A variant in ANKK1 modulates acute subjective effects of cocaine: a preliminary study.

This study aimed to evaluate whether functional variants in the ankyrin repeat and kinase domain-containing 1 (ANKK1) gene and/or the dopamine receptor D2 (DRD2) gene modulate the subjective effects (reward or non-reward response to a stimulus) produced by cocaine administration. Cocaine-dependent participants (N = 47) were administered 40 mg of cocaine or placebo at time 0, and a subjective effects questionnaire (visual analog scale) was administered 15 min prior to cocaine administration, and at 5, 10, 15 and 20 min following administration. The influence of polymorphisms in the ANKK1 and DRD2 genes on subjective experience of cocaine in the laboratory was tested. Participants with a T allele of ANKK1 rs1800497 experienced greater subjective 'high' (P = 0.00006), 'any drug effect' (P = 0.0003) and 'like' (P = 0.0004) relative to the CC genotype group. Although the variant in the DRD2 gene was shown to be associated with subjective effects, linkage disequilibrium analysis revealed that this association was driven by the ANKK1 rs1800497 variant. A participant's ANKK1 genotype may identify individuals who are likely to experience greater positive subjective effects following cocaine exposure, including greater 'high' and 'like', and these individuals may have increased vulnerability to continue using cocaine or they may be at greater risk to relapse during periods of abstinence. However, these results are preliminary and replication is necessary to confirm these findings.

Assessment of safety, cardiovascular and subjective effects after intravenous cocaine and lofexidine.

The primary objective of this study was to determine the safety of lofexidine, an α2 receptor agonist, alone and concurrent with cocaine in non-treatment seeking cocaine-dependent or cocaine-abusing participants. After screening, eligible participants received double-blind, randomized infusions of saline and 20mg of cocaine on Day 1, and saline and 40mg of cocaine on Day 2. Subjects were randomized and started receiving daily administration of placebo (N=4) or lofexidine on Day 3 and continued on this schedule until Day 7. Two dosing regimens for lofexedine were investigated: 0.8 QID (N=3) and 0.2mg QID (N=11). On Days 6 and 7, subjects received double-blind infusions of saline and 20mg of cocaine on Day 6, and saline and 40mg of cocaine on Day 7. The data reveal a notable incidence of hemodynamic-related AEs over the course of the study. Two of the three participants at the 0.8mg dose level discontinued, and five of 11 participants at the 0.2mg dose level were withdrawn (or voluntarily discontinued) after hemodynamic AEs. Subjective effects and cardiovascular data were derived from all participants who were eligible to receive infusions (i.e., did not meet stopping criteria) on Days 6 and 7 (6 received lofexidine 0.2mg, QID and 4 received placebo, QID). As expected, cocaine significantly increased heart rate and blood pressure, as well as several positive subjective effects. There was a trend for lofexidine to decrease cocaine-induced cardiovascular changes and cocaine-induced ratings for "any drug effect", "good effects", and "desire cocaine", but sample size issues limit the conclusions that can be drawn. Despite the trends to reduce cocaine-induced subjective effects, cardiovascular AEs may limit future utility of lofexidine as a treatment for this population.

Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression.

Ketamine produces rapid antidepressant effects in treatment-resistant depression (TRD), but the magnitude of response varies considerably between individual patients. Brain-derived neurotrophic factor (BDNF) has been investigated as a biomarker of treatment response in depression and has been implicated in the mechanism of action of ketamine. We evaluated plasma BDNF and associations with symptoms in 22 patients with TRD enrolled in a randomized controlled trial of ketamine compared to an anaesthetic control (midazolam). Ketamine significantly increased plasma BDNF levels in responders compared to non-responders 240 min post-infusion, and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were negatively correlated with BDNF (r=-0.701, p = 0.008). Plasma BDNF levels at 240 min post-infusion were highly negatively associated with MADRS scores at 240 min (r = -0.897, p=.002), 24 h (r = -0.791, p = 0.038), 48 h (r = -0.944, p = 0.001) and 72 h (r = -0.977, p = 0.010). No associations with BDNF were found for patients receiving midazolam. These data support plasma BDNF as a peripheral biomarker relevant to ketamine antidepressant response.

d-Cycloserine administration does not affect neurocognition in concurrent cocaine- and nicotine-dependent volunteers.

