David M. Penetar

Effects of cholinergic drugs on delayed match-to-sample performance of rhesus monkeys ☆

Three adult rhesus monkeys were trained to stable performance baselines on a delayed match-to-sample (DMS) procedure. Subject-initiated trials resulted in brief presentations of a sample color stimulus (red, green, or blue) with matching performance tested after retention intervals of 0, 4, 8, and 16 seconds. The effects of graded doses of atropine SO4, benactyzine HCl and physostigmine salicylate on performance were studied. Only atropine produced a clear interaction between drug and retention interval with the greatest impairments being observed at the longest delays. Benactyzine only affected overall error rates, while physostigmine did not disrupt matching accuracy. The two highest doses of each compound produced reliable elevations in session times and drug-specific changes in the pattern of performance. The results with atropine confirm and extend previously reported work with scopolamine indicating a critical role for cholinergic mechanisms in short-term memory.

Age-related differences in soman toxicity and in blood and brain regional cholinesterase activity

The toxicity (lethality, acute toxic signs and body weight loss) of the irreversible ChE inhibitor soman was assessed in four groups of male rats differing in age: 30, 60, 120 and 240 days old. Plasma and brain regional ChE activity profiles were also studied in these groups. All measures of the toxicity of soman were found to increase with age. The calculated 24-hr LD50s were 110, 87, 66 and 59 micrograms/kg, IM, for 30-, 60-, 120- and 240-day-old rats, respectively. A significant and positive age-related effect on toxic sign rating scores was observed at one hr following soman injection. Furthermore, during a 14-day postsoman observation period, it was observed that young rats had less initial weight loss and more rapid, sustained recovery of growth than older animals. Survivors from the two oldest age groups did not recover to baseline body weights by the end of the 14-day observation period. Basal level of plasma ChE activity did not change significantly with age, while brain regional ChE showed two distinct age-dependent patterns: a linear decrease in the brainstem, midbrain and cerebellum and an inverted U-shaped change in the cortex, hippocampus and striatum. Our data suggest a relationship between soman toxicity and the aging process, but fails to demonstrate a definite relationship between soman toxicity and basal ChE activity in blood and brain of rats.

The isoflavone puerarin reduces alcohol intake in heavy drinkers: A pilot study

BACKGROUND Isoflavone compounds naturally occurring in the root of the kudzu plant have been used historically to treat alcohol-related problems. A pilot study was conducted to assess the effects of one primary isoflavone--puerarin--for its ability to modify alcohol intake in humans. METHODS Ten (10) healthy adult volunteers were administered puerarin (1200 mg daily) in a double-blind, placebo-controlled, crossover design experiment for one week prior to an afternoon drinking session lasting 1.5h. Participants had access to up to six bottles of their preferred brand of beer in addition to juice and water. A time course of drinking, sip volumes, and total amount consumed were recorded. RESULTS Participants consumed on average 3.5 (±0.55) beers when treated with placebo and 2.4 (±0.41) beers when treated with puerarin. In contrast to drinking following placebo treatment when 3 participants drank 5 beers and 1 participant drank all 6 beers, none drank 5 or 6 beers when treated with puerarin. Drinking topography also changed. When treated with puerarin, participants decreased sip size, took more sips to finish a beer, and took longer to consume each beer. Additionally, after finishing a beer, latency to opening the next beer was increased. CONCLUSIONS This study is the first demonstration that a single isoflavone found in the kudzu root can alter alcohol drinking in humans. These results suggest that alcohol consumption patterns are influenced by puerarin administration and this botanical medication may be a useful adjunct in the treatment of excessive alcohol intake.

Response inhibition and psychomotor speed during methadone maintenance: impact of treatment duration, dose, and sleep deprivation

