PPARγ activation by pioglitazone does not suppress cravings for alcohol, and is associated with a risk of myopathy in treatment seeking alcohol dependent patients: a randomized controlled proof of principle study.

RATIONALE: Proinflammatory processes have been implicated in alcohol addiction, craving, and relapse, while studies in experimental animals have suggested that activation of peroxisome proliferator-activated receptor gamma (PPARγ) inhibits proinflammatory signaling. Accordingly, it is hypothesized that medications with PPARγ activity may have therapeutic potential in alcohol dependence. OBJECTIVES: We conducted a double-blind, placebo-controlled mechanistic proof of principle study in alcohol-dependent inpatients to investigate the effect of pioglitazone on alcohol craving. METHODS: Participants were treated for withdrawal, if needed, and then randomized to pioglitazone (target dose 45 mg/day) or placebo. Once at target dose, they completed two experimental manipulations: guided imagery, which used personalized auditory scripts to induce alcohol cravings, and a low-dose challenge with i.v. lipopolysaccharide (LPS; 0.8 ng/kg) or placebo, on two separate sessions, in counterbalanced order. Behavioral and endocrine responses as well as CSF levels of proinflammatory cytokines were evaluated. RESULTS: The study was prematurely terminated after randomization of 16 subjects, following an independent review that established a high risk of myopathy in the active treatment group. Analysis of those who completed the study indicated that pioglitazone was associated with elevated, rather than suppressed alcohol cravings in response to alcohol-associated stimuli. LPS did not induce cravings for alcohol and thus did not lend itself to evaluating pioglitazone effects; however, pioglitazone increased the neuroendocrine stress response to LPS. CSF levels of IL-6, TNF-α, or MCP-1 were unaffected by pioglitazone treatment. CONCLUSIONS: Both safety and efficacy biomarker data suggest that pioglitazone lacks potential as a medication for the treatment of alcohol dependence. CLINICAL TRIAL REGISTRATION: NCT01631630.

The Affective and Neural Correlates of Heroin versus Cocaine Use in Addiction Are Influenced by Environmental Setting But in Opposite Directions.

Previous studies have shown that individuals with heroin and cocaine addiction prefer to use these drugs in distinct settings: mostly at home in the case of heroin and mostly outside the home in the case of cocaine. Here we investigated whether the context would modulate the affective and neural responses to these drugs in a similar way. First, we used a novel emotional task to assess the affective state produced by heroin or cocaine in different settings, based on the recollections of male and female drug users. Then we used fMRI to monitor neural activity during drug imagery (re-creating the setting of drug use) in male drug users. Consistent with our working hypothesis, the majority of participants reported a shift in the affective valence of heroin from mostly pleasant at home to mostly unpleasant outside the home (p < 0.0001). The opposite shift was observed for cocaine; that is, most participants who found cocaine pleasant outside the home found it unpleasant when taken at home (p < 0.0014). Furthermore, we found a double dissociation, as a function of drug and setting imagery, in BOLD signal changes in the left PFC and caudate, and bilaterally in the cerebellum (all p values <0.01), suggesting that the fronto-striatal-cerebellar network is implicated in the contextualization of drug-induced affect. In summary, we report that the same setting can influence in opposite directions the affective and neural response to psychostimulants versus opiates in humans, adding to growing evidence of distinct substrates for the rewarding effects of these two drug classes.SIGNIFICANCE STATEMENT The rewarding effects of addictive drugs are often thought to depend on shared substrates. Yet, environmental influences can unmask striking differences between psychostimulants and opiates. Here we used emotional tasks and fMRI to explore the influence of setting on the response to heroin versus cocaine in individuals with addiction. Simply moving from one setting to another significantly decreased heroin pleasure but increased cocaine pleasure, and vice versa. Similar double dissociation was observed in the activity of the fronto-striatal-cerebellar network. These findings suggest that the effects of opiates and psychostimulants depend on dissociable psychological and neural substrates and that therapeutic approaches to addiction should take into account the peculiarities of different drug classes and the settings of drug use.

Peripheral Immune System Adaptations and Motivation for Alcohol in Non-Dependent Problem Drinkers.

