One Month of Cannabis Abstinence in Adolescents and Young Adults Is Associated With Improved Memory.

OBJECTIVE: Associations between adolescent cannabis use and poor neurocognitive functioning have been reported from cross-sectional studies that cannot determine causality. Prospective designs can assess whether extended cannabis abstinence has a beneficial effect on cognition. METHODS: Eighty-eight adolescents and young adults (aged 16-25 years) who used cannabis regularly were recruited from the community and a local high school between July 2015 and December 2016. Participants were randomly assigned to 4 weeks of cannabis abstinence, verified by decreasing 11-nor-9-carboxy-∆9-tetrahydrocannabinol urine concentration (MJ-Abst; n = 62), or a monitoring control condition with no abstinence requirement (MJ-Mon; n = 26). Attention and memory were assessed at baseline and weekly for 4 weeks with the Cambridge Neuropsychological Test Automated Battery. RESULTS: Among MJ-Abst participants, 55 (88.7%) met a priori criteria for biochemically confirmed 30-day continuous abstinence. There was an effect of abstinence on verbal memory (P = .002) that was consistent across 4 weeks of abstinence, with no time-by-abstinence interaction, and was driven by improved verbal learning in the first week of abstinence. MJ-Abst participants had better memory overall and at weeks 1, 2, 3 than MJ-Mon participants, and only MJ-Abst participants improved in memory from baseline to week 1. There was no effect of abstinence on attention: both groups improved similarly, consistent with a practice effect. CONCLUSIONS: This study suggests that cannabis abstinence is associated with improvements in verbal learning that appear to occur largely in the first week following last use. Future studies are needed to determine whether the improvement in cognition with abstinence is associated with improvement in academic and other functional outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03276221.

Cognitive impairments and cancer chemotherapy: translational research at a crossroads.

Cancer chemotherapy is often associated with cognitive deficits which may remain after the treatment has ended. As more people survive cancer, concern is increasing about the impact of these problems with memory and executive function when they return to everyday life. When chemotherapeutic drugs are administered to healthy animals in dosing regimens modeling those used in humans, cognitive deficits also occur, and these preclinical studies can provide information about the biological mechanisms by which the cancer fighting drugs affect the brain. Evidence from animal studies points to damage to hippocampus, particularly a disruption of neurogenesis, whereas human studies emphasize cognitive deficits associated with impairments in frontal cortical function. This discrepancy may be due more to the tasks selected by researchers, and the choice of biochemical endpoints than inherently different effects of chemotherapy in humans and rodents. These differences in approach must be reconciled if common underlying mechanisms are to be identified, with the hope of leading to novel drug or non-pharmacological treatments. This may be achieved by broadening the scope of human and animal studies, and by looking outside the topic of chemotherapy-induced cancer deficits to learn from the advances being made by studying the effects of stress and somatic disease on brain function, and the cognitive impairments now recognized to result from a wide range of mental and physical illnesses.

A novel operant conflict procedure using incrementing shock intensities to assess the anxiolytic and anxiogenic effects of drugs.

There is a need for novel anxiolytics, which are effective, but do not cause sedation, tolerance, and rebound anxiety on discontinuation. To investigate a procedure that can be used to assess these characteristics preclinically, rats were initially trained to press a lever at a high rate to obtain food. Once trained, periods of punishment were introduced in which electric shocks were superimposed. The intensity of these electric shocks was increased every 90 s from very low (0.01 mA) to sufficiently high to stop most subjects responding (0.4 mA), so that a complete rate/intensity function was obtained during each punishment period. The benzodiazepine, chlordiazepoxide, and two novel subtype-selective gamma-aminobutyric acid-A agonists, TP003 and TPA023, significantly increased response rates mildly suppressed by intermediate levels of electric shock without any effect on unpunished response rate. Two clinically anxiogenic agents, yohimbine and flumazenil, reduced the rate of punished responding. Aripiprazole and amphetamine reduced both punished and unpunished responding. Repeated treatment with diazepam 2.5 mg/kg daily for 15 days, initially markedly reduced unpunished response rates, but also increased punished response rates, an effect which became greater with repeated treatment. Abrupt cessation of diazepam treatment produced a reduction in punished responding. Diazepam (5 mg/kg daily) produced a greater reduction in unpunished responding, a smaller increase in punished responding, and a larger and longer lasting reduction in punished rates on withdrawal. In conclusion, the procedure detected anxiolytic and anxiogenic effects of drugs, and the sedative side effects, development of tolerance, and rebound-anxiety on discontinuation of a benzodiazepine. This procedure should have utility in the characterization of novel treatments of anxiety.

The effects of psychotomimetic and putative cognitive-enhancing drugs on the performance of a n-back working memory task in rats.

