Conditioned stimuli affect ethanol-seeking by female alcohol-preferring (P) rats: the role of repeated-deprivations, cue-pretreatment, and cue-temporal intervals Abstract Rationale Evidence indicates that drug-paired stimuli can evoke drug-craving leading to drug-seeking and repeated relapse periods can influence drug-seeking behaviors. Objectives The present study examined (1) the effect of an interaction between repeated deprivation cycles and excitatory conditioning stimuli (CS+) on ethanol (EtOH)-seeking; (2) the effects of EtOH-paired cue-exposure in a non-drug-paired environment on subsequent conditioning in a drug-paired environment; and (3) the temporal effects of conditioned cues on subsequent EtOH-seeking. Methods Adult female alcohol-preferring (P) rats were exposed to three conditioned odor cues; CS+ associated with EtOH self-administration, CS− associated with the absence of EtOH (extinction training), and a neutral stimulus (CS0) presented in a neutral non-drug-paired environment. The rats underwent four deprivation cycles or were non-deprived, following extinction they were maintained in a home cage for an EtOH-free period, and then exposed to no cue, CS+, CS−, or CS0 to assess the effect of the conditioned cues on EtOH-seeking behavior. Results Repeated deprivations enhanced and prolonged the duration of CS+ effects on EtOH-seeking. Presentation of the CS− in a non-drug-paired environment blocked the ability of a CS+ to enhance EtOH-seeking in a drug-paired environment. Presentation of the CS+ or CS− in a non-drug-paired environment 2 or 4 h earlier significantly altered EtOH-seeking. Conclusion Results indicated an interaction between repeated deprivation cycles and CS+ resulted in a potentiation of CS+ evoked EtOH-seeking. In addition, a CS− may have therapeutic potential by providing prophylactic protection against relapse behavior in the presence of cues in the drug-using environment.

A single inhalation of vapor from dried toad secretion containing 5-methoxy- N , N -dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms Abstract Background 5-methoxy-N,N-dimethyltryptamine (hereinafter referred to as 5-MeO-DMT) is a psychedelic substance found in the secretion from the parotoid glands of the Bufo alvarius toad. Inhalation of vapor from toad secretion containing 5-MeO-DMT has become popular in naturalistic settings as a treatment of mental health problems or as a means for spiritual exploration. However, knowledge of the effects of 5-MeO-DMT in humans is limited. Aims The first objective of this study was to assess sub-acute and long-term effects of inhaling vapor from dried toad secretion containing 5-MeO-DMT on affect and cognition. The second objective was to assess whether any changes were associated with the psychedelic experience. Methods Assessments at baseline, within 24 h and 4 weeks following intake, were made in 42 individuals who inhaled vapor from dried toad secretion at several European locations. Results Relative to baseline, ratings of satisfaction with life and convergent thinking significantly increased right after intake and were maintained at follow-up 4 weeks later. Ratings of mindfulness also increased over time and reached statistical significance at 4 weeks. Ratings of depression, anxiety, and stress decreased after the session, and reached significance at 4 weeks. Participants that experienced high levels of ego dissolution or oceanic boundlessness during the session displayed higher ratings of satisfaction with life and lower ratings of depression and stress. Conclusion A single inhalation of vapor from dried toad secretion containing 5-MeO-DMT produces sub-acute and long-term changes in affect and cognition in volunteers. These results warrant exploratory research into therapeutic applications of 5-MeO-DMT.