BACKGROUND: Increasing evidence suggests that levels of pro-inflammatory and anti-inflammatory cytokines are dysfunctional in alcohol dependence. Moreover, some initial findings demonstrate that these adaptations in peripheral inflammation may contribute to motivation for alcohol and problem drinking via possible direct effects or the indirect effects of stress responsivity. Importantly, the role of pro-inflammatory and anti-inflammatory cytokines in the progression from healthy to problem drinking is not well understood. The aim of this study was to assess whether alcohol-related peripheral immune system changes affect stress and alcohol cue-induced craving and anxiety and behavioral alcohol motivation and intake in the laboratory among problem drinkers compared with socially drinking controls. METHODS: Twenty-six problem drinkers and 38 moderate, social drinkers participated in a laboratory challenge procedure during which they were exposed to 3 personalized 5-minute imagery conditions (stress [S], relaxing [R], and alcohol cue [C]), followed by the "alcohol taste test" (ATT) as a measure of implicit alcohol motivation and intake, presented across 3 consecutive days, 1 per day in a randomized and counterbalanced order. Measures of tumor necrosis factor-alpha (TNFα), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), alcohol craving, and anxiety were assessed at baseline, immediately following imagery exposure and at discreet beer cue presentation in the ATT. RESULTS: Compared with moderate drinkers, problem drinkers demonstrated tonic attenuation of IL-6 and IL-1ra. In problem drinkers, these changes also accompanied elevated levels of stress- and cue-induced alcohol craving and anxiety and were predictive of provoked alcohol craving, behavioral alcohol motivation and intake, and severity of problem drinking. CONCLUSIONS: Current findings indicate that selective immunosuppression in problem drinkers may play a key role in motivation for alcohol intake.

LSD modulates music-induced imagery via changes in parahippocampal connectivity.

Psychedelic drugs such as lysergic acid diethylamide (LSD) were used extensively in psychiatry in the past and their therapeutic potential is beginning to be re-examined today. Psychedelic psychotherapy typically involves a patient lying with their eyes-closed during peak drug effects, while listening to music and being supervised by trained psychotherapists. In this context, music is considered to be a key element in the therapeutic model; working in synergy with the drug to evoke therapeutically meaningful thoughts, emotions and imagery. The underlying mechanisms involved in this process have, however, never been formally investigated. Here we studied the interaction between LSD and music-listening on eyes-closed imagery by means of a placebo-controlled, functional magnetic resonance imaging (fMRI) study. Twelve healthy volunteers received intravenously administered LSD (75µg) and, on a separate occasion, placebo, before being scanned under eyes-closed resting conditions with and without music-listening. The parahippocampal cortex (PHC) has previously been linked with (1) music-evoked emotion, (2) the action of psychedelics, and (3) mental imagery. Imaging analyses therefore focused on changes in the connectivity profile of this particular structure. Results revealed increased PHC-visual cortex (VC) functional connectivity and PHC to VC information flow in the interaction between music and LSD. This latter result correlated positively with ratings of enhanced eyes-closed visual imagery, including imagery of an autobiographical nature. These findings suggest a plausible mechanism by which LSD works in combination with music listening to enhance certain subjective experiences that may be useful in a therapeutic context.

Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies.

Posttraumatic stress disorder (PTSD) may involve over-consolidated emotional memories of the traumatic event. Reactivation (RP) can return a memory to an unstable state, from which it must be restabilized (reconsolidated) if it is to persist. Pharmacological agents administered while the memory is unstable have been shown to impair reconsolidation. The N-methyl-d-aspartate (NMDA) partial agonist d-cycloserine (DCS) may promote memory destabilization. In the three studies reported here, we investigated whether the ß-adrenergic blocker propranolol or the glucocorticoid (GR) antagonist mifepristone, given at the time of traumatic memory reactivation, could reduce PTSD symptoms and physiological responding during subsequent traumatic imagery. Individuals with PTSD were randomized as follows: Study One: propranolol with memory reactivation (n=10) or without reactivation (n=8); Study Two: reactivation mifepristone (n=13), non-reactivation (NRP) mifepristone (n=15), or double placebo (PL) (n=15); Study Three: reactivation mifepristone plus d-cycloserine (n=16), or two placebos (n=15). Subjects underwent memory retrieval by describing their traumatic event. A week later they engaged in script-driven traumatic mental imagery, while heart rate (HR), skin conductance (SC), and facial electromyogram (EMG) responses were measured. There were no significant group differences in physiological responsivity or change in PTSD symptoms in any of the studies. These results do not support successful blockade of reconsolidation of traumatic memories in PTSD.

