis of four randomised, double-blind, active comparator, 6-month trials in MDD. RESULTS: Patients received double-blind treatment with escitalopram (N=699) or a comparator (citalopram, duloxetine, or paroxetine) (N=699). Onset of effect at week 2 was correlated with response at week 8, and response at week 8 with completion of 6-month treatment. Week 8 response was associated with a greater probability of achieving later remission. Week 24 remission (MADRS>or=10) was significantly (p<0.01) higher for patients treated with escitalopram (70.7%) than for the pooled comparators (64.7%). Week 24 complete remission (MADRS

The changing roles and targets for animal models of schizophrenia.

Unlike disorders of other fields of medicine (eg., diabetes, heart disease), schizophrenia has been only marginally impacted by the study of animal models. This gap reflects the incomplete understanding of the causes and mechanisms of schizophrenia and the resulting lack of defined targets for model development. However, prior attempts at modeling in animals the complex symptoms of schizophrenia have given way to more promising component models. This review will address the evolving field of animal models of schizophrenia with a focus on models of errors in neurotransmission, and of psychophysiological deficits, with a concluding discussion of the present and future promise of genetic-based models. Evolving models based on the long-held conceptualization of schizophrenia as being based on errors in neurotransmission are discussed as regards the integration of newer findings implicating alterations in dopamine, glutamate and neurotensin function in the pathophysiology and pharmacotherapy of schizophrenia. The case for the more recent conceptualization of schizophrenia as a core deficit in information processing and stimulus filtering is discussed. Animal behavioral paradigms that model psychophysiologic constructs of stimulus processing deficits related to schizophrenia include prepulse inhibition (PPI), a model of sensorimotor gating, or latent inhibition (LI), a model of salience learning. These models represent both better supported associations with schizophrenia and more productive targets and are providing important new information regarding the psychopharmacology of schizophrenia. Genetic models of schizophrenia are based on the demonstrated heritability of the disorder and more recent pharmacogenetic findings for antipsychotic medications. Genetic-based animal models use behavioral or molecular genetic techniques to manipulate behaviors related to schizophrenia by altering the frequencies of related genes. The future development of increasingly informative animal models of schizophrenia will be dependent on a more complete understanding of schizophrenia, an integration of findings across animal models and refinements in the criteria used to assess model "validity" that better reflect the changing nature and roles of animal models of schizophrenia.

Neural activity related to drug craving in cocaine addiction.

BACKGROUND: Crack cocaine dependence and addiction is typically associated with frequent and intense drug wanting or craving triggered by internal or environmental cues associated with past drug use. METHODS: Water O 15 positron emission tomography (PET) studies were used to localize alterations in synaptic activity related to cue-induced drug craving in 8 crack cocaine-dependent African American men. In a novel approach, script-guided imagery of autobiographical memories were used as individualized cues to internally generate a cocaine craving state and 2 control (ie, anger and neutral episodic memory recall) states during PET image acquisition. RESULTS: The mental imagery of personalized drug use and anger-related scripts was associated with self-ratings of robust drug craving or anger, and comparable alterations in heart rate. Compared with the neutral imagery control condition, imagery-induced drug craving was associated with bilateral (right hemisphere amygdala activation greater than left) activation of the amygdala, the left insula and anterior cingulate gyrus, and the right subcallosal gyrus and nucleus accumbens area. Compared with the anger control condition, internally generated drug craving was associated with bilateral activation of the insula and subcallosal cortex, left hippocampus, and anterior cingulate cortex and brainstem. A brain-wide pixel-by-pixel search indicated significant positive and negative correlations between imagery-induced cocaine craving and regional cerebral blood flow (rCBF) in distributed sites. CONCLUSIONS: The collected findings suggest the craving-related activation of a network of limbic, paralimbic, and striatal brain regions, including structures involved in stimulus-reward association (amygdala), incentive motivation (subcallosal gyrus/nucleus accumbens), and anticipation (anterior cingulate cortex).

Synthesis and characterization of fluorinated and iodinated pyrrolopyrimidines as PET/SPECT ligands for the CRF1 receptor.