RATIONALE: Working memory impairment is a core symptom of schizophrenia, but no existing treatment remediates this deficit. Inconsistent conceptualizations and few reliable translational measures are major hindrances to understanding the neurobiology of this aspect of cognition. Using comparable task designs may help bridge clinical and preclinical research efforts. OBJECTIVE: A novel rodent procedure was designed to translate the n-back working memory task used in schizophrenic patients. MATERIALS AND METHODS: Rats were trained in five-lever operant chambers to recall either the last (one-back) or penultimate (two-back) lever from random sequences of lever presentations of variable lengths. Psychotomimetic doses of amphetamine, dizocilpine maleate (MK801), and (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) were tested for disruption of accuracy, and cognitive-enhancing doses of amphetamine, nicotine, and (+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF38393 hydrochloride) were examined for improvements in performance. RESULTS: High doses of amphetamine (0.8 and 1.6 mg/kg) significantly reduced accuracy while increasing total trials; 0.1 mg/kg MK801 and 2.0 mg/kg DOI also reduced accuracy, but the latter concurrently impaired responding. At the lowest dose (0.2 mg/kg), amphetamine increased total trials and rewards without affecting accuracy; 1.0 mg/kg nicotine reduced accuracy without affecting total trials, whereas 10.0 mg/kg SKF38393 had the opposite effect. DISCUSSION: Although the possibility for mediating behaviors may exist, the rodent n-back task provides a clinically relevant model of working memory. Amphetamine and MK801 produced selective impairments without disrupting responding. The cognitive enhancers did not improve working memory, but low doses of amphetamine improved response efficiency. This novel procedure may be useful for examining cognitive deficits and their potential reversal in animal models of schizophrenia.

The effects of anorexic drugs on free-fed rats responding under a second-order FI15-min (FR10:S) schedule for high incentive foods.

Many similarities exist between the overconsumption of food, which results in obesity, and drug addiction. The present study investigated the effects of anorectic drugs on responding maintained by high incentive, but nutritionally unnecessary, food reinforcers using an FI15(fixed-ratio 10:S) schedule of reinforcement, similar to that used in studies on the incentive properties of drugs of abuse. Rats were trained to respond on a lever to gain access to two high incentive foods--chocolate chip cookies and cheese. Under the FI15(FR10:S) schedule, every 10th response (fixed-ratio 10) delivered a tone and light conditioned stimulus. The first ratio completed 15 min after the start of the session produced the conditioned stimulus and opened a door to give access to a piece of cookie. After 5 min to consume the high incentive food, a second 15-min interval was started, terminating in access to a second reinforcer, cheese. Once trained, the rats were given free access to laboratory chow in the home cage. They continued to work for the high incentive foods for a period of over 1 year, showing a pattern of responding appropriate to an FI(fixed-ratio) schedule. Naloxone (1.0 mg/kg), fenfluramine (1 and 2 mg/kg), D-amphetamine (0.25 and 0.5 mg/kg), and rimonabant (3 mg/kg) significantly reduced responding, especially in the second interval. In contrast, complete removal of the high incentive food from the test procedure did not immediately reduce the rate of responding, tending to increase it in the second of the intervals. Apparently, the drugs did not reduce responding by reducing the experienced magnitude of the high incentive food, but more probably by reducing the animals' motivation.

A comparison of the effects of psychotomimetics and anxiolytics on punished and unpunished responding maintained by fixed interval schedules of food reinforcement in the rat.

Characterization of anxiolytic drugs often employs conflict paradigms in which the drug effects on punished and unpunished responding can be compared. In this study, a fixed interval schedule generating a range of baseline response rates allowed comparison of the effects of anxiolytic drugs with those of psychotomimetic drugs on equivalent and differing rates of punished and unpunished responding. The first response made by the rat after a 40-s fixed interval elapsed resulted in food pellet delivery. In punished intervals, signalled by the illumination of stimulus lamps above each lever, a 0.6-mA shock was delivered after every 20th response, resulting in a lower rate of responding than that in the unpunished intervals. Three psychotomimetic agents, D-amphetamine, MK801 and DOI were compared with the anxiolytics chlordiazepoxide, NS2710 and pregabalin. The three psychotomimetics preferentially increased rates of unpunished responding compared with those of punished responding. Chlordiazepoxide, NS2710 and, to a lesser extent, pregabalin increased rates of both unpunished and punished responding. In comparison studies, yohimbine also increased rates of both unpunished and punished responding whereas the antidepressant citalopram had no effect. In conclusion, stable baseline performance over many months allowed the direct comparison of several different drugs in the same subjects with no need to adjust shock levels or equate baseline response rates. The drugs had systematic and replicable effects in this procedure, which, in the case of amphetamine and chlordiazepoxide, were similar to those in other species, and psychotomimetic drugs could clearly be distinguished from anxiolytic drugs. The procedure, however, has limited value for characterizing novel anxiolytic agents as the examples used here increased punished and unpunished responding to the same extent, and were indistinguishable in that regard from the clinically anxiogenic agent, yohimbine.