Neurocognitive impairment is a well-documented consequence of long-term, repeated cocaine exposure and has been identified as an important target of treatment. Thus, this study sought to determine whether the N-methyl-d-aspartate (NMDA) partial agonist, d-cycloserine could improve neurocognitive performance in a sample of 27 long-term, high dose cocaine dependent individuals who were not seeking treatment at the time of enrollment in the study. This double-blind, placebo-controlled study evaluated whether a single dose of 0 or 50mg of d-cycloserine would enhance performance on measures of attention/information processing speed, episodic memory, and executive/frontal lobe functioning relative to test performance at baseline. The results revealed that d-cycloserine did not modulate neurocognition in this cohort, though there are a number of factors that may have mitigated the effects of d-cycloserine in this particular study. The negative findings notwithstanding, the current study serves as a springboard for future investigations that will examine whether other medications that can modulate neurocognition in cocaine-dependent study participants.

Rivastigmine reduces "Likely to use methamphetamine" in methamphetamine-dependent volunteers.

We previously reported that treatment with the cholinesterase inhibitor rivastigmine (3mg, PO for 5days) significantly attenuated "Desire for METH". Given that higher dosages of rivastigmine produce greater increases in synaptic ACh, we predicted that 6mg should have more pronounced effects on craving and other subjective measures. In the current study, we sought to characterize the effects of short-term exposure to rivastigmine (0, 3 or 6mg) on the subjective and reinforcing effects produced by administration of methamphetamine (METH) in non-treatment-seeking, METH-dependent volunteers. This was a double-blind, placebo-controlled, crossover study. Participants received METH on day 1, and were then randomized to placebo or rivastigmine on day 2 in the morning and treatment continued through day 8. METH dosing was repeated on day 6. The data indicate that METH (15 and 30mg), but not saline, increased several positive subjective effects, including "Any Drug Effect", "High", "Stimulated", "Desire METH", and "Likely to Use METH" (all p's<0.0001). In addition, during self-administration sessions, participants were significantly more likely to choose METH over saline (p<0.0001). Evaluating outcomes as peak effects, there was a trend for rivastigmine to reduce "Desire METH" (p=0.27), and rivastigmine significantly attenuated "Likely to Use METH" (p=0.01). These effects were most prominent for rivastigmine 6mg when participants were exposed to the low dose (15mg, IV), but not high dose (30mg, IV), of METH. The self-administration data reveal that rivastigmine did not alter total choices for METH (5mg, IV/choice). Overall, the results indicate some efficacy for rivastigmine in attenuating key subjective effects produced by METH, though additional research using higher doses and longer treatment periods is likely needed. These data extend previous findings and indicate that cholinesterase inhibitors, and other drugs that target acetylcholine systems, warrant continued consideration as treatments for METH dependence.

A perhaps unexpected role of norepinephrine in actions of MDMA.

In this issue, Hysek and colleagues present new data describing the impact of treatment with reboxetine on the effects produced by 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") in human volunteers. They demonstrate that several effects of MDMA are mediated by reboxetine's actions on norepinephrine (NE) transporters, an unexpected finding. Building on earlier work, their new data provide new insights into the pharmacodynamics of MDMA and other monoamine-releasing agents.

Unrestricted access to methamphetamine or cocaine in the past is associated with increased current use.

Laboratory animals allowed to self-administer stimulants for extended periods of time escalate drug intake compared to animals that self-administer under temporally limited conditions. To our knowledge, this phenomenon has not been systematically investigated in humans. We interviewed 106 (77 male, 29 female) methamphetamine (Meth) and 96 (81 male, 15 female) cocaine (Coc) users to determine if they had experienced discrete period(s) of unrestricted access to unlimited quantities of Meth or Coc in the past. Fifty-eight Meth users and 53 Coc users reported having a discrete period of unrestricted access in the past, but not in the present. Meth-using participants with a prior history of unrestricted access reported significantly more current Meth use, compared to Meth users with no prior history of unrestricted access. Specifically, these participants reported more days used in the past 30 d, more days of use per week, greater use per day and greater total use per week (p<0.05 for each). Coc-using participants with a prior history of unrestricted access also reported significantly more current Coc use, compared to Coc users with no prior history of unrestricted access. This was true across all measures of current use for these participants, including more days used in the past 30 d, more days of use per week, greater use per day, and higher total use per week (p<0.02 for each). Taken together, these results suggest that a history of unrestricted access to stimulants is associated with long-lasting increases in stimulant use.

The acetylcholinesterase inhibitor rivastigmine does not alter total choices for methamphetamine, but may reduce positive subjective effects, in a laboratory model of intravenous self-administration in human volunteers.

