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the three participants at the 0.8mg dose level discontinued, and five of 11 participants at the 0.2mg dose level were withdrawn (or voluntarily discontinued) after hemodynamic AEs.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.

Ketamine is associated with lower urinary tract signs and symptoms.

BACKGROUND: Case reports and series indicate that ketamine, an anesthetic agent, causes lower urinary tract symptoms (LUTS). This study explored whether ketamine users were more likely to report LUTS compared to other substance users. METHODS: Participants were recruited through an online survey on erowid.org, a drug information website. A notice posted on the website invited substance users to participate in a web-based survey on "drug use and health". The notice did not mention ketamine, or other aspects of the research questions, to avoid participation bias. The anonymous survey collected demographics, drug use history, and history of LUTS (urinary frequency, urgency, incontinence, hematuria, and dysuria). RESULTS: Of 18,802 participants, 18.7% and 5.8% reported ever (lifetime) and recent (past-6-month) use of ketamine, respectively. Prevalence of LUTS among ever, recent, and never users of ketamine were 28%, 30%, and 24% respectively. Multivariate analysis showed significant associations between recent ketamine use and urinary symptoms. For each additional day of ketamine use in the last 180 days, the odds of developing urinary frequency, urgency, dysuria, and hematuria increased by 1.6%, 1.4%, 1.7%, and 1.9% respectively. One excess case of urinary frequency was reported per 17 recent users of ketamine. CONCLUSION: Compared to non-users, recent ketamine users had increased odds of LUTS. This is the first large-scale community-based study assessing the association of non-medical ketamine use with LUTS. Associations between ketamine and urological symptoms should be confirmed through longitudinal studies.

A randomized, placebo-controlled trial of sustained-release dextroamphetamine for treatment of methamphetamine addiction.

Sixty treatment-seeking individuals with methamphetamine (MA) dependence entered a randomized, placebo-controlled, double-blind clinical trial of oral dextroamphetamine (d-AMP) as a replacement therapy for MA dependence. The subjects took 60 mg sustained-release d-AMP for 8 weeks, during which time they received eight 50-min sessions of individual psychotherapy. Adverse events and urine toxicology for MA were assessed two times a week. There were no serious adverse events. Urine samples containing <1,000 ng/ml of MA were classified as negative for MA. The MA-negative scores in the d-AMP group (3.1 ± SD 4.6) were no higher than those in the placebo group (3.3 ± SD 5.3; P > 0.05). However, withdrawal and craving scores were significantly lower in the d-AMP group (P < 0.05 for both). Although subjects taking d-AMP did not reduce their use of MA, the significant reductions observed in withdrawal and craving scores in this group support the need for further exploration of d-AMP as a pharmacologic intervention for MA dependence, possibly at higher doses.

Efficacy, safety, and ethics of cosmetic neurology far from settled.

In this issue, Larriviere and colleagues discuss the emerging use of drugs to enhance cognitive function. Several cautions they raise warrant amplification. People have tried to pharmacologically improve cognitive function for millennia, but Larriviere and colleagues postulate that new, more effective drugs will lead to the emergence of  "cosmetic neurology." The ethics of using drugs to improve performance, as opposed to treating disease or restoring normal function, are far from settled.

The effects of inhaled L-methamphetamine on athletic performance while riding a stationary bike: a randomised placebo-controlled trial.