Fluorine-18 labeled fluorobutyl[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d] pyrimidin-4-yl]ethylamine (FBPPA) and iodine-123 labeled butyl[2,5-dimethyl-7-(4-iodo-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]ethyl-amine (IBPPA) were synthesized in the development of a CRF receptor ligand. The methods of synthesis, in vitro binding assays, radiolabeling and in vivo tissue distribution in rats are described. Fluorine-18 labeled FBPPA was prepared with high specific activity (3 x 10(4) Ci/mmol) by nucleophilic displacement with an average radiochemical yield of 6% (EOB). Iodine-123 labeled IBPPA was prepared by electrophilic iododestannylation with good yield (60%) and high specific activity (3.3 x 10(3) Ci/mmol). The retention of FBPPA and IBPPA in the pituitary was good (1.16% i.d./g and 2.35% i.d./g respectively at 60 min). However, the accumulation of radioactivity in the brain for both radiotracers was very low at all time points of the study, which demonstrated the difficulties for these radiopharmaceuticals to penetrate the blood brain barrier (BBB).

Biodistribution and radiation dosimetry of the dopamine transporter ligand.

UNLABELLED: 18F-labeled 2 beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(-2-fluoroethyl)nortropane ([18F]FECNT) is a recently developed dopamine transporter ligand with potential applications in patients with Parkinson's disease and cocaine addiction. METHODS: Estimates of the effective dose equivalent and doses for specific organs were made using biodistribution data from 16 Sprague-Dawley rats and nine rhesus monkeys. PET images from two rhesus monkeys were used to calculate the residence time for the basal ganglia. The computer program MIRDOSE3 was used to calculate the dosimetry according to the methodology recommended by MIRD. RESULTS: The basal ganglia were the targeted tissues receiving the highest dose, 0.11 mGy/MBq (0.39 rad/mCi). The effective dose equivalent was 0.018 mSv/MBq (0.065 rem/mCi), and the effective dose was 0.016 mSv/MBq (0.058 rem/mCi). CONCLUSION: Our data show that a 185-MBq (5-mCi) injection of [18F]FECNT leads to an estimated effective dose of 3 mSv (0.3 rem) and an estimated dose to the target organ or tissue of 19.4 mGy (1.93 rad).

Neural correlates of maternal separation in rhesus monkeys.

BACKGROUND: The neurobiological basis of stress and anxiety in primates remains poorly understood. In this study, we examined the neural response to a naturalistic social stressor: maternal separation. We used rhesus monkeys as an animal model because of their close phylogenetic affinity with humans. METHODS: Six juvenile rhesus monkeys received [(18)F]-fluorodeoxyglucose positron emission tomography scans following 1) a period together with their mothers and again after separation from their mothers 2) with or 3) without visual contact. Image subtraction revealed brain regions that exhibited altered activity during separation. In addition, plasma cortisol concentrations obtained following each condition were tested for correlations with regional brain activity. RESULTS: Maternal separation activated the right dorsolateral prefrontal cortex and the right ventral temporal/occipital lobe. There was also decreased activity in left dorsolateral prefrontal cortex associated with separation stress. Correlational analyses demonstrated these activated and deactivated regions to be positively and negatively correlated with cortisol, respectively. Additionally, correlational analyses revealed cortisol-related activation in brainstem areas previously implicated in stress and anxiety. CONCLUSIONS: In juvenile rhesus monkeys, the stress of maternal separation is associated with activation in the right dorsolateral prefrontal cortex and ventral temporal/occipital lobes and decreased activity in the left dorsolateral prefrontal cortex.

Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: evidence from animal models of sensorimotor gating.

To date, none of the available antipsychotic drugs are curative, all have significant side-effect potential, and a receptor-binding profile predictive of superior therapeutic ability has not been determined. It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather from an imbalance between several interacting systems. Targeting neuropeptide neuromodulator systems that concertedly regulate all affected neurotransmitter systems could be a promising novel therapeutic approach for schizophrenia. A considerable database is concordant with the hypothesis that antipsychotic drugs act, at least in part, by increasing the synthesis and release of the neuropeptide neurotensin (NT). In this report, we demonstrate that NT neurotransmission is critically involved in the behavioral effects of antipsychotic drugs in two models of antipsychotic drug activity: disrupted prepulse inhibition of the acoustic startle response (PPI) and the latent inhibition (LI) paradigm. Blockade of NT neurotransmission using the NT receptor antagonist 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H- pyrazole-3-carbonyl]-amino]-adamantane-2-carboxylic acid, hydrochloride (SR 142948A) prevented the normal acquisition of LI and haloperidol-induced enhancement of LI. In addition, SR 142948A blocked the PPI-restoring effects of haloperidol and the atypical antipsychotic drug quetiapine in isolation-reared animals deficient in PPI. We also provide evidence of deficient NT neurotransmission as well as a left-shifted antipsychotic drug dose-response curve in isolation-reared rats. These novel findings, together with previous observations, suggest that neurotensin receptor agonists may represent a novel class of antipsychotic drugs.