A human laboratory model of intravenous methamphetamine self-administration may facilitate study of putative treatments for methamphetamine addiction. We conducted a double-blind, placebo-controlled, between groups investigation of the acetylcholinesterase (AChE) inhibitor rivastigmine in non-treatment-seeking volunteers who met criteria for methamphetamine abuse or dependence. Safety and subjective effects data derived from days 1-10 of this protocol are described in a separate publication. In this report, we describe self-administration outcomes in participants randomized to treatment with rivastigmine (0 mg, N=7; 1.5 mg, N=6; 3 mg, N=9); data that were collected on days 11-15 of the inpatient protocol. On day 11, participants sampled two infusions of methamphetamine (0 and 30 mg, i.v.). On days 12-15, participants made ten choices each day to receive an infusion of either methamphetamine (3 mg, IV) or saline or a monetary alternative ($0.05-$16). The study design allowed for evaluation of differences in behavior on days in which infusions were performed by the physician (experimenter-administered) versus by the participant using a PCA pump (self-administered), and when monetary alternatives were presented in either ascending or descending sequence. The data show that rivastigmine (1.5 and 3 mg), as compared to placebo, did not significantly alter total choices for methamphetamine (p=0.150). Importantly, the number of infusion choices was greater when methamphetamine was available then when saline was available (p<0.0001), and the number of money choices was greater when saline was available then when methamphetamine was available (p<0.0001). The total number of choices for methamphetamine was not altered as a function of a participant's preferred route of methamphetamine use (p=0.57), and did not differ significantly whether they were experimenter-administered or self-administered (p=0.30). In addition, total choices for methamphetamine were similar made when money was available in an ascending versus descending sequence (p=0.49). The participants' years of methamphetamine use, recent use of methamphetamine (in the past 30 days), or baseline craving (indexed here as "Desire") on the day of the self-administration task were not predictive of number of choices for methamphetamine. In a subset of participants (N=8) for which data was available, individual dose of methamphetamine (3 x 3 mg, i.v.) produced significant increases in positive subjective effects, and a preliminary analysis revealed that 3 mg rivastigmine was associated with reductions in these responses, as compared to placebo. In summary, the current report indicates that there were no effects of rivastigmine on total choices for methamphetamine, that there were low levels of methamphetamine self-administration but these were 8 times greater than saline, and that choice behavior was insensitive to alternative reinforcers. In addition, we showed that rivastigmine may reduce the positive subjective effects produced by methamphetamine during self-administration.

Neurocognitive functioning is associated with employment status: a quantitative review.

Neurocognitive assessment is frequently used as a basis for making determinations regarding a person's ability to work; yet, to our knowledge, a review of the association between neurocognition and employment status has not been conducted. For this review, we utilized meta-analysis to quantify objectively the association between eight neurocognitive domains and employment status. The meta-analysis revealed that performance in each domain was significantly associated with employment status, and that the associations were greatest for the following domains: intellectual functioning, executive functioning, and memory. These findings support the ecological validity of neurocognitive assessment.

Risperidone pre-treatment reduces the euphoric effects of experimentally administered cocaine.

Pre-clinical research implicates dopaminergic neurotransmission as critical in producing the effects of stimulants. Previous stimulant challenge studies using volunteers treated with dopaminergic antagonists have generally failed to demonstrate reduction of subjective effects. We performed this study to determine whether repeated dosing with risperidone reduced the subjective effects of experimentally administered cocaine. Nine non-treatment seeking hospitalized cocaine-dependent volunteers received 40 mg cocaine IV before and following 5 days of treatment with risperidone, 2 mg per day. Risperidone pre-treatment reduced the self-rated 'high' produced by cocaine. Repeated, rather than single, dosing with a D2 antagonist may be necessary to reduce the subjective effects produced by cocaine. The degree of D2 receptor blockade produced by risperidone appears to be greater than the reduction in euphoric effects produced by cocaine, suggesting that mechanisms other than those involving D2 receptors may be important in drug-induced euphoria.

Psychiatric comorbidity of methamphetamine dependence in a forensic sample.

The objective of this study was to examine the association between psychiatric symptoms and methamphetamine dependence. A four-hour survey was administered to 1,580 arrestees sampled from the 14 most populous counties in California. The survey included items assessing demographic profile, history of substance dependence, and psychiatric symptomatology. In the 12 months prior to the assessment, methamphetamine-dependent individuals were more likely to report depressive symptoms and suicidal ideation than individuals denying methamphetamine dependence, even after controlling for demographic profile and dependence on other drugs. Methamphetamine-dependent individuals also were more likely to report a need for psychiatric assistance at the time of the interview. These findings suggest that methamphetamine-dependent individuals are at greater risk to experience particular psychiatric symptoms. Further study to determine the etiology of these symptoms is warranted.

