Pharmacology Biochemistry and Behavior最新文献

Cannabis and its main psychoactive constituent, delta-9-tetrahydrocannabinol (THC), impair cognitive processes, including the ability to inhibit inappropriate responses. However, responses to cannabinoid drugs vary widely, and little is known about the factors that influence the risk for adverse effects. One potential source of variation in response to cannabinoids in women is circulating ovarian hormones such as estradiol and progesterone. Whereas there is some evidence that estradiol affects responses to cannabinoids in rodents, little is known about such interactions in humans. Here, we investigate whether variations in estradiol levels across the follicular phase of the menstrual cycle modulate the effect of THC on inhibitory control in healthy women. Healthy female occasional cannabis users (N = 60) received THC (7.5 mg and 15 mg, oral) and placebo during either the early follicular phase, when estradiol levels are low, or the late follicular phase, when estradiol levels are higher. They completed a Go/No Go (GNG) task at the time of peak drug effect. We hypothesized that the effects of THC on GNG performance would be greater when estradiol levels were elevated. As expected, THC impaired GNG task performance: it increased response time and errors of commission/false alarms and decreased accuracy, relative to placebo. However, these impairments were not related to estradiol levels. These results suggest that THC-induced impairments in inhibitory control are not affected by cycle-related fluctuations in estradiol levels.

Prefrontal and striatal glutamate plays an important role in modulating striatal dopamine levels and an imbalance in regional glutamate has been identified in several psychiatric conditions. We hypothesized that this imbalance also exists in cannabis use disorder (CUD). We recently quantified the difference in glutamate of dorsal anterior cingulate (dACC) and striatum regions in the frontostriatal pathway using proton MRS at baseline and on verified abstinent days 7 and 21 in chronic users of cannabis (n = 20) in comparison with age- and sex- matched non-using controls (n = 10). In addition, the Barratt Impulsiveness Scale-11 (BIS) was collected as a measure of inhibitory impulse control of the participants. We found that the difference in glutamate concentrations between the dACC and striatum (Δ_dACC-strGlu) of the controls was significantly higher than that of cannabis users across the study timeline (F(1,28) = 18.32, p < 0.0005). The group difference was not affected by age, sex, or alcohol/cigarette consumption. On abstinent day 7, Δ_dACC-strGlu was significantly correlated with the corresponding Δ_dACC-strGABA among the users (r = 0.837, p < 0.00001). On day 21, Δ_dACC-strGlu was negatively associated with monthly cannabis use days (Spearman's rho = −0.444, p = 0.05). Self-reported BIS and its subscales were significantly altered among the users compared to the controls across the study timeline (total F(1,28) = 7.0, p = 0.013; non-planning F(1,28) = 16.1, p < 0.0005; motor F(1,28) = 5.9, p = 0.022; cognitive F(1,28) = 6.1, p = 0.019). These data provide preliminary evidence that chronic cannabis use may lead to a dACC-striatal glutamate imbalance in conjunction with poor impulse control.

Cocaine use disorder (CUD) is a significant problem worldwide, with no FDA-approved treatments. Epidemiological data indicate that only about 17 % of people that use cocaine will meet DSM criteria for CUD. Thus, the identification of biomarkers predictive of eventual cocaine use may be of great value. Two potentially useful predictors of CUD are social hierarchies in nonhuman primates and delay discounting. Both social rank and preference for a smaller, immediate reinforcer relative to a larger, delayed reinforcer have been predictive of CUD. Therefore, we wanted to determine if there was also a relationship between these two predictors of CUD. In the present study, monkeys cocaine-naive responded under a concurrent schedule of 1- vs. 3-food pellets and delivery of the 3-pellet option was delayed. The primary dependent variable was the indifference point (IP), which is the delay that results in 50 % choice for both options. In the initial determination of IP, there were no differences based on sex or social rank of the monkeys. When the delays were redetermined after ~25 baseline sessions (range 5–128 sessions), dominant females and subordinate males showed the largest increases in IP scores from the first determination to the second. Because 13 of these monkeys had prior PET scans of the kappa opioid receptor (KOR), we examined the relationship between KOR availability and IP values and found that the change in IP scores from the first to the second determination significantly negatively predicted average KOR availability in most brain regions. Future studies will examine acquisition to cocaine self-administration in these same monkeys, to determine if IP values are predictive of vulnerability to cocaine reinforcement.