OBJECTIVE: L-methamphetamine (the non-abused isomer of methamphetamine) is banned in athletic competition because it may improve athletic performance, but there are no studies assessing its effects on performance. In the United States L-methamphetamine is formulated in the non-prescription Vick's Vapor Inhaler (VVI) nasal decongestant. VVIs sold elsewhere (we used ones from the UK) contain similar inactive ingredients (menthol, camphor and Siberian pine oil) but no L-methamphetamine. This study tested the effects of inhaled L-methamphetamine delivered from a widely available non-prescription product on athletic performance. DESIGN: In a 2-session double-blind placebo-controlled study 12 participants (ages 14-17) were dosed with 4 (session 1) and 12 (session 2) inhalations from VVIs with (USA) or without (UK) L-methamphetamine and then performed two 20 minute rides on a stationary bike with rides separated by a 30 minute rest. OUTCOME MEASURE: The main outcome measure was miles travelled during each 20 minute ride. Secondary outcome measures included postride urine toxicology; heart rate and blood pressure before, 1, 5 and 10 minutes postride; energy, performance, endurance, and ability to breathe; and VVI preference. Data were analysed using Excel statistical macros. RESULTS: After approximately 16 microg L-methamphetamine distance travelled was 5.26 (SD 0.53) miles vs 5.30 (0.55) with placebo; p = 0.81. After approximately 48 microg L-methamphetamine distance travelled was 5.30 (0.51) vs 5.35 (0.43) with placebo; p = 0.85. The approximately 16 microg dose increased systolic blood pressure from 72.6 (4.3) to 79.6 (6.6) mm Hg (p = 0.03) at 5 minutes postride but there were no other differences in outcomes. CONCLUSIONS: Modest doses of inhaled L-methamphetamine probably do not improve athletic performance but do minimally raise diastolic blood pressure.

Disruption of transforming growth factor-beta signaling through beta-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation.

Transforming growth factor-beta (TGF-beta) signaling members, TGF-beta receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf(+/-) mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (P<0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-beta signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.

Enhanced spatial ability in aged dogs following dietary and behavioural enrichment.

We examined the benefits of a broad spectrum antioxidant diet and enrichment comprised of physical exercise, environmental stimulants and cognitive testing, on spatial memory performance in beagle dogs. Both aged (N=48) and young (N=16) beagle dogs (Canus familiaris) were tested yearly on a three-component delayed non-match to position spatial task for three consecutive years. The results showed that young enriched animals acquired the task in fewer sessions, made fewer errors, responded slower and made fewer positional responses, compared to aged enriched animals. An analysis restricted to aged animals revealed that antioxidant administration and enrichment resulted in fewer errors, slower responses and decreased positional responses, particularly in Year 3. Finally, cohort differences emerged, which exemplify the significance of early environmental intervention. Aged dogs that were housed with other animals and exposed to an outdoor environment in early development displayed greater benefits from both interventions. These findings indicate that long-term dietary intervention and enrichment can buffer age-associated cognitive decline.

Catecholamine response to methamphetamine is related to glucocorticoid levels but not to pleasurable subjective response.

INTRODUCTION: Corticosteroids may modulate addiction. We previously described subjective, physiological, and endocrine effects of 0.5 mg/kg of intravenous methamphetamine after augmenting cortisol level with hydrocortisone or blocking cortisol response with the corticosteroid synthesis inhibitor metyrapone in a double-blind, balanced crossover study. Although the pharmacologic manipulations produced the expected hormonal changes, pleasurable subjective effects of methamphetamine were unchanged. Metyrapone was followed by frequent premature ventricular complexes (PVCs) in two subjects during methamphetamine administration. In order to better understand these results, we examined changes in two plasma catecholamine metabolites, homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), and their relationship to the previously reported hormonal changes and physiological and subjective responses. METHODS: Plasma from 10 methamphetamine subjects from the earlier study was assayed for HVA and MHPG by high performance liquid chromatography. RESULTS: HVA levels were greater after hydrocortisone or metyrapone pretreatment compared to placebo, and MHPG levels were greater after metyrapone pretreatment. Hydrocortisone pretreatment diminished HVA and MHPG increases after methamphetamine (perhaps explaining the lack of expected increase in pleasurable effects), but metyrapone did not. HVA and MHPG concentrations were not correlated with pleasurable drug effects but were inversely related to reports of "Bad Drug Effect." Increases in MHPG and DHEA concentrations were positively correlated. Metyrapone pre-treated subjects with PVCs had lower HVA and MHPG concentrations. CONCLUSION: Raising cortisol concentration and blocking cortisol synthesis did not produce opposite effects, perhaps because of metyrapone's effect on the hypothalamic-pituitary-adrenal axis, its stress-like effects, and its effects on neurosteroids.