Modulation by chronic antipsychotic administration of PKA- and GSK3β-mediated pathways and the NMDA receptor in rat ventral midbrain Abstract Rationale Antipsychotics exert therapeutic effects by modulating various cellular signalling pathways and several types of receptors, including PKA- and GSK3β-mediated signalling pathways, and NMDA receptors. The ventral midbrain, mainly containing the ventral tegmental area (VTA) and substantia nigra (SN), are the nuclei with dopamine origins in the brain, which are also involved in the actions of antipsychotics. Whether antipsychotics can modulate these cellular pathways in the ventral midbrain is unknown. Objective This study aims to investigate the effects of antipsychotics, including aripiprazole (a dopamine D2 receptor (D2R) partial agonist), bifeprunox (a D2R partial agonist), and haloperidol (a D2R antagonist) on the PKA- and GSK3β-mediated pathways and NMDA receptors in the ventral midbrain. Methods Male rats were orally administered aripiprazole (0.75 mg/kg, t.i.d. (ter in die)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for either 1 week or 10 weeks. The levels of PKA, p-PKA, Akt, p-Akt, GSK3β, p-GSK3β, Dvl-3, β-catenin, and NMDA receptor subunits in the ventral midbrain were assessed by Western Blots. Results The results showed that chronic antipsychotic treatment with aripiprazole selectively increased PKA activity in the VTA. Additionally, all three drugs elevated the activity of the Akt–GSK3β signalling pathway in a time-dependent manner, while only aripiprazole stimulated the Dvl-3–GSK3β–β-catenin signalling pathway in the SN. Furthermore, chronic administration with both aripiprazole and haloperidol decreased the expression of NMDA receptors. Conclusion This study suggests that activating PKA- and GSK3β-mediated pathways and downregulating NMDA receptor expression in the ventral midbrain might contribute to the clinical effects of antipsychotics.

Methylphenidate administration promotes sociability and reduces aggression in a mouse model of callousness Abstract Rationale Deficits in empathy constitute a distinctive feature of several psychopathologies, including conduct disorder (CD). The co-occurrence of callous-unemotional (CU) traits, excess rates of aggression and violation of societal norms confers specific risk for adult psychopathy. To date, the off-label use of methylphenidate (MPH) constitutes the drug treatment of choice. Objectives Herein, we tested the therapeutic potential of MPH in a recently devised mouse model recapitulating the core phenotypic abnormalities of CD. Methods Two subgroups of BALB/cJ male mice exhibiting opposite profiles of emotional contagion (i.e. socially transmitted adoption of another’s emotional states) were investigated for reactive aggression, sociability, attention control, anxiety-related behaviours and locomotor activity, in response to MPH administration (0.0, 3.0 or 6.0 mg/kg). Results Our data indicate that mice selected for excess callousness exhibit phenotypic abnormalities isomorphic to the symptoms of CD: stability of the low emotional contagion trait, increased aggression and reduced sociability. In accordance with our predictions, MPH reduced aggression and increased sociability in callous mice; yet, it failed to restore the low responsiveness to the emotions of a conspecific in pain, isomorphic to CU traits. Conclusions Although our data support the notion that MPH may contribute to the management of excess aggression in CD patients, additional studies shall identify specific treatments to target the callousness domain. The latter, unaffected by MPH in our experimental model, demands focused consideration whereby it constitutes a specifier associated with a worse prognosis.

Moral decision making under modafinil: a randomized placebo-controlled double-blind crossover fMRI study Abstract Rationale Modafinil is increasingly used by healthy humans as a neuroenhancer in order to improve cognitive functioning. Research on the effects of modafinil on cognition yielded most consistent findings for complex tasks relying on the prefrontal cortex (PFC). Objectives The present randomized placebo-controlled double-blind crossover study aimed to investigate the effect of a single dose of modafinil (200 mg) on everyday moral decision making and its neural correlates, which have been linked to the ventro- and dorsomedial PFC. Methods Healthy male study participants were presented with short stories describing everyday moral or neutral dilemmas. Each moral dilemma required a decision between a personal desire and a moral standard, while the neutral dilemmas required decisions between two personal desires. The participants underwent this task twice, once under the influence of modafinil and once under placebo. Brain activity associated with the processing of the dilemmas was assessed by means of functional magnetic resonance imaging. Results For the processing of moral vs. neutral dilemmas, activations were found in a network of brain regions linked to social cognitive processes including, among others, the bilateral medial PFC, the insula, and the precuneus. Modafinil was found to increase the number of moral decisions and had no effect on brain activity associated with dilemma processing. Exploratory analyses revealed reduced response-locked activity in the dorsomedial PFC for moral compared to neutral dilemmas under modafinil, but not under placebo. Conclusions The results are discussed in terms of altered predictions of others’ emotional states under modafinil, possibly due to higher processing efficiency.

