Igor Elman

Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach.

Agents that antagonize the glutamatergic N‐methyl‐d‐aspartate (NMDA) receptor, such as phenylcyclidine (PCP) and ketamine, produce a behavioral state in healthy volunteers that resembles some aspects of schizophrenia. A dysfunction in NMDA–dopaminergic interactions has been proposed as a mechanism for these behavioral effects. In this study, we examined the effects of ketamine on striatal dopamine release in healthy human subjects with a novel 11C‐raclopride/PET displacement paradigm and compared these effects to administration of saline and the direct‐acting dopamine agonist amphetamine. We found that the percent decreases (mean ± SD) in specific 11C‐raclopride binding from baseline for ketamine (11.2 ± 8.9) was greater than for saline (1.9 ± 3.7) (t = 2.4, df = 13, P = 0.003) indicating that ketamine caused increases in striatal synaptic dopamine concentrations. Ketamine‐related binding changes were not significantly different than the decreases in percent change (mean ± SD) in specific 11C‐raclopride binding caused by amphetamine (15.5 ± 6.2) (t = 1.3, df = 19, P = 0.21). Ketamine‐induced changes in 11C‐raclopride‐specific binding were significantly correlated with induction of schizophrenia‐like symptoms. The implications of this brain imaging method for studies of schizophrenia and the mechanism of action of antipsychotic drugs are discussed. Synapse 29:142–147, 1998. Published 1998 Wiley‐Liss, Inc.

Alterations in brain structure and functional connectivity in prescription opioid-dependent patients.

A dramatic increase in the use and dependence of prescription opioids has occurred within the last 10 years. The consequences of long-term prescription opioid use and dependence on the brain are largely unknown, and any speculation is inferred from heroin and methadone studies. Thus, no data have directly demonstrated the effects of prescription opioid use on brain structure and function in humans. To pursue this issue, we used structural magnetic resonance imaging, diffusion tensor imaging and resting-state functional magnetic resonance imaging in a highly enriched group of prescription opioid-dependent patients [(n=10); from a larger study on prescription opioid dependent patients (n=133)] and matched healthy individuals (n=10) to characterize possible brain alterations that may be caused by long-term prescription opioid use. Criteria for patient selection included: (i) no dependence on alcohol or other drugs; (ii) no comorbid psychiatric or neurological disease; and (iii) no medical conditions, including pain. In comparison to control subjects, individuals with opioid dependence displayed bilateral volumetric loss in the amygdala. Prescription opioid-dependent subjects had significantly decreased anisotropy in axonal pathways specific to the amygdala (i.e. stria terminalis, ventral amygdalofugal pathway and uncinate fasciculus) as well as the internal and external capsules. In the patient group, significant decreases in functional connectivity were observed for seed regions that included the anterior insula, nucleus accumbens and amygdala subdivisions. Correlation analyses revealed that longer duration of prescription opioid exposure was associated with greater changes in functional connectivity. Finally, changes in amygdala functional connectivity were observed to have a significant dependence on amygdala volume and white matter anisotropy of efferent and afferent pathways of the amygdala. These findings suggest that prescription opioid dependence is associated with structural and functional changes in brain regions implicated in the regulation of affect and impulse control, as well as in reward and motivational functions. These results may have important clinical implications for uncovering the effects of long-term prescription opioid use on brain structure and function.

Clozapine Blunts N-Methyl-d-Aspartate Antagonist-Induced Psychosis: A Study with Ketamine

Several lines of evidence suggest that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in the antipsychotic efficacy of the atypical antipsychotic agent clozapine. Clinical data on the interaction between clozapines mechanism of action and NMDA receptor function have been lacking secondary to a paucity of pharmacologic probes of the NMDA system. We have utilized a double-blind, placebo-controlled infusion paradigm with subanesthetic doses of the NMDA antagonist ketamine to test the hypothesis that clozapine would blunt ketamine-induced psychotic symptoms in schizophrenic patients. Ten schizophrenic patients underwent ketamine infusions while antipsychotic drug free and also during treatment with clozapine. Antipsychotic drug-free patients experienced increases in ratings of positive and negative symptoms. Clozapine treatment significantly blunted the ketamine-induced increase in positive symptoms. These data suggest that NMDA receptor function may be involved in the unique antipsychotic efficacy of clozapine.

