Psychopharmacology最新文献

Rationale: Given the nascency of tobacco-free oral nicotine pouches (NPs) and the heterogeneity of commercially available NP brands, there is a need for scientific evaluation of different NP formulations. Nordic Spirit, novel NPs are distinguished by their unique composition.

Objectives: To characterize blood nicotine delivery, pharmacokinetics (PK), subjective and physiological effects and to monitor safety of three Nordic Spirit NPs (6 mg, 9 mg and 11.2 mg/pouch) compared with LD tobacco snus (11.2 mg/pouch) and Nicorette® gum (4 mg/unit) following single 30 min use.

Methods: This was a randomized, open-label, ten-sequence, single-use, cross-over clinical study with 30 healthy adult Swedish snus users.

Results: Peak nicotine concentrations (C_max) ranged from 10.92 to 17.32 ng/mL for the three Nordic Spirit NPs, with a trend toward dose proportionality, and 8.18 ng/mL and 9.23 ng/mL for the LD snus and Nicorette® gum comparators, respectively. Peak concentration for Nordic Spirit NPs was reached (T_max) after 30 to 38 min, and after 45 min for LD snus and Nicorette® gum. No notable safety concerns were observed after single use for any of the study products.

Conclusions: Delivery of nicotine from the three Nordic Spirit NPs appeared to be nicotine content-dependent, based on C_max and AUC. The amount of nicotine extracted showed positive correlation with the reported C_max and AUC. For Nordic Spirit NPs, T_max was immediately after end of use. The characteristics of Nordic Spirit NPs were found to be favourable for profiling NP nicotine delivery and safety in human use, and for further product development. ISRCTN registry study no. ISRCTN75583947.

Rationale: Alcohol is one of the most frequently used drugs of abuse and has a major impact on human health worldwide. People assigned female at birth and those with adverse childhood experiences are stress-vulnerable and more likely to report drinking as a means of "self-medication." Prior studies in our laboratory showed that adolescent social isolation stress (SIS) increases vulnerability to ethanol (EtOH) intake and consumption despite negative consequences in female rats.

Objectives: Here, we explored modulation of the dorsal raphe nucleus (DRN)-serotonin (5-HT) system, a sexually dimorphic neurotransmitter system involved in stress-reward interactions, to determine its contribution to EtOH-motivated behaviors in rats that have undergone SIS.

Results: We employed electrophysiological and functional neuroanatomy strategies to show that both SIS and EtOH exposure induce persistent hypofunction of the DRN 5-HT system, particularly in females. Chemogenetic activation of DRN 5-HT neurons attenuated reward value for both EtOH and sucrose and elevated punished responding for EtOH in a stress-dependent manner.

Conclusions: Our results highlight an inverse relationship between EtOH consumption and the 5-HT system, the sex- and stress-dependent nature of this relationship, and a connection between DRN 5-HT signaling and acute responding to rewards and punishment. These data support the DRN 5-HT system as a potential target to treat aberrant alcohol consumption and drinking despite negative consequences in stress-vulnerable populations.

Rationale: Rapid adaptation to stressful events is essential for survival and requires acute stress response and stress-coping strategy. However, the molecular mechanisms that govern this coping strategy have yet to be fully discovered.

Objectives: This study aims to investigate the effects of poly ADP-ribosylation (PARylation) on stress-coping strategies following acute stress and to identify the target genes influenced by Parp1-induced histone PARylation.

Methods: Mice were subjected to a forced swim test, a well-established acute stress paradigm, to evaluate cortical PARylation and assess the expression of activity-dependent genes. The pharmacological inhibition of Parp1 was conducted using ABT888 (Veliparib) to determine its effects on stress-coping behavior and related molecular changes.

Results: The forced swim test increased cortical PARylation and upregulated the expression of activity-dependent genes. Systemic inhibition of Parp1 with ABT888 led to impaired stress-coping behavior, evidenced by a reduced immobility response during a subsequent forced swim test done 24 hours later. This impairment was associated with decreased chromatin PARylation and histone H4 acetylation at the Arc promoter and reduced Arc expression observed one hour after Parp1 inhibition.

Conclusion: Our findings indicate that chromatin PARylation at the Arc promoters regulates histone H4 acetylation and Arc gene expression, and a subsequent impact on successful stress-coping behavior in response to acute stress.

Rationale: A central component of substance use disorder is the maladaptive choice of the drug over natural reinforcers. Compared to other drugs of abuse, methamphetamine (METH) choice has received limited study.

Objective: We sought to characterize the role of intertrial interval on METH choice behavior.

Methods: We examined the choice of METH versus food, across multiple METH doses (0.05-0.2 mg/kg/infusion), between male and female rats, employing a fixed ratio (FR1) reinforcement schedule with intertrial intervals (ITIs) of 20 and 600 s. Rats learned to lever-press for either the METH or the food reinforcer during separate, alternating training sessions. Rats then underwent choice testing, where both levers were presented for 25 discreet trials per session. Lastly, under a progressive ratio (PR) schedule, breakpoints for METH and food were assessed during separate, alternating sessions.