The psychopharmacology of impulsive behaviour in rats VIII: effects of amphetamine, methylphenidate, and other drugs on responding maintained by a fixed consecutive number avoidance schedule.

RATIONALE: Impulsive behaviour is a component of psychiatric disorders such as bipolar disorder, attention deficit hyperactivity disorder (ADHD), or personality disorders. Most experimental studies on impulsive behaviour punish impulsive choices by loss or delay of reward. In the present study, impulsive behaviour was punished by an explicitly aversive stimulus, using a novel fixed consecutive number (FCN) schedule of electric shock avoidance. OBJECTIVES: This study was conducted to demonstrate stable performance using the FCN avoidance procedure, and examine the effects of drugs previously shown to affect impulsive behaviour using a conventional FCN schedule. METHODS: First, rats were trained in the appetitive FCN procedure. Pressing the right lever in an operant conditioning chamber after having pressed the left lever at least six times delivered a food pellet (FCN6). Responses on the right lever before completing this ratio resulted in a time out and restarted the ratio. The rats were then switched to FCN avoidance. Responses on the right lever made before completion of the ratio also resulted in food delivery, but were accompanied by an electric shock. RESULTS: Chlordiazepoxide (10.0 mg/kg), ethanol (1.0 g/kg), and haloperidol (0.1 mg/kg) increased impulsive behaviour by reducing the number of left lever responses made before the right lever was pressed. Imipramine (1.0-10.0 mg/kg) and desipramine (1.0-10.0 mg/kg) had no effect on impulsive choice. Amphetamine (0.4 and 0.8 mg/kg) and methylphenidate (6.0 mg/kg) significantly increased the mean chain length, and the proportion of very long chains, indicative of reduced impulsivity, although this did not improve efficiency. CONCLUSIONS: The increases in impulsivity produced by chlordiazepoxide, ethanol, and haloperidol were similar to those under appetitive FCN schedules. In contrast, amphetamine and methylphenidate, by reducing impulsivity in the FCN avoidance, induced effects opposite to those observed in an appetitive FCN procedure. These results suggest that the therapeutic actions of stimulants, to reduce impulsive behaviour in ADHD, may arise in part by increasing the control of behaviour by aversive stimuli.

The effects of psychotomimetics and psychomotor stimulants on two schedules promoting response switching in the rat.

RATIONALE: Psychosis and psychotomimetic drugs result in a disorganisation of the structure of thought and behaviour. Normalising these is one of the objects of antipsychotic therapy, and methods for predicting such a therapeutic effect would be of value. OBJECTIVE: The effects of a number of psychotomimetic agents were examined on the way in which rats distributed responding over two response levers using two different procedures, to assay their effects on behavioural organisation. Previously, amphetamine has been found to increase response switching using these schedules. METHODS: In the first, the random reinforcement procedure, one of the two levers was selected at random as "correct", and responses on this lever were reinforced with food under a random ratio schedule. No signal was given to distinguish the levers. Responding could also result in the food tray being illuminated, but no food pellet was delivered ("no-food" event). Responses on the second lever ("incorrect") had no programmed consequences. After each food delivery or "no-food" event the levers designated as "correct" and "incorrect" were reassigned at random, and the rat had to open the food tray to restart the schedule. In the second procedure, the rats were required to make 21 responses before a switch between the two levers resulted in food delivery [Fixed Ratio (FR) 21-switch]. The responses making up the FR could be distributed freely between the two levers. RESULTS: Phencyclidine (PCP), scopolamine, caffeine and ethanol increased switching under the random reinforcement procedure, but (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) and atropine did not. PCP, caffeine, lysergic acid diethylamide (LSD) and atropine increased switching under the FR21-switch procedure, but ethanol did not. The increases in switching produced by PCP, LSD and the anticholinergics were accompanied by marked reductions in response rate, whereas those produced by amphetamine and caffeine were not. The effects of amphetamine, and PCP were strongly dependent on the baseline probability of switching, those of atropine and caffeine moderately so, and those of LSD and ethanol only weakly so. CONCLUSIONS: Of the agents tested, psychomotor stimulants appear to produce the most selective increases in switching. The procedures described here may be useful for assaying the disorganisation of behaviour produced by other psychotomimetics and may have value in the detection of novel antipsychotic drugs.