Decreased Absolute Amygdala Volume in Cocaine Addicts

The amygdala is instrumental to a set of brain processes that lead to cocaine consumption, including those that mediate reward and drug craving. This study examined the volumes of the amygdala and hippocampus in cocaine-addicted subjects and matched healthy controls and determined that the amygdala but not the hippocampus was significantly reduced in volume. The right-left amygdala asymmetry in control subjects was absent in the cocaine addicts. Topological analysis of amygdala isosurfaces (population averages) revealed that the isosurface of the cocaine-dependent group undercut the anterior and superior surfaces of the control group, implicating a difference in the corticomedial and basolateral nuclei. In cocaine addicts, amygdala volume did not correlate with any measure of cocaine use. The amygdala symmetry coefficient did correlate with baseline but not cocaine-primed craving. These findings argue for a condition that predisposes the individual to cocaine dependence by affecting the amygdala, or a primary event early in the course of cocaine use.

Psychological processing in chronic pain: a neural systems approach.

Our understanding of chronic pain involves complex brain circuits that include sensory, emotional, cognitive and interoceptive processing. The feed-forward interactions between physical (e.g., trauma) and emotional pain and the consequences of altered psychological status on the expression of pain have made the evaluation and treatment of chronic pain a challenge in the clinic. By understanding the neural circuits involved in psychological processes, a mechanistic approach to the implementation of psychology-based treatments may be better understood. In this review we evaluate some of the principle processes that may be altered as a consequence of chronic pain in the context of localized and integrated neural networks. These changes are ongoing, vary in their magnitude, and their hierarchical manifestations, and may be temporally and sequentially altered by treatments, and all contribute to an overall pain phenotype. Furthermore, we link altered psychological processes to specific evidence-based treatments to put forth a model of pain neuroscience psychology.

GENDER DIFFERENCES IN COCAINE CRAVING AMONG NON-TREATMENT- SEEKING INDIVIDUALS WITH COCAINE DEPENDENCE

The purpose of this pilot study was to evaluate potential gender differences in cocaine craving among non–treatment seekers with cocaine dependence. We examined 10 female and 11 male individuals matched by demographic characteristics and severity of drug use; we used a multidimensional questionnaire that assesses various aspects of craving: (a) current intensity, (b) projected intensity, (c) resistance to use cocaine, (d) responsiveness to drug-related conditioned stimuli, and (e) imagined likelihood of use if in a setting with access to drugs. Other instruments utilized were the Hamilton Rating Scale for Depression and Addiction Severity Index. Female subjects had higher total craving scores (p <. 05), with post hoc tests showing more present desire to use cocaine and responsivity to drug-conditioned stimuli, along with lower scores on the desire not to use cocaine. In exploratory analyses, we found greater depressive symptomatology (p =. 02) and severity of family/social problems (p =. 02) in females than their males counterparts. These results suggest that gender may influence different aspects of cocaine craving. As estrogen is purported to modulate craving-related dopaminergic systems, further studies will be needed to confirm these observed gender differences and to investigate their possible mechanisms, particularly estrogendopamine interactions and their effect on craving and mood.

Aversion-related circuitry in the cerebellum: responses to noxious heat and unpleasant images.