Emotion-related impulsivity is an important behavioural phenotype in clinical psychology and public health. Here, we test the hypothesis that emotion-related impulsivity moderates the effects of arousal on cognition using pharmacological manipulation. Participants completed a measure of emotion-related impulsivity, four cognitive tasks tapping onto different facets of impulsive behaviours, and a blinded arousal manipulation using yohimbine hydrochloride, which acts on noradrenergic receptors. Our findings suggest that emotion-related impulsivity moderates the role of arousal on impulsive performance on the Information Sampling Task. As expected, more severe emotion-related impulsivity was related to more impulsive decisions in the yohimbine but not in the placebo group. Results provide some of the first experimental evidence that emotion-related impulsivity is related to differential behavioural responses in the face of high arousal. Despite this preliminary support, we discuss findings for one task that did not fit hypotheses, and provide suggestions for replication and extension.

There are a few studies suggesting that the hippocampus is involved in the regulation of impulsivity, and which attempt to explain drug seeking behavior in addiction. In addition, cannabinoid receptor 1 (CB1R) is highly expressed in the hippocampus (HPP). To further understand the potential role of the hippocampal CB1R in impulsive and drug seeking behaviors, we characterized impulsivity in adolescent and adult male rats, by means of a delay discounting task (DDT) by evaluating preference and seeking motivation for alcohol (10 % v/v) consumption, and analyzing CB1R expression in CA1, CA3 and the dentate gyrus (DG) of the HPP as well as in the medial prefrontal cortex (mPFC). Our results show that adolescent rats display more impulsive choices than adult rats in the DDT. The k value is statistically higher in adolescents, further supporting that they are more impulsive. Besides, adolescent rats have higher forced and voluntary alcohol consumption and display a higher alcohol conditioned place preference (CPP) vs. adult rats. In addition, CB1R expression in CA3 and the DG is higher in adolescent vs. adult rats. Our data further support the role of the hippocampus in impulsivity with the potential involvement of the endocannabinoid system, considering that CB1R in CA3 and DG is higher in adolescents, who display impulsivity and alcohol seeking and consumption.

This study investigated the interactive effect of glucocorticoid and β-adrenoceptors in the infralimbic (IL) cortex on the acquisition and consolidation of fear extinction in rats' auditory fear conditioning (AFC) task. On day 1, rats underwent habituation for 9 min (12 tones, 10 s, 4 kHz, 80 dB, without footshock). On day 2 (conditioning), rats received 3 mild electrical footshocks (US; 2 s, 0.5 mA) paired with the auditory-conditioned stimulus (CS; tone: 30 s, 4 kHz, 80 dB). On days 3–5 (Ext 1–3), rats received 15 tones with no footshock in the test box. Intra-IL injection of corticosterone (CORT, 20 ng/0.5 μl per side) before Ext 1 and after Ext 1–2, respectively, facilitated the acquisition and consolidation of fear memory extinction. Intra-IL injection of the β₂-adrenoceptor agonist clenbuterol (CLEN, 50 ng/0.5 μl per side) inhibited, but the β-adrenoceptor antagonist propranolol (PROP, 500 ng/0.5 μl per side) enhanced the facilitatory effects of CORT on fear memory extinction. CORT injection before the acquisition of fear extinction increased p-ERK levels in the IL. Co-injection of CORT with CLEN increased, but PROP decreased p-ERK activities. CORT injection after the consolidation of fear extinction increased p-CREB in the IL. Co-injection of CORT with CLEN increased, but PROP reduced p-CREB activities. Our findings show that corticosterone facilitates the acquisition and consolidation of fear memory extinction. GRs and β-adrenoceptors in the IL jointly regulate fear memory extinction via ERK and CREB signaling pathways. This pre-clinical animal study may highlight the effect of GRs and β-adrenoceptors of the IL cortex in regulating fear memory processes in fear-related disorders such as PTSD.

Pharmacological effects of ketamine may affect homeostatic sleep regulation via slow wave related mechanisms.

In the present study effects of ketamine applied at anesthetic dose (80 mg/kg) were tested on neocortical electric activity for 24 h in freely moving rats. Ketamine effects were compared to changes during control (saline) injections and after 6 h gentle handling sleep deprivation (SD). As circadian factors may mask drug effects, an illumination protocol consisting of short light-dark cycles was applied.

Ketamine application induced a short hypnotic stage with characteristic slow cortical rhythm followed by a long-lasting hyperactive waking resulting pharmacological SD. Coherence analysis indicated an increased level of local synchronization in broad local field potential frequency ranges during hyperactive waking but not during natural- or SD-evoked waking. Both slow wave sleep and rapid eye movement sleep were replaced after the termination of the ketamine effect.