BACKGROUND In opiate-dependent individuals, abstinence results in deficits in cognitive functioning, which may be exacerbated by medication-associated sleep disruption. METHOD To assess cognitive function and the influence of sleep deprivation (SD), 14 healthy control (HC) and 22 methadone maintained (MM) participants completed the continuous performance task (CPT) after a baseline night, a night of total SD, and two recovery sleep nights. The digit symbol substitution task (DSST) was administered at bedtime and in the morning. Secondary analyses separated MM participants into short- (< 12 months; n=8) and long-term (≥ 12 months; n=14) treatment duration groups, and into low- (< 80 mg; n=9) and high-dose (≥ 80 mg; n=13) groups. RESULTS Linear mixed model ANOVAs revealed that there was no effect of SD. Across all days MM participants had more errors of omission, fewer correct responses, and slower reaction times (RTs) on the CPT, and fewer accurate substitutions on the evening and morning DSST. Short-term MM participants exhibited slower RTs on the CPT, and fewer correct substitutions on the evening DSST compared to long-term MM participants. Low-dose MM participants had slower RTs on the CPT than HCs and high-dose MM participants. CONCLUSION These data demonstrate that methadone-maintained individuals exhibit poorer performance on tasks of psychomotor speed and selective attention/impulsivity, but with longer-term treatment, performance appears to return toward control levels. Furthermore, while one day of SD was enough to alter subjective reports of sleep quality, cognitive function may be more resilient.

THE SUBJECTIVE PSYCHOACTIVE EFFECTS OF ORAL DRONABINOL STUDIED IN A RANDOMIZED, CONTROLLED CROSSOVER CLINICAL TRIAL FOR PAIN

Background:Many cannabinoid medications are approved in North America or in phase III trials, such as dronabinol, nabilone, or nabiximols. Little is known about their subjective psychoactive effects when used for pain management. We hypothesized that when used for pain, dronabinol has psychoactive effects in a dose-response relationship, whose peak effects are comparable with smoking marijuana. Methods:This was a randomized controlled trial of single dose placebo, 10 or 20 mg dronabinol in 30 chronic noncancer pain patients taking opioids and not using marijuana. Participants completed the Addiction Research Center Inventory (ARCI) hourly for 8 hours during 3 monitored sessions. Comparison sample was the ARCI ratings in participants with no pain (N=20), monitored every 30 minutes after smoking a 1.99% THC (low) and a 3.51% (high strength) marijuana cigarette. Results:The 10 and 20 mg dronabinol doses had significantly elevated scores over time on 4/5 subscales versus placebo (P<0.05). Average daily morphine use, total pain relief (TOTPAR), age, sex, and baseline pain level were not significant covariates. ARCI peak effects at 2 hours were similar to peak effects of smoked marijuana at 30 minutes (P=0.80, 10 mg=low strength, 20 mg=high strength). Conclusions:In pain patients, oral dronabinol has similar psychoactive effects to smoking marijuana. This risk must be considered in any decision to prescribe cannabinoid medications for pain.

The effects of atropine, benactyzine, and physostigmine on a repeated acquisition baseline in monkeys

A repeated acquisition procedure was used with cynomolgus monkeys to test the effects of one anticholinesterase (physostigmine) and two anticholinergic (atropine and benactyzine) compounds on learning and performance. Learning was defined as the number of response chains (trials) required to meet a criterion of three consecutive chains at 90% accuracy or better. Measures were the number of trials to criterion and the number of errors made. Following learning, behavior was analyzed as performance. Measures were total errors after learning and errors per trial. Time-out minutes (i.e., periods of enforced no responding after errors) were analyzed separately from total session time. Atropine (0.014, 0.044, 0.14, and 0.44 mg/kg) produced large learning disruptions and performance decrements at the highest dose. Learning decrements due to benactyzine (0.057, 0.18, 0.57, and 1.82 mg/kg) were not significant and produced little effect on performance. The effect of physostigmine (0.025, 0.050, and 0.075 mg/kg on learning was not consistent. The anticholinergics increased performance errors per trial, while the anticholinesterase had little effect. Session times showed dose-related increases for all drugs and were significantly increased by the highest doses of each. The session time increases observed after the anticholinergics were interpreted to be due to both an effect on learning and an effect on response rate, whereas the anticholinesterase effect was due primarily to response suppression.