Effects in rats of adolescent exposure to cannabis smoke or THC on emotional behavior and cognitive function in adulthood Abstract Rationale Cannabis use is common among adolescents and some research suggests that adolescent cannabis use increases the risk for depression, anxiety, and cognitive impairments in adulthood. In human studies, however, confounds may affect the association between cannabis use and the development of brain disorders. Objectives These experiments investigated the effects of adolescent exposure to either cannabis smoke or THC on anxiety- and depressive-like behavior and cognitive performance in adulthood in Long-Evans rats. Methods Adolescent rats of both sexes were exposed to either cannabis smoke from postnatal days (P) 29–49 or ascending doses of THC from P35–45. When the rats reached adulthood (P70), anxiety-like behavior was investigated in the large open field and elevated plus maze, depressive-like behavior in the sucrose preference and forced swim tests, and cognitive function in the novel object recognition test. Results Despite sex differences on some measures in the open field, elevated plus maze, forced swim, and novel object recognition tests, there were no effects of either adolescent cannabis smoke or THC exposure, and only relatively subtle interactions between exposure conditions and sex, such that sex differences on some performance measures were slightly attenuated. Conclusion Neither cannabis smoke nor THC exposure during adolescence produced robust alterations in adult behavior after a period of abstinence, suggesting that adverse effects associated with adolescent cannabis use might be due to non-cannabinoid concomitants of cannabis use.

Influence of phendimetrazine maintenance on the reinforcing, subjective, performance, and physiological effects of intranasal cocaine Abstract Rationale No pharmacotherapies are approved for cocaine use disorder. Phendimetrazine, a prodrug of the monoamine-releaser phenmetrazine, attenuates the reinforcing effects of cocaine in preclinical models, has minimal abuse potential, and is safe when combined with cocaine. Objectives This study determined the influence of phendimetrazine maintenance on the reinforcing effects of cocaine (i.e., choice to self-administer cocaine), along with the subjective, performance, and physiological effects of cocaine. We hypothesized that phendimetrazine would attenuate the reinforcing effects of cocaine. Methods Twenty-nine subjects with cocaine use disorder completed this within-subject, inpatient study. The subjects were maintained on placebo and 210 mg phendimetrazine in a counterbalanced order. After at least 7 days of maintenance on the target dose, the subjects completed experimental sessions in which the effects of single doses of 0, 20, 40, and 80 mg of intranasal cocaine were determined. Results Cocaine functioned as a reinforcer, producing significant dose-related increases in self-administration. Cocaine increased prototypic effects (e.g., ratings of stimulated and blood pressure). Phendimetrazine attenuated ratings on a select set of subjective outcomes (e.g., ratings of talkative/friendly), but failed to reduce the reinforcing effects of cocaine or a majority of positive subjective cocaine effects. Phendimetrazine increased heart rate, indicating a physiologically active dose was tested, but heart rate increases were not clinically significant. Conclusions These results indicate that although phendimetrazine can safely be combined with cocaine, it does not attenuate the abuse-related effects of cocaine. It is unlikely, then, that phendimetrazine will be an effective standalone treatment for cocaine use disorder.

