Modeling Developmental Changes in Caffeine Clearance Considering Differences between Pre- and Postnatal Period.

Taguchi et al. reported that postmenstrual age (PMA) is a promising factor in describing and understanding the developmental change of caffeine (CAF) clearance. The aim of the present study was to quantify how developmental changes occur and to determine the effect of the length of the gestational period on CAF clearance. We performed a nonlinear mixed effect model (NONMEM) analysis and evaluated the fit of six models. A total of 115 samples were obtained from 52 patients with a mean age of 34.3 ± 18.2 d. The median values of gestational age (GA) and postnatal age (PNA) were 196 and 31 d, respectively. Serum CAF levels corrected for dose per body surface area (BSA) (C/D ratioBSA) were dependent on PMA rather than PNA, which supports the findings of a previous study. NONMEM analysis provided the following final model of oral clearance: CL/F = 0.00603∙WT∙∙0.877GA ≤ 196 L/h. This model takes into account developmental changes during prenatal and postnatal periods separately. The model successfully described the variation in clearance of CAF. Our findings suggest that the dosage of CAF in preterm infants should be determined based not only on body weight (WT) but also on both PNA and GA.

Dexamphetamine increased speech and visual unimodal illusions in healthy participants without affecting temporal binding window.

OBJECTIVE: Stimuli received beyond a very short timeframe, known as temporal binding windows (TBWs), are perceived as separate events. In previous audio-visual multisensory integration (McGurk effect) studies, widening of TBWs has been observed in people with schizophrenia. The present study aimed to determine if dexamphetamine could increase TBWs in unimodal auditory and unimodal visual illusions that may have some validity as experimental models for auditory and visual hallucinations in psychotic disorders. METHODS: A double-blind, placebo-controlled, counter-balanced crossover design with permuted block randomisation for drug order was followed. Dexamphetamine (0.45 mg/kg, PO, q.d.) was administered to healthy participants. Phantom word illusion (speech illusion) and visual-induced flash illusion/VIFI (visual illusion) tests were measured to determine if TBWs were altered as a function of delay between stimuli presentations. Word emotional content for phantom word illusions was also analysed. RESULTS: Dexamphetamine significantly increased the total number of phantom words/speech illusions (p < 0.01) for pooled 220-1100 ms ISIs in kernel density estimation and the number of positive valence words heard (beta = 2.20, 95% CI [1.86, 2.55], t = 12.46, p < 0.001) with a large effect size (std. beta = 1.05, 95% CI [0.89, 1.22]) relative to placebo without affecting the TBWs. For the VIFI test, kernel density estimation for pooled 0-801 ms ISIs showed a significant difference (p < 0.01) in the data distributions of number of target flash (es) perceived by participants after receiving dexamphetamine as compared with placebo. CONCLUSIONS: Overall, healthy participants who were administered dexamphetamine (0.45 mg/kg, PO, q.d.) experienced increases in auditory and visual illusions in both phantom word illusion and VIFI tests without affecting their TBWs.

Brain connectivity changes to fast versus slow dopamine increases.

The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [11C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = -0.54, pspin < 0.001). GBC showed "fast>slow" associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and "slow>fast" associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex (pFDR < 0.05). "Fast>slow" GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [11C]SCH23390 binding; rho = 0.22, pspin < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported 'high' ratings to intravenous MP across individuals (r(19) = -0.68, pbonferroni = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.

ASSESSMENT OF SIMULATED SURGICAL DEXTERITY AFTER MODIFIABLE EXTERNAL EXPOSURES AMONG NOVICE VERSUS EXPERIENCED VITREORETINAL SURGEONS.