The effects of antioxidants in the senescent auditory cortex.

We investigated whether a 2-month dietary supplementation of antioxidants, in the form of blueberry phytochemicals, could reverse or retard the age-related decline in temporal processing speed observed in the aged rat. To this end, extracellular single unit responses to frequency modulated (FM) sweeps were recorded in the primary auditory cortex (AI) of aged rats that had been placed on either a blueberry-supplemented or control diet 2 months prior to the physiological recordings. Results showed that most cells recorded from the blueberry-fed rats responded most vigorously to fast FM sweeps, similar to that observed in young rats. In contrast, the majority of cells recorded from the control rats showed a preference for slow FM sweep rates. These results suggest that age-related changes in temporal processing speed in A1 may be reversed by dietary supplementation of blueberry phytochemicals.

The effects of aging in the medial geniculate nucleus: a comparison with the inferior colliculus and auditory cortex.

A common problem among the elderly is a difficulty in discriminating speech. One factor that may contribute to this is deterioration in the ability to process the dynamic components of speech such as formant transitions. The frequency-modulated (FM) sweep is a useful stimulus for investigating the neural basis of temporal processing speed since it has features in common with formant transitions. Previously, we showed that when cells in the auditory cortex of aged animals were presented with FM sweeps, they exhibited a decrease in temporal processing speed when compared to cells recorded from young animals. However, this was not the case for cells in the inferior colliculus (IC) where neural responses did not appear to be affected by aging. One question that remains is how the auditory thalamus is affected by aging: Is it similar to that of the auditory cortex or of the IC. To this end, single units were recorded from the ventral division of the medial geniculate nucleus (MGNv) of young and aged anaesthetized rats in response to FM sweeps. Results showed that there were no age-related differences in speed or direction selectivity of FM sweep responses in the MGNv. When compared with units recorded from the IC and AI, the responses of MGNv neurons were similar to those of the IC. This suggests that temporal processing speed is affected by aging in the cortex, but not in the auditory thalamus or midbrain.

Factors associated with the catastrophic decline of a cloudforest frog fauna in Guatemala.

Comparison of recent and historical surveys of frog populations in cloudforest habitat in Sierra de las Minas, Guatemala, indicated population declines and local extirpation of several species. Pathological exams of diseased tadpoles indicated infection by amphibian chytridiomycosis. The local habitat has been severely altered by recent establishment of large-scale leatherleaf fern production. Analysis of water chemistry at our study site suggested increased nitrogenation associated with the leatherleaf industry.

Frequency modulated sweep responses in the medial geniculate nucleus.

A basic feature of communication signals is a dynamic change in frequency. One stimulus that lends itself well to investigating the frequency changes contained in these signals is the frequency modulated (FM) sweep. While many studies have investigated FM sweep responses in the auditory midbrain and cortex, relatively few have examined them in the thalamus. To this end, we investigated the responses of single units in the ventral division of the medial geniculate nucleus (MGNv) of the rat to FM sweeps. Both upward- (changing from low to high frequency) and downward-directed (changing from high to low frequency) FM sweeps were presented at four rates of frequency modulation (i.e., speed). Results showed that the majority (76%) of the cells preferred fast or medium FM sweeps. For direction selectivity, just under half of the units (47%) exhibited a preference for the direction of FM sweep. The results suggest that there is a greater degree of direction but not speed selectivity at progressively higher levels in the auditory pathway.

Temporal processing speed in the inferior colliculus of young and aged rats.

A common problem among the elderly is a difficulty in discriminating speech. One factor that may contribute to this is a deterioration in the ability to process dynamic aspects of speech such as formant transitions. Recently, Mendelson and Ricketts [Mendelson, J.R., Ricketts, C., Hear. Res. 158 (2001) 84-94] showed that cells recorded from the auditory cortex of aged animals exhibited a decrease in temporal processing speed compared to young animals. In the present study, we examined whether this age-related effect was exclusive to the auditory cortex or whether it was apparent subcortically. To this end, single units were recorded from the inferior colliculus (IC) of young and aged rats in response to frequency modulated (FM) sweeps. Results showed that there was no age-related difference in speed or direction selectivity of FM sweep responses in the IC. The present results suggest that the effect of aging on temporal processing speed occurs in the cortex, but not subcortically.