Quantitative EEG effects of nicotine replacement by cigarette smoking.

The effects of cigarette smoking on the central nervous system can be assessed directly using the electroencephalogram (EEG). Nicotine withdrawal and subsequent replacement have been studied, but have produced conflicting effects on brain electrical activity. We studied the effect of smoking 2 cigarettes at subjects' own pace in 20 subjects. EEG was recorded using the EEGSYS program in the eyes-closed awake state using a bipolar montage. Delta power decreased in central-posterior head regions. Theta power and power in the lower half of the alpha band decreased. Beta power and power in the upper half of the alpha band increased significantly over frontotemporal head regions. Examination of spectra underlying the usual frequency bands revealed that many effects of smoking on EEG power probably resulted from a shift of the overall power spectrum toward higher frequencies, rather than resulting from alterations in activity in specific frequency bands.

The face of craving? Facial muscle EMG and reported craving in abstinent and non-abstinent cocaine users.

We studied 12 subjects, half of whom were current cocaine users and half of whom were abstinent former users, using facial EMG before and after subjects completed questionnaires describing cocaine use, craving and mood. Changes in zygomatic EMG tone before and after cocaine questionnaire completion correlated with reported craving in current users. This preliminary study suggests that facial EMG correlates with cocaine craving in current users.

EEG power correlates with subcortical metabolic activity in AIDS.

The authors studied the relationship between brain metabolic activity and quantitative electroencephalographic power in AIDS. Basal ganglia and thalamic metabolic activity, measured with positron emission tomography, correlated positively with EEG power in the 6-10-Hz band across most head regions. Metabolic activity of anatomically defined cortical regions did not correlate with EEG power recorded over each region. These results support previously reported associations between abnormalities in subcortical metabolic activity and EEG activity. The lack of correlation between cortical metabolic activity and EEG activity suggests that previously observed abnormalities in EEG activity are primarily subcortical in origin.

Effect of white matter disease on functional connections in the aging brain.

Periventricular white matter hyperintensities (PVHs) seen on T2 weighted MRI studies are common in elderly people and often represent demyelination of fibres. Damage to these fibres could lead to functional disconnection between brain regions. Electroencephalographic coherence, a measure of shared electrical activity between regions, was examined to determine if there was evidence for such disconnection. Twenty two subjects with clinically diagnosed dementia of the Alzheimer's type, 16 with multi-infarct dementia, and 18 normal controls were studied. It was hypothesised that coherence between areas presumably linked by fibres that traverse the periventricular region would be decreased in subjects with PVHs, and that PVHs would have a stronger association with decreased coherence than clinical diagnosis. It was also hypothesised that coherence between areas presumably connected by long corticocortical tracts that are neuroanatomically separated from the ventricles would be low in patients with Alzheimer's disease because of pyramidal cell death in this group, but would not be affected by the presence of PVHs. Patients with PVHs in fact had lower coherence than those without PVHs in the pre-Rolandic and post-Rolandic areas, where connecting fibres traverse the periventricular region. There was no effect of PVHs, however, on coherence between areas separated by the Rolandic fissure that were connected by long corticocortical tracts; this coherence was lowest among the patients with Alzheimer's disease. These patterns of association suggest that coherence may detect different types of neurophysiological "disconnection," and may be sensitive to selective damage to different fibre pathways.

Electroencephalographic coherence in acquired immune deficiency syndrome.

We studied a quantitative electroencephalographic (EEG) measure, coherence, in 28 patients with acquired immune deficiency syndrome (AIDS) and 56 uninfected volunteers. Compared with uninfected subjects, AIDS patients had increased coherence in the 6- to 10-Hz band. The largest increases in coherence were between frontal and occipital regions and between temporal and frontal regions. Coherence within contiguous regions was less affected. Eight of the 28 AIDS patients (29%) had clinically abnormal EEG findings, compared with four of the 56 uninfected control subjects (7%). Among the AIDS patients, 12 had normal neuropsychological performance, nine had mild impairment, and six had moderate impairment. Coherence was increased in each subgroup of AIDS patients, including those with normal neuropsychologic performance and/or normal clinical EEG results. AIDS patients were then classified by quantitative EEG power in frontal head regions as "abnormal" (the upper third of patients) or "normal" (the remainder). Increased coherence was found among both groups. Because the development of abnormal neuropsychological performance or a clinically abnormal EEG examination indicates relatively advanced central nervous system disease, alterations in specific coherence measures may detect subclinical effects of the human immunodeficiency virus on brain function before other changes are evident.