PURPOSE: To evaluate novice and senior vitreoretinal surgeons after various exposures. Multiple comparisons ranked the importance of these exposures for surgical dexterity based on experience. METHODS: This prospective cohort study included 15 novice and 11 senior vitreoretinal surgeons (<2 and >10 years' practice, respectively). Eyesi-simulator tasks were performed after each exposure. Day 1, placebo, 2.5 mg/kg caffeine, and 5.0 mg/kg caffeine; day 2, placebo, 0.2 mg/kg propranolol, and 0.6 mg/kg propranolol; day 3, baseline simulation, breathalyzer readings of 0.06% to 0.10% and 0.11% to 0.15% blood alcohol concentrations; day 4, baseline simulation, push-up sets with 50% and 85% repetitions maximum; and day 5, 3-hour sleep deprivation. Eyesi-generated score (0-700, worst-best), out-of-tolerance tremor (0-100, best-worst), task completion time (minutes), and intraocular pathway (in millimeters) were measured. RESULTS: Novice surgeons performed worse after caffeine (-29.53, 95% confidence interval [CI]: -57.80 to -1.27, P = 0.041) and alcohol (-51.33, 95% CI: -80.49 to -22.16, P = 0.001) consumption. Alcohol caused longer intraocular instrument movement pathways (212.84 mm, 95% CI: 34.03-391.65 mm, P = 0.02) and greater tremor (7.72, 95% CI: 0.74-14.70, P = 0.003) among novices. Sleep deprivation negatively affected novice performance time (2.57 minutes, 95% CI: 1.09-4.05 minutes, P = 0.001) and tremor (8.62, 95% CI: 0.80-16.45, P = 0.03); however, their speed increased after propranolol (-1.43 minutes, 95% CI: -2.71 to -0.15 minutes, P = 0.029). Senior surgeons' scores deteriorated only following alcohol consumption (-47.36, 95% CI: -80.37 to -14.36, P = 0.005). CONCLUSION: Alcohol compromised all participants despite their expertise level. Experience negated the effects of caffeine, propranolol, exercise, and sleep deprivation on surgical skills.

Development of a novel rodent rapid serial visual presentation task reveals dissociable effects of stimulant versus nonstimulant treatments on attentional processes.

The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task, a false-alarm image was included, so performance could be assessed relative to two types of nontarget distractors. The effects of acute administration of stimulant and nonstimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine, and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine, and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus nonstimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.

Amphetamine increases motivation of humans and mice as measured by breakpoint, but does not affect an Electroencephalographic biomarker.

Translation of drug targets from preclinical studies to clinical trials has been aided by cross-species behavioral tasks, but evidence for brain-based engagement during task performance is still required. Cross-species progressive ratio breakpoint tasks (PRBTs) measure motivation-related behavior and are pharmacologically and clinically sensitive. We recently advanced elevated parietal alpha power as a cross-species electroencephalographic (EEG) biomarker of PRBT engagement. Given that amphetamine increases breakpoint in mice, we tested its effects on breakpoint and parietal alpha power in both humans and mice. Twenty-three healthy participants performed the PRBT with EEG after amphetamine or placebo in a double-blind design. C57BL/6J mice were trained on PRBT with EEG (n = 24) and were treated with amphetamine or vehicle. A second cohort of mice was trained on PRBT without EEG (n = 40) and was treated with amphetamine or vehicle. In humans, amphetamine increased breakpoint. In mice, during concomitant EEG, 1 mg/kg of amphetamine significantly decreased breakpoint. In cohort 2, however, 0.3 mg/kg of amphetamine increased breakpoint consistent with human findings. Increased alpha power was observed in both species as they reached breakpoint, replicating previous findings. Amphetamine did not affect alpha power in either species. Amphetamine increased effort in humans and mice. Consistent with previous reports, elevated parietal alpha power was observed in humans and mice as they performed the PRBT. Amphetamine did not affect this EEG biomarker of effort. Hence, these findings support the pharmacological predictive validity of the PRBT to measure effort in humans and mice and suggest that this EEG biomarker is not directly reflective of amphetamine-induced changes in effort.

Collaborative rp-hplc method development for modafinil and scopolamine hydrobromide in sublingual tablets: involving key industry players

Objective: This research aims to develop and validate a collaborative RP-HPLC method, with input from key industry players, for the simultaneous determination of modafinil and scopolamine hydrobromide in compound sublingual tablets. The focus is on ensuring the safety and efficacy of these substances for enhancing the physical and cognitive fitness of athletes and players. Method: Utilizing a C18 chromatographic column (200mm×4.6mm, 5μm), the method employs a mobile phase of acetonitrile-water (25:75) with 0.02mol/L ammonium acetate and 0.02% triethylamine, pH adjusted to 6.0. The flow rate was set at 1 mL/min, detection at 225 nm wavelength, and an injection volume of 20 μL.Results: Scopolamine hydrobromide showed a linear range of 1-50 μg/mL, with a standard curve equation of A=0.2187C+0.0708 (R²=0.9993), and modafinil exhibited a range of 10-500 μg/mL, with A=0.6702C-1.6855 (R²=0.9993). Both substances demonstrated average recoveries of over 99%, within acceptable variance limits, signifying reliable quantification for fitness-related applications. Conclusion: The developed method is sensitive, precise, accurate, and reproducible, conforming to the standards of the Chinese Pharmacopoeia (2020 edition). It is particularly valuable for monitoring the quality of substances used by athletes and players to ensure their safe application in enhancing fitness and performance. The method benefits significantly from the collaboration with industry experts, addressing the specific needs of fitness and sports professionals (AU)