The cerebellum is reliably activated during both acute and chronic pain conditions, but it is unclear whether the response to aversive painful stimuli can be generalized to other aversive stimuli. We hypothesized that cerebellar activation during pain reflects higher-level encoding of aversive stimuli. We used functional magnetic resonance imaging (fMRI) to compare cerebellar responses in 11 healthy volunteers to noxious heat (46°C) applied to the hand and to the passive viewing of images selected from the International Affective Picture System. Aversive stimuli in the form of noxious heat and unpleasant pictures (unpleasant vs neutral) activated overlapping areas in the posterior cerebellum, specifically in hemispheric lobule VI, Crus I, and VIIb. Pleasant pictures (pleasant vs neutral) did not share the same pattern of activation as observed with the aversive stimuli. Cerebellar areas that showed functional overlap with both heat pain and unpleasant picture viewing were significantly inversely correlated with fMRI signals measured in limbic system structures, including the anterior hypothalamus, subgenual anterior cingulate cortex, and the parahippocampal gyrus. Heat-specific functional connectivity was detected in many regions including primary motor cortex, secondary somatosensory cortex, anterior insula, and the periaqueductal gray. The overlap between cerebellar lobuli reactive to noxious heat and passive viewing of unpleasant images suggest that the cerebellum may contain specific regions involved in encoding generalized aversive processing. The separate cortical networks suggest that noxious heat-evoked responses in the cerebellum can be divided into sensorimotor and emotional networks.

Reward-aversion circuitry in analgesia and pain: implications for psychiatric disorders.

Sensory and emotional systems normally interact in a manner that optimizes an organisms ability to survive using conscious and unconscious processing. Pain and analgesia are interpreted by the nervous system as aversive and rewarding processes that trigger specific behavioral responses. Under normal physiological conditions these processes are adaptive. However, under chronic pain conditions, functional alterations of the central nervous system frequently result in maladaptive behaviors. In this review, we examine: (a) the interactions between sensory and emotional systems involved in processing pain and analgesia in the physiological state; (b) the role of reward/aversion circuitry in pain and analgesia; and (c) the role of alterations in reward/aversion circuitry in the development of chronic pain and co‐morbid psychiatric disorders. These underlying features have implications for understanding the neurobiology of functional illnesses such as depression and anxiety and for the development and evaluation of novel therapeutic interventions.

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Obesity is highly prevalent among patients with schizophrenia and is associated with detrimental health consequences. Although excessive consumption of fast food and pharmacotherapy with such second-generation antipsychotic agents (SGAs) as clozapine and olanzapine has been implicated in the schizophrenia/obesity comorbidity, the pathophysiology of this link remains unclear. Here, we propose a mechanism based on brain reward function, a relevant etiologic factor in both schizophrenia and overeating. A comprehensive literature search on neurobiology of schizophrenia and of eating behavior was performed. The collected articles were critically reviewed and relevant data were extracted and summarized within four key areas: (1) energy homeostasis, (2) food reward and hedonics, (3) reward function in schizophrenia, and (4) metabolic effects of the SGAs. A mesolimbic hyperdopaminergic state may render motivational/incentive reward system insensitive to low salience/palatability food. This, together with poor cognitive control from hypofunctional prefrontal cortex and enhanced hedonic impact of food, owing to exaggerated opioidergic drive (clinically manifested as pain insensitivity), may underlie unhealthy eating habits in patients with schizophrenia. Treatment with SGAs purportedly improves dopamine-mediated reward aspects, but at the cost of increased appetite and worsened or at least not improved opiodergic capacity. These effects can further deteriorate eating patterns. Pathophysiological and therapeutic implications of these insights need further validation via prospective clinical trials and neuroimaging studies.

Effects of Acute Metabolic Stress on Striatal Dopamine Release in Healthy Volunteers

Several lines of evidence indicate that a variety of metabolic stressors, including acute glucose deprivation are associated with dopamine release. Pharmacologic doses of the glucose analogue, 2-deoxyglucose (2DG) cause acute glucoprivation and are associated with enhanced dopamine turnover in preclinical studies. In this study, we utilized [11C]raclopride PET to examine 2DG-induced striatal dopamine release in healthy volunteers. Six healthy volunteers underwent PET scans involving assessment of 2DG-induced (40 mg/kg) decrements in striatal binding of the D2/D3 receptor radioligand [11C]raclopride. Decreases in [11C]raclopride specific binding reflect 2DG-induced changes in synaptic dopamine. Specific binding significantly decreased following 2DG administration, reflecting enhanced synaptic dopamine concentrations (p = .02). The administration of 2DG is associated with significant striatal dopamine release in healthy volunteers. Implications of these data for investigations of the role of stress in psychiatric disorders are discussed.