Assessment of cerebral perfusion using quantitative EEG cordance.

Brain electrical activity is related to cerebral perfusion. The nature of this relationship is unclear, however, and surface-recorded activity has not been a reliable indicator of brain perfusion. We studied 27 subjects, all of whom were examined with single photon emission tomography (SPECT) and quantitative electroencephalography (QEEG), to assess associations between QEEG cordance and relative brain perfusion. Cordance has two indicator states: concordance, which may indicate high perfusion; and discordance, which may indicate low perfusion. We used multiple linear regression to assess the association between cordance and SPECT values, and found that cordance values were strongly associated with tissue perfusion. Concordance in the alpha band was associated both with mean tissue perfusion and the volume of normally perfused tissue, and it had a stronger association with perfusion than any other QEEG variable. Discordance in the beta 1 band was associated with mean perfusion, and it had a stronger association than did relative but not absolute power. These data suggest that cordance may be useful for the noninvasive assessment of brain perfusion.

Reduced EEG coherence in dementia: state or trait marker?

Recent work from our laboratory demonstrated that quantitative electroencephalographic (EEG) coherence between brain areas linked by long cortico-cortical fibers (termed "fascicle" coherence) was differentially reduced in subjects with Alzheimer's disease, whereas coherence between brain areas linked by short cortico-cortical and cortico-subcortical fibers in postcentral areas (termed "visual" coherence) was differentially reduced in subjects with multi-infarct dementia. In this study, we investigated whether these differences in coherence represent "trait" or "state" markers for dementia. Visual coherence demonstrated high stability in both demented groups as assessed by both one-year test-retest reliabilities and analysis of group mean change. Fascicle coherence demonstrated good stability in multi-infarct dementia and control subjects, but some variability was observed in Alzheimer's subjects, suggesting both state and trait factors may be involved. These findings complement neuropathologic studies, and suggest that decreases in coherence may serve as a diagnostic trait markers for these two types of dementia. The role of state factors in Alzheimer's disease requires further investigation.

Cordance: a new method for assessment of cerebral perfusion and metabolism using quantitative electroencephalography.

Increased slow-wave and decreased fast-wave activity on the electroencephalogram is common in brain dysfunction and may be caused by partial cortical deafferentation. No measure that is specific or sensitive for this deafferentation, however, has yet been reported. We studied a series of subjects with white-matter lesions undercutting the cortex and developed a method for analyzing electrical activity called "cordance" that has face validity as a measure of cortical deafferentation. Cordance is measured along a continuum of values: positive values denote "concordance," an indicator associated with normally functioning brain tissue; negative values denote "discordance," an indicator associated with undercutting lesions, low perfusion, and low metabolism. We present a series of subjects studied with magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography that demonstrate strong associations between cordance and other measures of brain structure and function.

Quantitative EEG in patients with AIDS and asymptomatic HIV infection.

Although neuropsychiatric abnormalities are common in subjects with the acquired immunodeficiency syndrome (AIDS), they are less frequent in asymptomatic human immunodeficiency virus (HIV) seropositive subjects. In contrast, others have reported high rates of electroencephalographic (EEG) abnormality among asymptomatic subjects. Here we report clinical and quantitative EEG findings across all stages of the disease in order to define when during the course of illness abnormalities are detectable. We studied 28 men with AIDS, 32 men with asymptomatic HIV infection, and 56 uninfected controls using clinical and quantitative EEG, measures of immunosuppression, and tests of neuropsychological performance. All were gay or bisexual without other significant risk factors for encephalopathy. We found very low rates of clinical EEG abnormality (less than 7%) among the asymptomatic HIV-infected group, a rate comparable to those of the uninfected group (7.1%). There were no differences between asymptomatic HIV-seropositive subjects and uninfected controls on quantitative EEG measures. Among AIDS patients 28.6% had abnormal clinical electroencephalograms. On quantitative measures, the greatest differences were found in the 6-10 Hz band, where AIDS patients had consistently increased absolute power, relative power, and coherence compared to the uninfected and asymptomatic seropositive groups. A subgroup (n = 9) of asymptomatic HIV-seropositive subjects had worsening performance on Trailmaking test, part B, at or after the time of recording. This subgroup had quantitative electroencephalographic measures similar to those of the AIDS patients and different from the remainder of the asymptomatic HIV-seropositive group.(ABSTRACT TRUNCATED AT 250 WORDS)