Our results show that both ketamine-induced hypnotic state and hyperactive waking can induce homeostatic sleep pressure with comparable intensity as 6 h SD, but ketamine-induced waking was different compared to the SD-evoked one. Both types of waking stages were different compared to spontaneous waking but all three types of wakefulness can engage the homeostatic sleep regulating machinery to generate sleep pressure dissipated by subsequent sleep. Current-source density analysis of the slow waves showed that cortical transmembrane currents were stronger during ketamine-induced hypnotic stage compared to both sleep replacement after SD and ketamine application, but intracortical activation patterns showed only quantitative differences.

These findings may hold some translational value for human medical ketamine applications aiming the treatment of depression-associated sleep problems, which can be alleviated by the homeostatic sleep effect of the drug without the need for an intact circadian regulation.

Background

Drugs of abuse have rewarding and aversive effects that, in balance, impact abuse potential. Although such effects are generally examined in independent assays (e.g., CPP and CTA, respectively), a number of studies have examined these effects concurrently in rats in a combined CTA/CPP design. The present study assessed if similar effects can be produced in mice which would allow for determining how each is affected by subject and experiential factors relevant to drug use and abuse and the relationship between these affective properties.

Methods

Male and female C57BL/6 mice were exposed to a novel saccharin solution, injected (IP) with saline or 5.6, 10 or 18 mg/kg of the synthetic cathinone, methylone, and placed on one side of the place conditioning apparatus. The following day, they were injected with saline, given access to water and placed on the other side of the apparatus. After four conditioning cycles, saccharin avoidance and place preferences were assessed in a final two-bottle CTA test and a CPP Post-Test, respectively.

Results

In the combined CTA/CPP design, mice acquired a significant dose-dependent CTA (p = 0.003) and a significant CPP (p = 0.002). These effects were independent of sex (all ps > 0.05). Further, there was no significant relationship between the degree of taste avoidance and place preference (p > 0.05).

Conclusions

Similar to rats, mice displayed significant CTA and CPP in the combined design. It will be important to extend this design in mice to other drugs and to examine the impact of different subject and experiential factors on these effects to facilitate predictions of abuse liability.

The metabotropic glutamate receptor 7 (mGlu₇), encoded by the GRM7 gene in humans, is a presynaptic, G protein-coupled glutamate receptor that is essential for modulating neurotransmission. Mutations in or reduced expression of GRM7 have been identified in different genetic neurodevelopmental disorders (NDDs), and rare biallelic missense variants have been proposed to underlie a subset of NDDs. Clinical GRM7 variants have been associated with a range of symptoms consistent with neurodevelopmental molecular features, including hypomyelination, brain atrophy and defects in axon outgrowth. Here, we review the newest findings regarding the cellular and molecular defects caused by GRM7 variants in NDD patients.

The FDA has not yet approved a pharmacotherapy for cocaine use disorder despite nearly four decades of research. This study determined the initial efficacy, safety, and tolerability of naltrexone-bupropion combinations as a putative pharmacotherapy for cocaine use disorder.

Thirty-one (31) non-treatment seeking participants with cocaine use disorder completed a mixed-design human laboratory study. Participants were randomly assigned to the naltrexone conditions (i.e., 0, 50 mg/day; between-subject factor) and maintained on escalating doses of bupropion (i.e., 0, 100, 200, 400 mg/day; within-subject factor) for at least four days prior to the conduct of experimental sessions. Cocaine self-administration (IN, 0, 40, 80 mg) was then determined using a modified progressive ratio and relapse procedure. Subjective and cardiovascular effects were also measured. Cocaine produced prototypical dose-related increases in self-administration, subjective outcomes (e.g., “Like Drug”), and cardiovascular indices (e.g., heart rate, blood pressure) during placebo maintenance. Naltrexone and bupropion alone, or in combination, did not significantly decrease self-administration on either procedure. Low doses of bupropion (i.e., 100 mg) blunted the effects of the cocaine on subjective measures of “Like Drug” and “Stimulated”. No unexpected adverse effects were observed with naltrexone and bupropion, alone and combined, in conjunction with cocaine.

Together, these results do not support the use of these bupropion-naltrexone combinations for the treatment of cocaine use disorder. Future research should determine if novel drug combinations may decrease cocaine self-administration.