Radioligands for PET and SPECT Imaging of the central noradrenergic system.

In the central nervous system, the neurotransmitter norepinephrine is involved in normal physiology, neuropsychiatric disorders, and the effects of numerous drugs. Although alterations of the central noradrenergic system are involved in the pathophysiology and pharmacotherapy of mood disorders, the basis and nature of these changes remain unresolved. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging agents will be valuable for further elucidating the roles of norepinephrine in health and disease. This review discusses PET and SPECT radioligands that have been developed for the enzymes, receptors, and transporters involved in noradrenergic neurotransmission. Currently, imaging agents that exhibit specific in vivo uptake in the brain have been described for monoamine oxidase A and beta-adrenergic receptors, but have not undergone detailed evaluation or experimental application. Based on the successful development and utilization of in vivo imaging agents for elements of the central dopaminergic and serotoninergic systems, PET and SPECT radioligands are expected to serve as new tools for studying the physiology, pathophysiology, and pharmacology of the central noradrenergic system.

Imaging the roles of the amygdala in drug addiction.

The neurobiological processes that underlie initial use of drugs of abuse and the transition to drug abuse, addiction, and dependence are poorly understood. Intrinsic and drug-related alterations in complex brain functions such as motivation, learning, memory, reward, attention, and arousal seemingly underlie the process of drug abuse and addiction. This discussion focuses on the use of functional brain imaging techniques such as positron emission tomography and functional magnetic resonance imaging to define the roles of the amygdala in the sequence of behavioral processes that span initial drug use to addiction and its consequences. The functional images of the human amygdala demonstrate or implicate this limbic structure in the processes of reward learning and memory, conditioned reward and emotion dysregulation related to drug use, and the transition to addiction. While these roles of the amygdala reflect its involvement in the actions of large-scale neural systems comprising cortical and subcortical structures, its important roles as a neural substrate mediating or modulating behaviors related to initial drug use to addiction, and its personal and social consequences, are increasingly defined by functional brain imaging studies.

In vivo imaging of the pharmacodynamics and pharmacokinetics of lithium.

The therapeutic efficacy of lithium for the long-term management of bipolar disorder is well recognized, along with the risk of lithium-induced toxicity. The author describes the current findings of in vivo functional neuroimaging techniques with respect to the pharmacokinetics and pharmacodynamics of lithium and their future potential to elucidate the drug distribution and neural mechanisms that produce its therapeutic effects. Brain Li nuclear magnetic resonance spectroscopy findings have disassociated postdose brain and blood lithium concentrations and suggest a pharmacokinetic basis for lithium response and nonresponse. The application of in vivo synaptic activity and neurochemical imaging is providing new knowledge related to the distributed neural activity associated with lithium response and is contributing to the critical human testing of neuroprotective and signal transduction models of lithium's therapeutic effects.

18F-labeled FECNT: a selective radioligand for PET imaging of brain dopamine transporters.

Fluorine-18 labeled 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nort ropane (FECNT) was synthesized in the development of a dopamine transporter (DAT) imaging ligand for positron emission tomography (PET). The methods of radiolabeling and ligand synthesis of FECNT, and the results of the in vitro characterization and in vivo tissue distribution in rats and in vivo PET imaging in rhesus monkeys of [18F]FECNT are described. Fluorine-18 was introduced into 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nort ropane (4) by preparation of 1-[18F]fluoro-2-tosyloxyethane (2) followed by alkylation of 2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane (3) in 21% radiochemical yield (decay corrected to end of bombardment [EOB]). Competition binding in cells stably expressing the transfected human DAT serotonin transporter (SERT) and norepinephrine transporter (NET) labeled by [3H]WIN 35428, [3H]citalopram, and [3H]nisoxetine, respectively, indicated the following order of DAT affinity: GBR 12909 > CIT >> 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(3-fluoropropyl) nortropane (FPCT) > FECNT. The affinity of FECNT for SERT and NET was 25- and 156-fold lower, respectively, than for DAT. Blocking studies were performed in rats with a series of transporter-specific agents and demonstrated that the brain uptake of [18F]FECNT was selective and specific for DAT-rich regions. PET brain imaging studies in monkeys demonstrated high [18F]FECNT uptake in the caudate and putamen that resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 10.5 at 60 min. [18F]FECNT uptake in the caudate/putamen peaked in less than 75 min and exhibited higher caudate- and putamen-to-cerebellum ratios at transient equilibrium than reported for 11C-WIN 35,428, [11C]CIT/RTI-55, or [18F]beta-CIT-FP. Analysis of monkey arterial plasma samples using high performance liquid chromatography determined that there was no detectable formation of lipophilic radiolabeled metabolites capable of entering the brain. In equilibrium displacement experiments with CIT in rhesus monkeys, radioactivity in the putamen was displaced with an average half-time of 10.2 min. These results indicate that [18F]FECNT is a radioligand that is superior to 11C-WIN 35,428, [11C]CIT/RTI-55, [18F]beta-CIT-FP, and [18F]FPCT for mapping brain DAT in humans using PET.