Results: METH choice was substantially higher when using the 20 s versus 600 s ITI. When the 20 s ITI was used, choice was dose- but not sex-dependent. When using the 600 s ITI, choice was influenced by dose and sex, with female rats in the higher dose group choosing METH more than other groups. PR breakpoints were higher for METH than for food, and this effect was more pronounced among female rats. METH choice was positively correlated with the ratio of METH/food breakpoints.

Conclusion: Reinforcement schedule parameters, namely ITI, during discrete choice testing can markedly influence METH choice behavior; thus, this should be carefully considered during experiment design and selected based on overarching study aims.

Rationale: Anxiety is a chronic severe psychiatric disorder. In a series of studies, the implication of the gaseous molecule nitric oxide (NO) in anxiety has been evidenced. Further, the outcome of preclinical research suggests that different NO donors, including sodium nitroprusside (SNP), have expressed an anxiolytic profile revealed in animal models of anxiety. Regardless of this, it is not yet clarified the mechanism(s) of action by which SNP induces its beneficial effects on anxiety. In this context, it has been hypothesized that these effects might be attributed to a potential interaction of this NO donor with the GABA type A and the 5-HT_1A serotonergic receptors.

Objectives: The current study was designed to investigate this issue in the male rat.

Methods: To this end, the light/dark box and the open field tests were utilized.

Results: SNP (1 mg/kg, i.p.) applied acutely induced an anti-anxiety-like effect evidenced either in the light/dark box or in the open field test. Either the GABA_A receptor antagonist flumazenil (10 mg/kg, i.p.) or the 5-HT_1A serotonin receptor agonist 8-OH-DPAT (0.25 mg/kg, i.p.) suppressed the above reported anxiolytic effects of SNP.

Conclusions: The results here reported propose a functional interaction between SNP with the GABAergic and the serotonergic systems on anxiety and thus, might offer a plausible explanation for SNP's anxiolytic effects.

Rationale: Despite the critical role of choice processes in substance use disorders, the neurobehavioral mechanisms guiding human decisions about drugs remain poorly understood.

Objectives: We aimed to characterize the neural encoding of subjective value (SV) for cannabis versus non-drug rewards (snacks) in people who use cannabis on a near-daily/daily frequency (PWUCF) and assessed the impact of cannabis and snack stimuli ('cues') on SV encoding.

Methods: Twenty-one non-treatment-seeking PWUCF (≥4 days/week; 1 female) participated in an inpatient, crossover experiment with four counterbalanced conditions: 1. neutral cues/cannabis choices; 2. cannabis cues/cannabis choices; 3. neutral cues/snack choices; and 4. snack cues/snack choices. In each condition, participants were exposed to cues before an fMRI scan during which they repeatedly chose between 0-6 cannabis puffs/snacks and a set monetary amount, with randomly-selected choices implemented. The SV signal was operationalized as the neural correlates of the strength of preference for cannabis/snack choices. fMRI data were analyzed for twenty participants.

Results: Despite equivalent choice behavior, SV signals for cannabis, but not snacks, were observed in regions known to encode SV for various rewards (ventromedial prefrontal cortex, vmPFC; ventral striatum; dorsal posterior cingulate cortex, dPCC). SV encoding in vmPFC was stronger for cannabis than snacks. In the dPCC, the impact of cues on SV signals was moderated by reward type.

Conclusions: PWUCF had expected neural value encoding for cannabis but disrupted non-drug SV encoding, despite equivalent choice behavior. This provides tentative support for theories that highlight dysregulated neural valuation of non-drug rewards as a hallmark of problematic cannabis use.

Rationale: Substance use disorder (SUD) is a chronic relapsing brain disorder that is characterised by loss of control over substance use. A variety of rodent models employing punishment setups have been developed to assess loss of control over substance use, i.e. persistent substance use despite negative consequences, to facilitate the translation of findings from animal studies to the human situation.

Objectives: Since the negative consequences of addictive behaviour are typically unpredictable, we here present the Seeking under Threat of Adversity (STA) task in rats, that incorporates cued, probabilistic and response-contingent punishment of reward seeking.

Methods: Male rats were trained to lever press for sucrose, alcohol or cocaine and were subsequently tested in the STA task. In this task, a tone cue is presented during reward seeking which functions as a warning signal, since responding during tone presentation results in a probabilistic foot shock punishment. We first determined the optimal shock intensity to induce a moderate suppression of seeking. Next, we assessed the stability of punished reward seeking over repeated tests. Finally, we compared the development of loss of control over substance seeking for sucrose, alcohol and cocaine. (Loss of) control over substance seeking would be evident as the (in)ability to refrain from lever pressing to obtain a reward, despite the threat of a negative outcome.