Psychophysiological responding to emotional memories in healthy young men after cortisol and propranolol administration.

RATIONALE: Propranolol is found to reduce physiological hyper-responsiveness in post traumatic stress disorder (PTSD), possibly by affecting reconsolidation after the reactivation of traumatic memories. Cortisol is found to attenuate declarative memory retrieval, but it is unknown whether it also reduces physiological responses to emotional memories. OBJECTIVES: To examine whether the effects of propranolol on physiological responding to emotional memories can also be found in healthy controls and to investigate the immediate and prolonged effects of cortisol on physiological responding to emotional memories, we tested these effects in 79 healthy young men. MATERIALS AND METHODS: After preparing a script of a negative disturbing memory, participants were instructed to imagine this event 1 week later after ingestion of either 35 mg cortisol, 80 mg propranolol, or a placebo. Physiological responding to the script-driven imagery was recorded. Another week later, after washout, the imagery was repeated again. During all three sessions as well as 8 months later, subjective emotional reactions to the memories were assessed. RESULTS: The emotionality of the memories was reduced over time, which was not affected by the treatments, however. The personal emotional script did evoke higher skin conductance responses than a neutral story, which decreased 1 week later, but no effects were found of either propranolol or cortisol on this responsiveness. CONCLUSIONS: Whereas healthy males do show psychophysiological responding to personal emotional scripts, the effects of cortisol and propranolol on physiological responses to emotional memories might be specific to clinical groups characterized by hyper-responsiveness, like PTSD. Future studies using longer-acting doses and more elaborate reactivation procedures in both healthy men and women could shed more light on the effects of cortisol and propranolol on psychophysiological responding to emotional memories.

Enhancement of suggestibility and imaginative ability with nitrous oxide.

RATIONALE: Imaginative suggestibility, a trait closely related to hypnotic suggestibility, is modifiable under some circumstances. Nitrous oxide (laughing gas) is commonly used for sedation in dentistry and is reported to be more effective when combined with appropriate suggestions. OBJECTIVE: The aim of this study was to determine whether nitrous oxide inhalation alters imaginative suggestibility and imagery vividness. METHODS: Thirty participants were tested twice in a within-subjects design, once during inhalation of 25% nitrous oxide and once during inhalation of air plus oxygen. Before the study, participants' expectancies regarding the effects of nitrous oxide were assessed. Participants were blinded to drug administration. During each session, participants were verbally administered detailed measures of imagination and suggestibility: the Sheehan-Betts Quality of Mental Imagery scale and the Stanford Hypnotic Susceptibility Scale Form C, minus the hypnotic induction. RESULTS: Imaginative suggestibility and imaginative ability (imagery vividness) were both elevated in the nitrous oxide condition. This effect was unrelated to participants' expectations regarding the effects of the drug. CONCLUSIONS: Nitrous oxide increased imaginative suggestibility and imaginative ability. Possible explanations of these findings are discussed with respect to the effects of N-methyl-d-aspartate antagonists and to other pharmacological effects upon suggestibility and imagination.

Acute nicotine improves cognitive deficits in young adults with attention-deficit/hyperactivity disorder.