Estimulantes de tipo anfetamínico en estudiantes de medicina latinoamericanos: una revisión / Amphetamine-type stimulants in Latin American medicine students: a review

Introducción: el consumo de estimulantes de tipo anfetamínico (ETA) y sus derivados está cada vez más presente en los estudiantes universitarios y, en particular, en los programas de medicina. El objetivo principal de este estudio fue revisar la literatura sobre el uso de ETA y sus derivados en estudiantes de medicina latinoamericanos. Materiales y método: se realizó una revisión de la literatura disponible, utilizando las bases de datos PubMed, SciELO y LILACS. Se encontraron un total de 1.054 artículos, de los cuales 17 fueron seleccionados para esta revisión. Resultados: la revisión muestra, en general, una mayor frecuencia de uso de ETA en estudiantes de medicina de América Latina en comparación con la población general y estudiantes de otras carreras universitarias. También existe una tendencia a un mayor uso en hombres, de mayor nivel socioeconómico y en cursos posteriores del programa. La razón más informada para usar ETA fue aumentar el rendimiento académico. Como factor protector se destacaron los deportes, el tiempo en familia y la profesión de alguna creencia religiosa. De los artículos seleccionados, no se encontraron estudios sobre las consecuencias a largo plazo del uso de ETA en estudiantes de medicina. Discusión: en resumen, los estudiantes de medicina latinoamericanos tienen un alto consumo de ETA, por lo que es evidente la necesidad de nuevos estudios para mejorar la precisión estadística, determinar factores de riesgo específicos, estudiar las consecuencias a largo plazo y establecer políticas de prevención y tratamiento.

Introduction: the consumption of amphetamine-type stimulants (ATS) and their derivatives are increasingly present in university students and in particular in medical programs. The main objective of this study was to review the literature on the use of ATS and their derivatives in Latin American medical students. Materials and method: a review of the literature available was performed, using PubMed, SciELO, and LILACS databases. A total of 1054 articles were found, of which 17 were selected for this review. Results: the review generally shows a higher frequency of use of ATS in medical students of Latin America compared to the general population and students from other university degrees. There is also a tendency of a higher use in men, from higher socioeconomic status, and in later courses of the program. The most reported reason for using ATS was to increase the academic performance. As a protective factor, sports, family time and professing some religious belief stood out. Of the selected articles, no studies were found on the long-term consequences of the use of ATS in medical students. Discussion: in summary, Latin American medical students have a high consumption of ATS, and therefore there is an evident need for new studies to improve statistical precision, to determine specific risk factors, to study long-term consequences, and to stablish prevention policies and treatment.

Aminophylline in combination with caffeine citrate in neurodevelopmental treatment and follow-up of high-risk preterm infants using GMs assessment.

To explore the application effect of aminophylline combined with caffeine citrate and GMs in the evaluation of neurodevelopmental treatment and follow-up in high-risk preterm infants. A retrospective analysis of 66 high-risk preterm infants admitted to Hengshui People's Hospital from January 2020 to June 2021 was conducted. The children who received only conventional treatment were set as the control group, while those who received aminophylline and caffeine citrate on the basis of conventional treatment were set as the experimental group, 33 cases each group; GMs were used to evaluate the neurodevelopmental function of the children, and the treatment effect was analyzed. The normal proportion of GMs assessment results in the twisting phase and restless movement phase of the experimental group was superior to the control group (P<0.05); The proportion of children with normal neurodevelopment in the experimental group was significantly higher than that in the control group (P<0.05). Aminophylline in combination with caffeine citrate can help promote the neurodevelopment of children and improve their physical health using GMs assessment in the treatment and follow-up of high-risk preterm infants.

Methylphenidate and Other Pharmacologic Treatments for Apathy in Alzheimer's Disease.