Age-related changes in the visual cortex.

The ability to accurately perceive the speed of moving objects is one of many visual functions that decline with age. One factor that may contribute to this is a deterioration in temporal processing speed. At present, there is a dearth of information concerning how this may occur in the central nervous system, particularly in the visual cortex. Thus, in the present study, we investigated the neural basis of speed and temporal processing in areas 17 and 18 of visual cortex in young and aged rats using either a moving bar of light or a series of flashing lights. Our results showed that the mean preferred speed of a moving bar of light was significantly reduced in aged as compared to young animals. We also found that cells recorded from young animals were able to entrain to a higher frequency of flashing light stimuli than those recorded from aged animals. In addition, we found no age-related differences between cortical fields. These results suggest an age-related difference in temporal processing speed at the level of visual cortex.

Influence of baseline hematocrit and hemodilution on BOLD fMRI activation.

Current understanding of blood oxygenation level dependent (BOLD) fMRI physiology predicts a close relationship between BOLD signal and blood hematocrit level. However, neither this relationship nor its effect on BOLD percent activation (BPA) has been empirically examined in man. To that end, BPA in primary visual cortex in response to photic stimulation was determined in a group of 24 normal subjects. A positive linear relationship between BPA and hematocrit was seen, particularly in men. To evaluate the effect of change in hematocrit on BPA, 9 men were studied before and following isotonic saline hemodilution, resulting in an average 6% reduction in hematocrit and an 8-31% reduction in BPA. No significant change in the number of activated pixels was seen. A model of predicted BPA as a function of hematocrit and vessel size was developed, and results from this model closely mirrored the empiric data. These results suggest that hematocrit significantly influences the magnitude of BPA and that such baseline factors should be accounted for when comparing BOLD data across groups of subjects, particularly in the many instances in which hematocrit may vary systematically. Such instances include several disease states as well as studies involving sex differences, drug administration, stress and other factors. Finally, the robust agreement between predicted and empiric data serves to validate a semiquantitative approach to the analysis of BOLD fMRI data.

Age-related temporal processing speed deterioration in auditory cortex.

A common problem among the elderly is a difficulty in discriminating speech sounds. One factor that may contribute to this is a deterioration in the ability to process dynamic aspects of speech such as formant transitions. For the aging auditory system, this deterioration in temporal processing speed may be manifest as a deficit in encoding time-varying sounds that contain rapidly changing frequencies such as formant transitions. The primary goal of this study was to explore the neural basis of the effects of aging on temporal processing speed. To this end, single units were recorded from the auditory cortex of young and aged rats in response to frequency-modulated (FM) sweeps that changed from trial to trial in both direction and speed. Results showed that the majority of cells recorded from young rats responded most vigorously to fast and medium speeds. By contrast, the majority of units recorded from aged animals responded best to slow speeds. For preferred direction of FM sweep, similar results were observed for both age groups, namely, approximately half of the units exhibited a direction-selective response. The results of the present study demonstrate an age-related decrease in the rate of change of frequency that can be processed by the auditory cortex.

Critical flicker frequency responses in visual cortex.

Critical flicker frequency (CFF) threshold is defined as the frequency at which a flickering light is indistinguishable from a steady, non-flickering light. CFF is useful for assessing the temporal characteristics of the visual system. While CFF responses are believed to reflect activity in the central visual system, little is known about how these temporal frequencies are processed in the visual cortex. The current paper estimated the CFF threshold for cells in the rat visual cortex by recording single unit responses to flickering stimuli. Results showed that: (1) there was a broad range of temporal tuning, (2) CFF threshold was lower in simple cells than in complex and hypercomplex cells, and (3) there was no significant difference in CFF threshold between areas 17 and 18.