Effects of sleep deprivation on sleep homeostasis and restoration during methadone-maintenance: A [31]P MRS brain imaging study

Insomnia afflicts many individuals, but particularly those in chronic methadone treatment. Studies examining sleep deprivation (SD) have begun to identify sleep restoration processes involving brain bioenergetics. The technique ([31])P magnetic resonance spectroscopy (MRS) can measure brain changes in the high-energy phosphates: alpha-, beta-, and gamma-nucleoside triphosphate (NTP). In the present study, 21 methadone-maintained (MM) and 16 control participants underwent baseline (BL), SD (40 wakeful hours), recovery1 (RE1), and recovery2 (RE2) study nights. Polysomnographic sleep was recorded each night and ([31])P MRS brain scanning conducted each morning using a 4T MR scanner (dual-tuned proton/phosphorus head-coil). Interestingly, increases in total sleep time (TST) and sleep efficiency index (SEI) commonly associated with RE sleep were not apparent in MM participants. Analysis of methadone treatment duration revealed that the lack of RE sleep increases in TST and SEI was primarily exhibited by short-term MM participants (methadone <12 months), while RE sleep in long-term MM (methadone >12 months) participants was more comparable to control participants. Slow wave sleep increased during RE1, but there was no difference between MM and control participants. Spectral power analysis revealed that compared to control participants; MM participants had greater delta, theta, and alpha spectral power during BL and RE sleep. ([31])P MRS revealed that elevations in brain beta-NTP (a direct measure of ATP) following RE sleep were greater in MM compared to control participants. Results suggest that differences in sleep and brain chemistry during RE in MM participants may be reflective of a disruption in homeostatic sleep function.

A therapeutic dose of zolpidem has limited abuse-like effects in drug-naïve females: a pilot study.

Zolpidem has abuse potential, particularly among individuals with histories of drug abuse. This double-blind, placebo-controlled, cross over pilot study investigated the subjective effects of zolpidem (10 mg) in drug-naïve females. Over the course of a 5-h period vital signs were monitored and a series of computerized questionnaires was administered. Results indicate that zolpidem engendered subjective effects characteristic of hypnotic drugs, but reduced ratings of drug liking, willing to take again, and willing to pay for, relative to placebo. Thus, a therapeutic dose of zolpidem may have limited potential for misuse among females who have no experience with drugs of abuse.

Gray matter-specific changes in brain bioenergetics after acute sleep deprivation: a 31P magnetic resonance spectroscopy study at 4 Tesla.

STUDY OBJECTIVES A principal function of sleep may be restoration of brain energy metabolism caused by the energetic demands of wakefulness. Because energetic demands in the brain are greater in gray than white matter, this study used linear mixed-effects models to examine tissue-type specific changes in high-energy phosphates derived using 31P magnetic resonance spectroscopy (MRS) after sleep deprivation and recovery sleep. DESIGN Experimental laboratory study. SETTING Outpatient neuroimaging center at a private psychiatric hospital. PARTICIPANTS A total of 32 MRS scans performed in eight healthy individuals (mean age 35 y; range 23-51 y). INTERVENTIONS Phosphocreatine (PCr) and β-nucleoside triphosphate (NTP) were measured using 31P MRS three dimensional-chemical shift imaging at high field (4 Tesla) after a baseline night of sleep, acute sleep deprivation (SD), and 2 nights of recovery sleep. Novel linear mixed-effects models were constructed using spectral and tissue segmentation data to examine changes in bioenergetics in gray and white matter. MEASUREMENTS AND RESULTS PCr increased in gray matter after 2 nights of recovery sleep relative to SD with no significant changes in white matter. Exploratory analyses also demonstrated that increases in PCr were associated with increases in electroencephalographic slow wave activity during recovery sleep. No significant changes in β-NTP were observed. CONCLUSIONS These results demonstrate that sleep deprivation and subsequent recovery-induced changes in high-energy phosphates primarily occur in gray matter, and increases in PCr after recovery sleep may be related to sleep homeostasis.

Bupropion Reduces some of the symptoms of Marihuana Withdrawal in chronic Marihuana Users: A pilot study

Bupropions (Zyban® SR) effectiveness to treat symptoms experienced in marihuana withdrawal was tested in a double-blind, placebo-controlled study with chronic, heavy marihuana users. Participants maintained their usual marihuana intake until Quit Day after which they were required to cease intake of THC products for 14 days. A Withdrawal Discomfort Score revealed that for 7 days immediately following cessation, placebo-treated subjects reported more symptoms than bupropion-treated subjects. Self-reported craving for marihuana increased for the placebo-treated group but not for those treated with bupropion. Measures of sleep and cognitive performance were not different between the two groups. Participants in the bupropion treatment arm were more likely to complete the study than those randomized to the placebo arm (50% completion for bupropion vs. 33% completion for placebo). These results suggest that bupropion may be useful for alleviating marihuana withdrawal symptoms and be useful in subject retention during long-term cessation programs.