Alterations in the functional anatomy of working memory in adult attention deficit hyperactivity disorder.

OBJECTIVE: The authors used a functional neuroimaging study with a working memory probe to investigate the pathophysiology of attention deficit hyperactivity disorder (ADHD). Their goal was to compare regional cerebral blood flow (rCBF) changes related to working memory in adults with and without ADHD. METHOD: Using [(15)O]H(2)O positron emission tomography (PET) studies, the authors compared the sites of neural activation related to working memory in six adult men diagnosed with ADHD and six healthy men without ADHD who were matched in age and general intelligence. RESULTS: Task-related changes in rCBF in the men without ADHD were more prominent in the frontal and temporal regions, but rCBF changes in men with ADHD were more widespread and primarily located in the occipital regions. CONCLUSIONS: These data suggest the use of compensatory mental and neural strategies by subjects with ADHD in response to a disrupted ability to inhibit attention to nonrelevant stimuli and the use of internalized speech to guide behavior.

Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2beta-carbo-1'-fluoro-2-propoxy-3beta-(4-chlorophenyl)tr opanes. Ligands for the imaging of dopamine transporters by positron emission tomography.

2beta-(R)-Carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((R)-FIPCT, R-6) and 2beta-(S)-carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((S)-FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2beta-carbo-R-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (R-12) and 2beta-carbo-S-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (S-12) followed by treatment with no carrier-added potassium[(18)F]fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [(3)H]WIN 35428 and [(3)H]citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) >> (R)-FIPCT (3.2). The affinity of (S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [(18)F](R)-FIPCT and [(18)F](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [(18)F](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [(18)F](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT for DAT indicate [(18)F](R)-FIPCT and [(18)F](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.

Neural activity related to anger in cocaine-dependent men: a possible link to violence and relapse.

This study examined the neural correlates of cue-induced anger in cocaine-dependent men in an initial investigation of possible neurobiological explanations for the putative association between cocaine addiction and violence. We used positron emission tomography (PET) to localize alterations in regional cerebral blood flow (rCBF) during mental imagery of a personal anger-associated scene and of an emotionally neutral scene in ten cocaine-dependent men. Compared to the emotionally neutral imagery control condition, anger was associated with marked decreases in rCBF in multiple areas of the frontal cortex (particularly the right inferior frontal gyrus), left posterior insula, left fusiform gyrus, and midbrain. Conversely, this same inferior frontal area was activated by anger imagery in nicotine-dependent men. Anger was also associated with increases in rCBF in the right fusiform gyrus, right and left middle occipital gyri, left post-central gyrus, left medial frontal gyrus, left cuneus, and in the left anterior cingulate gyrus. The study showed that cue-induced anger in cocaine-dependent men was associated with decreased activity in frontal cortical areas involved in response monitoring and inhibition. The lack of this association in nicotine-dependent men suggests a possible deficit in anger regulation associated with cocaine dependence and a possible link between cocaine dependence, violence, and relapse.

Chronic lithium treatment decreases neuronal activity in the nucleus accumbens and cingulate cortex of the rat.

Although the efficacy of lithium as a mood stabilizer is well documented, the mechanism of its therapeutic effect associated with prolonged treatment remains unknown. Identifying discrete brain regions and neural pathways that are functionally altered following long-term lithium treatment is central to elucidating a psychotherapeutic mechanism. We have used a sensitive and quantitative histochemical assay for the determination of cytochrome oxidase (CO) activity, a mitochondrial marker of neuronal activity, to determine the effect of repeated lithium treatment on regional neuronal activity in the rat brain. Oral lithium treatment (21 days) selectively decreased cytochrome oxidase activity in the cingulate cortex and regions of the nucleus accumbens. These decreases were not seen after 5 days of lithium administration, although serum lithium concentrations were similar after both 5 and 21 days of treatment. The analysis of interregional correlations further suggests a role for amygdala pathways in the effects of lithium following 21 days of treatment. The implications of these data for understanding the mechanisms of action of lithium are discussed.