Apathy is a common and important yet often ignored neuropsychiatric symptom of Alzheimer's disease (AD). Cholinesterase inhibitors and memantine, used to treat AD, appear ineffective against apathy. A meta-analysis of 4 randomized, placebo-controlled trials (RCTs) found that psychostimulants significantly attenuated apathy ratings in AD. However, the pooled sample size in this meta-analysis was just 156, and one of the trials was a 2-week crossover study with a large effect. A large RCT (n = 200) has now been published. This study found that methylphenidate (MPH; 20 mg/d) was superior to placebo in the attenuation of apathy scores in patients with possible or probable, mild to moderate AD; the advantage was evident by the end of the second month of treatment and remained evident to the end of 6 months. The effect size at 6 months was small (Cohen d = 0.37). In this RCT, disappointingly, MPH was not superior to placebo on secondary outcomes, including informant-rated apathy, dependence, activities of daily living, quality of life, and neurocognitive performance; caregiver burden was not formally studied. Speculatively, the psychosocial intervention provided to all participants in this RCT may have boosted response in the placebo group, thereby attenuating differences in outcomes between the MPH and placebo groups. A reasonable conclusion is that whereas MPH may attenuate the severity of apathy in patients with AD across as long as 6 months, the absence of improvements in measures of dependence, activities of daily living, and quality of life suggest that this effect of MPH on apathy may not be clinically significant. An unanswered question is whether the benefits of MPH may be clinically significant in real world practice settings in which the delivery of behavioral interventions is not feasible.

Reassessment of amphetamine- and phencyclidine-induced locomotor hyperactivity as a model of psychosis-like behavior in rats.

Locomotor hyperactivity induced by psychotomimetic drugs, such as amphetamine and phencyclidine, is widely used as an animal model of psychosis-like behaviour and is commonly attributed to an interaction with dopamine release and N-methyl-D-aspartate (NMDA) receptors, respectively. However, what is often not sufficiently taken into account is that the pharmacological profile of these drugs is complex and may involve other neurotransmitter/receptor systems. Therefore, this study aimed to assess the effect of three antagonists targeting different monoamine pathways on amphetamine- and phencyclidine-induced locomotor hyperactivity. A total of 32 rats were pre-treated with antagonists affecting dopaminergic, noradrenergic and serotonergic transmission: haloperidol (0.05 mg/kg), prazosin (2 mg/kg) and ritanserin (1 mg/kg), respectively. After 30 min of spontaneous activity, rats were injected with amphetamine (0.5 mg/kg) or phencyclidine (2.5 mg/kg) and distance travelled, stereotypy and rearing recorded in photocell cages over 90 min. Pre-treatment with haloperidol or prazosin both reduced amphetamine-induced hyperactivity although pre-treatment with ritanserin had only a partial effect. None of the pre-treatments significantly altered the hyperlocomotion effects of phencyclidine. These findings suggest that noradrenergic as well as dopaminergic neurotransmission is critical for amphetamine-induced locomotor hyperactivity. Hyperlocomotion effects of phencyclidine are dependent on other factors, most likely NMDA receptor antagonism. These results help to interpret psychotomimetic drug-induced locomotor hyperactivity as an experimental model of psychosis.

The effects of alcohol drinking on subsequent methamphetamine self-administration and relapse in adolescent female rats.

Alcohol and Methamphetamine (Meth) are widely abused drugs that are frequently co-abused, though this pattern of polysubstance abuse is rarely studied. Alcohol use during adolescence is associated with subsequent Meth dependence in humans and female adolescents may be more vulnerable than males to serial alcohol and Meth use. However, it is unknown if prior alcohol drinking impacts subsequent Meth-taking in female rats. This study uses a novel method of serial voluntary alcohol drinking and Meth self-administration in female adolescent Sprague Dawley rats (n = 35) to model human patterns of co-abuse. Rats demonstrated a steady time-based increase in alcohol preference versus water, starting at 33.3 ± 3.4% on day 1-48.0 ± 3.6% by the final day of EtOH, with a peak EtOH preference of 49.7 ± 3.7% on day 17 of the drinking paradigm (P < 0.001, one-way repeated measures ANOVA). All rats rapidly acquired Meth self-administration, demonstrating a 4.6 ± 1.4 fold increase in active presses for Meth and a 5.2 ± 1.8 fold increase in Meth intake (mg/kg) within 7 days, and maintained high levels of Meth intake throughout 21 days of self-administration. Prior alcohol drinking did not alter the increase in Meth self-administration compared to alcohol naïve control rats. However, after 7 days of Meth abstinence, a history of alcohol drinking reduced cue-primed reinstatement of Meth seeking. These findings demonstrate that prior alcohol consumption does not alter overall Meth self-administration but does persistently reduce cue-primed Meth seeking after prolonged alcohol abstinence.