OBJECTIVE: The strong association between ADHD and cigarette smoking and the known effects of nicotine on cognition has lead to interest in the role of cholinergic function in ADHD cognitive deficits. We have previously demonstrated that acute nicotine improves behavioral inhibition in adolescents with ADHD. This study examined acute nicotine in young adults with ADHD-Combined type on cognitive domains including behavioral inhibition, delay aversion, and recognition memory. METHODS: 15 non-smoking young adults (20+/-1.7 years) diagnosed with ADHD-C received acute nicotine (7 mg patch for 45 min) and placebo on separate days. Cognitive tasks included the Stop Signal Task, Choice Delay task, and the High-Low Imagery Task (a verbal recognition memory task). Three subjects experienced side effects and their data was excluded from analysis of cognitive measures. RESULTS: There was a significant (p<.05) positive effect of nicotine on the Stop Signal Reaction Time measure of the Stop Signal Task. The SSRT was improved without changes in GO reaction time or accuracy. There was a trend (p=.09) for nicotine to increase tolerance for delay and a strong trend (p=.06) for nicotine to improve recognition memory. CONCLUSIONS: Non-smoking young adults with ADHD-C showed improvements in cognitive performance following nicotine administration in several domains that are central to ADHD. The results from this study support the hypothesis that cholinergic system activity may be important in the cognitive deficits of ADHD and may be a useful therapeutic target.

Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder.

The beta-adrenergic blocker propranolol given within hours of a psychologically traumatic event reduces physiologic responses during subsequent mental imagery of the event. Here we tested the effect of propranolol given after the retrieval of memories of past traumatic events. Subjects with chronic post-traumatic stress disorder described their traumatic event during a script preparation session and then received a one-day dose of propranolol (n=9) or placebo (n=10), randomized and double-blind. A week later, they engaged in script-driven mental imagery of their traumatic event while heart rate, skin conductance, and left corrugator electromyogram were measured. Physiologic responses were significantly smaller in the subjects who had received post-reactivation propranolol a week earlier. Propranolol given after reactivation of the memory of a past traumatic event reduces physiologic responding during subsequent mental imagery of the event in a similar manner to propranolol given shortly after the occurrence of a traumatic event.

Effect of tobacco craving cues on memory encoding and retrieval in smokers.

Previous studies have shown that cue-elicited tobacco craving disrupted performance on cognitive tasks; however, no study has examined directly the effect of cue-elicited craving on memory encoding and retrieval. A distinction between encoding and retireval has been reported such that memory is more impaired when attention is divided at encoding than at retrieval. This study tested the hypothesis that active imagery of smoking situations would impair encoding processes, but have little effect on retrieval. Imagery scripts (cigarette craving and neutral content) were presented either before presentation of a word list (encoding trials) or before word recall (retrieval trials). A working memory task at encoding and free recall of words were assessed. Results indicated that active imagery disrupted working memory on encoding trials, but not on retrieval trials. There was a trend toward impaired working memory following craving scripts compared with neutral scripts. These data support the hypothesis that the cognitive underpinnings of encoding and retrieval processes are distinct.

Nonstereotyped responding in positive schizotypy after a single dose of levodopa.

Stereotyped behavior and left-sided orientation biases, associated with the dopamine (DA) system, were observed in populations of the schizophrenia spectrum disorders. We investigated whether heightened DA concentrations influence both side biases and stereotyped responding in a visuo-motor computer task, in which 90, 180, and 270 degrees rotated objects had to be brought into a target position. To account for the role of the schizophrenia spectrum, task performance was also analyzed as a function of healthy participants' high or low magical ideation (MI), a positive schizotypal feature. The first 36 participants (20 women) remained substance free. In a second sample, 20 men received levodopa and 20 men a placebo in a double-blind procedure. Results showed that high MI scorers responded more stereotyped than low MI scorers, without being specifically biased towards the left side. Rotation preferences toward one or the other side made high MI scorers less flexible for objects efficiently to be rotated into the opposite direction. This inflexibility may reflect impaired left hemisphere functioning. Unexpectedly, in the levodopa group, high MI scorers performed superior to low MI scorers. Since DA actions appear to follow an inverted U-shape function, the 'low' performing high MI scorers profited from the enhanced DA availability. Our observation in the levodopa group points to a dissociation between schizotypy and schizophrenia: while cognitive improvement in schizophrenia can occur after treatment with atypical neuroleptic agents, in our positive schizotypal participants a DA agonist resulted in improved task performance. This dissociation may point to protective neurochemical mechanisms preventing healthy schizotypes from developing full-blown psychotic symptoms.

Imagery of craving in opiate addicts undergoing detoxification.