Results: Parametric experiments revealed suppression of responding for both sucrose and alcohol in the STA task at shock intensities between 0.25 and 0.35 mA. The suppression of responding was stable with repeated testing. Furthermore, less control over alcohol and cocaine seeking, when compared to sucrose seeking, was observed in male rats using the STA task.

Conclusions: The STA task is a novel behavioural task that includes two important aspects of human substance use despite negative consequences, i.e. response contingency and unpredictability of adversity. Combined with other behavioural tasks and neural manipulations, the STA task can further our understanding of the psychopathology of substance use disorders.

Introduction: Epilepsy is a common neurological disorder that affects the quality of life globally. Its pathophysiology involves disruptions in ion transport, excitatory-inhibitory imbalances, and regulatory systems. It has been shown that there is a crosstalk between the brain and the gut, where the brain influences the digestive system and the gut can affect brain functions and behavior. This study postulates that probiotic supplementation has both preventive and therapeutic impacts on epilepsy through modulation of inflammatory responses and improvement of brain function.

Materials and methods: Male rats were gavaged with three probiotic strains (Lactobacillus reuteri, Bifidobacterium longum, Bifidobacterium lactis) daily for 28 days (10^9 CFU/mL) before inducing epilepsy with pentylenetetrazol (PTZ) injections (37.5 mg/kg every 48 h for 14 injections). Probiotic supplements were continued during disease induction. The effects of probiotics on seizure behavior, histopathology, and pro-inflammatory gene expression were assessed.

Results: Probiotic consumption significantly reduced seizure severity, with evident effects from the fourth injection onwards (days 8-28). It delayed the onset of stage 2 and 5 seizures during kindling but had no major effect on stage 5 stability time. Histopathological analysis revealed amelioration of neuronal injury. Besides, there was a significant decrease in the expression of pro-inflammatory genes (Il-1β, Il-6, Ifng) and an increase in the expression of the anti-inflammatory Il-10 in the probiotic-treated model group.

Conclusion: Probiotics may have both preventive and therapeutic effects on PTZ-induced seizures through reduction of severity of seizures and modulating inflammatory responses. Additional studies are necessary to clarify the mechanisms, as treatment was given before and during kindling.

Rationale: Alcohol-intoxication is implicated in negative social behaviours, however the mechanisms underlying this relationship are poorly understood. Impaired emotion perception following alcohol consumption may partially account for this link, however limited methodology in prior studies undermines the efficacy of this explanation.

Objectives: The current study investigated the effect of acute moderate-dose alcohol-intoxication on basic and compound emotion perception abilities using contextualised video vignettes. Self-appraisals of performance accuracy were also investigated.

Methods: Sixty-eight participants consumed a beverage containing either (a) an alcohol dose calculated to achieve a BrAC of 0.08%, or (b) a placebo. The Complex Audio-Visual Emotion Assessment Task (CAVEAT) was used to assess emotion perception ability. Anticipatory performance accuracy and emergent confidence judgements were made on the CAVEAT.

Results: There were no significant between-group differences on emotion perception ability and emergent confidence judgements. However, anticipatory performance accuracy was more aligned to actual performance in the alcohol intoxication group compared to the placebo group.

Conclusions: Overall, these results suggest that (1) deficits in perception of facial emotional expressions following alcohol intoxication may not be as pronounced as originally suspected; and (2) the questioning of performance accuracy may prompt intoxicated individuals to anticipate poorer emotion perception performance, which may lead to better monitoring of-and improvements in-task performance.

Rationale and objectives: In vivo receptor interactions vary as a function of behavioral endpoint, with key differences between reflexive and non-reflexive measures that assess the motivational aspects of pain and pain relief. There have been no assessments of D₁ dopamine agonist / mu opioid receptor (MOR) agonist interactions in non-reflexive behavioral measures of pain. We examined the hypothesis that D₁/MOR mixtures show enhanced effectiveness in blocking pain depressed behaviors while showing decreased side effects such as sedation and drug reward.

Methods: SKF82958 and methadone were used as selective/high efficacy D₁ and mu agonists, respectively. An FR10 operant schedule was utilized in the presence and absence of a lactic acid inflammatory pain-like manipulation, to measure antinociceptive and operant-rate-suppressing effects, respectively. Rewarding properties of the drug combinations were determined using a conditioned place preference procedure.

Results: Methadone alone, but not SKF82958 alone, produced dose-dependent restoration of pain-depressed responding. Both SKF82958 and methadone produced dose-dependent response rate suppression. Three fixed proportion mixtures, based on the relative potencies of the drugs in the rate suppression assay, produced dose-dependent antinociception and sedation. Isobolographic analysis indicated that the 0.17:1 mixture produced supra-additive antinociception and additive sedation. The 0.055:1 mixture produced additive antinociception with sub-additive sedation, and the 0.018:1 mixture had the highest therapeutic index (TI) relative to other mixtures and drugs alone. The antinociceptive doses and component doses for the 0.018:1 mixture did not produce conditioned place preference.

Conclusions: These results suggest that D₁-selective dopamine agonists may have utility as candidate opioid-sparing analgesics.