Evaluating non-medical prescription opioid demand using commodity purchase tasks: test-retest reliability and incremental validity Abstract Rationale Non-medical prescription opioid use and opioid use disorder (OUD) present a significant public health concern. Identifying behavioral mechanisms underlying OUD will assist in developing improved prevention and intervention approaches. Behavioral economic demand has been extensively evaluated as a measure of reinforcer valuation for alcohol and cigarettes, whereas prescription opioids have received comparatively little attention. Objectives Utilize a purchase task procedure to measure the incremental validity and test-retest reliability of opioid demand. Methods Individuals reporting past year non-medical prescription opioid use were recruited using the crowdsourcing platform Amazon Mechanical Turk (mTurk). Participants completed an opioid purchase task as well as measures of cannabis demand, delay discounting, and self-reported pain. A 1-month follow-up was used to evaluate test-retest reliability. Results More intense and inelastic opioid demand was associated with OUD and more intense cannabis demand was associated with cannabis use disorder. Multivariable models indicated that higher opioid intensity and steeper opioid delay discounting rates each significantly and uniquely predicted OUD. Increased opioid demand intensity, but not elasticity, was associated with higher self-reported pain, and no relationship was observed with perceived pain relief from opioids. Opioid demand showed acceptable-to-good test-retest reliability (e.g., intensity rxx = .75; elasticity rxx = .63). Temporal reliability was lower for cannabis demand (e.g., intensity rxx = .53; elasticity rxx = .58) and discounting rates (rxx = .42–.61). Conclusions Opioid demand was incrementally valid and test-retest reliable as measured by purchase tasks. These findings support behavioral economic demand as a clinically useful measure of drug valuation that is sensitive to individual difference variables.

Anabolic androgenic steroid dependence is associated with impaired emotion recognition Abstract Rationale Illicit use of anabolic androgenic steroids (AAS) has grown into a serious public health concern throughout the Western World. AAS use is associated with adverse medical, psychological, and social consequences. Around 30% of AAS users develop a dependence syndrome with sustained use despite adverse side effects. AAS dependence is associated with a high frequency of intra- and interpersonal problems, and it is central to identify factors related to the development and maintenance of dependence. Methods The present study investigated the ability to recognize emotion from biological motion. The emotional biological motion task was administered to male AAS dependent users (AAS dependents; n = 45), AAS non-dependent users (AAS non-dependents; n = 38) and a comparison-group of non-using weightlifters (non-users; n = 69). Results Multivariate analysis of variance showed a general impairment in emotion recognition in AAS dependents, compared to the non-using weightlifters, whereas no significant impairment was observed in AAS non-dependents. Furthermore, AAS dependents showed impaired recognition of fearful stimuli compared to both AAS non-dependents and non-using weightlifters. The between-group effect remained significant after controlling for Intelligence Quotient (IQ), past 6 months of non-AAS drug use, antisocial personality problems, anxiety, and depression. Conclusion AAS dependents show impaired emotion recognition from body movement, fear in particular, which could potentially contribute to higher frequency of interpersonal problems and antisocial behaviors in this population.

An increase in plasma brain derived neurotrophic factor levels is related to n-3 polyunsaturated fatty acid efficacy in first episode schizophrenia: secondary outcome analysis of the OFFER randomized clinical trial Abstract Rationale N−3 polyunsaturated fatty acids (n−3 PUFA) influence multiple biochemical mechanisms postulated in the pathogenesis of schizophrenia that may influence BDNF synthesis. Objectives A randomized placebo-controlled study was designed to compare the efficacy of a 26-week intervention composed of either 2.2 g/day of n−3 PUFA or olive oil placebo, with regard to symptom severity in first-episode schizophrenia patients. The secondary outcome measure of the study was to describe the association between n−3 PUFA clinical effect and changes in peripheral BDNF levels. Methods Seventy-one patients aged 16–35 were enrolled in the study and randomly assigned to the following study arms: 36 to the EPA + DHA group and 35 to the placebo group. Plasma BDNF levels were assessed three times, at baseline and at weeks 8 and 26 of the intervention. BDNF levels were determined in plasma samples using Quantikine Human BDNF ELISA kit. Plasma BDNF level changes were further correlated with changes in the severity of symptoms in different clinical domains. Results A significantly greater increase in plasma BDNF levels was observed in the intervention compared to the placebo group (Cohen’s d = 1.54). Changes of BDNF levels inversely correlated with change in depressive symptoms assessed using the Calgary Depression Rating Scale in Schizophrenia (Pearson’s r = − 0.195; p = 0.018). Conclusions The efficacy of a six-month intervention with n−3 PUFA observed in first-episode schizophrenia may be related to an increase in BDNF levels, which may be triggered by the activation of intracellular signaling pathways including transcription factors such as cAMP-reactive element binding protein.