Craving is a significant factor in opiate addiction that is associated with drug-dependence and in relapse to drug use after treatment. In order to better understand the psychological and physiological mechanisms of craving for opiates, we have developed an imagery-based procedure using personal verbal descriptions of craving in abstinent opiate addicts. Thirteen opiate addicts in detoxification were required to imagine and describe their craving experiences while autonomic measures of heart rate and arterial pressure were taken. Subjects displayed a significant increase in systolic blood pressure and heart rate while describing drug craving compared with neutral descriptions. Furthermore, an increase in systolic blood pressure during imagery of craving descriptions compared with neutral descriptions was observed. These results provide preliminary evidence that imagery is powerful in eliciting craving for opiates, as indicated by subjective ratings and autonomic measures. The implications of the results of this paper for the cue-exposure paradigm and contemporary models of addiction are being discussed.

Visuospatial perception, construction and memory in alcoholism.

OBJECTIVE: To analyze visuospatial cognition in recently detoxified alcoholics from the perspectives of three ways of conceptualizing spatial information processing: egocentric versus allocentric orientation, featural versus configural analysis, and categorical versus coordinate spatial judgements. METHOD: Twenty-eight chronic alcoholics (19 men, 9 women) were compared to 20 (10 men, 10 women) controls of comparable age and education on a battery of tests of visuospatial scanning, construction, mental imagery, and anterograde and remote spatial memory. Tests were administered 21-40 days after alcoholics entered treatment. RESULTS: Alcoholics displayed impairment in visuospatial scanning, construction, utilizing and manipulating information from visual images and on three tests of anterograde spatial memory, but remote spatial memory was not significantly affected. Their deficits were evident on some measures of allocentric orientation, featural and configural analysis, but consistent deficits on egocentric orientation or categorical or coordinate spatial judgments were not seen. CONCLUSIONS: Deficits in spatial cognition exhibited by alcoholics do not seem to arise from dysfunction in any localized brain region. Small but potentially important impairments in fundamental aspects of spatial information processing such as scanning and use of visual imagery were found. The empirical basis and clinical significance of these deficits requires further study.

Source localization of brain electric field frequency bands during conscious, spontaneous, visual imagery and abstract thought.

This paper addresses the issue of mind-brain correspondence, using a novel way to reduce brain electric field data in the frequency domain to estimates of intracerebral model source locations, and applying this method to brain electric data collected during the 2-s epochs immediately before the randomly solicited reports of spontaneous, conscious, covert experiences from 12 normal volunteers. The mentation reports were classified into visual imagery and abstract thought. The mean locations of the EEG model sources associated with abstract thoughts were generally more anterior and deeper than those of visual imagery, particularly significant for the delta/theta band; the finding was common across subjects. Thus, different brain functional states involving different geometries of activated neural populations exist during conscious, spontaneous, task-free mentations of the visual imagery type and of the abstract thought type.

Effects of intranasal vasopressin and oxytocin on physiologic responding during personal combat imagery in Vietnam veterans with posttraumatic stress disorder.

This study measured heart rate, skin conductance, and lateral frontalis electromyographic (EMG) responses in 43 male Vietnam veterans with posttraumatic stress disorder during personal combat imagery. In a double-blind research design, subjects were randomly assigned to receive intranasal arginine vasopressin (20 IU), placebo, or oxytocin (20 IU) an hour before the experiment. The group order of physiologic responding was as predicted: vasopressin > placebo > oxytocin. The most specific effect was exerted by vasopressin on EMG responses. This drug effect was not accounted for by nonspecific changes in responsiveness. Results are consistent with enhancing and inhibiting effects on memory retrieval and conditioned responding of vasopressin and oxytocin, respectively.

Marijuana effects on visual imagery in a paired-associate task.

Marijuana effects on visual imagery, examined using a paired-associate learning task, differed from expectations based on previous subjective reports that marijuana enhances visual imagery. Subjects (48 men, mean age 22.4 yr.) were assigned to four groups (12 subjects per group) differing in (a) whether or not they received specific instructions to use imagery to facilitate learning and (b) whether they received marijuana or placebo. Imagery instructions improved recall, but marijuana did not influence the amount of this improvement. After the memory tests, subjects instructed to use imagery described their images. Marijuana decreased the rated vividness of these imagery descriptions.