Chronic treatment and abstinence from methylphenidate exposure dose-dependently changes glucose metabolism in the rat brain.

Methylphenidate (MP) is extensively prescribed for attention deficit hyperactivity disorder (ADHD). While MP is effective in ameliorating symptoms of ADHD, MP is also used illicitly among healthy subjects without ADHD for cognitive-enhancing purposes. The deleterious consequences associated with long-term MP use as well as its cessation on brain activity remains to be understood. To address this, we administered either water, low dose MP (LD MP), or high dose MP (HD MP) to healthy adolescent Sprague Dawley rats, with five days on the treatment and two days off for thirteen consecutive weeks. Rats were then abstinent from their respective treatments for four weeks. Using positron emission tomography (PET) and fluorodeoxyglucose [18F] (FDG), we scanned rats at three time points: after thirteen weeks of treatment, after one week of abstinence, and after four weeks of abstinence. After thirteen weeks of LD and HD MP treatment, increases in brain glucose metabolism (BGluM) were seen in several cortical and subcortical regions associated with sensory and motor functions as well as learning and memory. One-week abstinence from LD MP treatment promoted increased BGluM compared to both water treated and HP MP treated groups. After four weeks of abstinence, little group differences were seen. Longitudinally, we observed contrasting differences on BGluM depending on whether a LD or HD of MP was administered. Our results demonstrate that MP treatment during adolescence can significantly alter BGluM. Moreover, these changes in brain activity do not subside in many areas of the brain after both one and four-week drug abstinence.

Effects of synthetic cathinone naphyrone in the conditioned place preference test - Evidence of its addictive potential.

Naphyrone, also known as NRG-1, is a novel psychoactive substance (NPS), a cathinone with stimulatory properties available on the grey/illicit drug market for almost a decade. It is structurally related to infamously known powerful stimulants with the pyrovalerone structure, such as alpha-pyrrolidinovalerophenone (α-PVP) or methylenedioxypyrovalerone (MDPV) that are labeled as a cheap replacement for cocaine and other stimulants. Despite the known addictive potential of α-PVP and MDPV, there are no studies directly evaluating naphyrone's addictive potential e.g., in conditioned place preference (CPP) test or using self-administration. Therefore, our study was designed to evaluate the addictive potential in a CPP test in male Wistar rats and compare its effect to another powerful stimulant with a high addictive potential - methamphetamine. Naphyrone increased time spent in the drug-paired compartment with 5 and 20 mg/kg s.c. being significant and 10 mg/kg s.c. reaching the threshold (p = 0.07); the effect was comparable to that of methamphetamine 1.5 mg/kg s.c. The lowest dose, naphyrone 1 mg/kg s.c., had no effect on CPP. Interestingly, no dose response effect was detected. Based on these data, we are able to conclude that naphyrone has an addictive potential and may possess a significant risk to users.

Differential effects of intra-ventral tegmental area ghrelin and glucagon-like peptide-1 on the stimulatory action of D-amphetamine and cocaine-induced ethanol intake in male Sprague Dawley rats.

In order to further elucidate the role of mesolimbic peptides in the expression of ethanol reward, the present study investigated the effects of ghrelin and glucagon-like peptide-1 (GLP-1) on ethanol intake, in addition to ethanol intake stimulated by systemic d-amphetamine or cocaine treatment. While a number of studies suggest that ghrelin plays an important role in mesolimbic reward, emerging data now indicate that GLP-1 receptor mechanisms inhibit reward signaling, possibly by directly or indirectly inhibiting ghrelinergic activity within the mesolimbic system. In the present study all rats were initially habituated to a 6% ethanol solution. We then demonstrated that intraperitoneal injections of d-amphetamine and cocaine increased ethanol intake compared to the vehicle condition. In subsequent testing we examined the effects of ventral tegmental area (VTA) ghrelin or vehicle paired with a fixed dose of d-amphetamine or vehicle. In separate rats we then investigated the impact of the GLP-1 agonist exendin-4 (Ex-4), injected into the VTA, on ethanol intake alone, or when Ex-4 was co-administered with d-amphetamine or cocaine. Our results indicated that VTA ghrelin significantly increased ethanol intake, and most importantly, potentiated the effect of d-amphetamine and cocaine on ethanol consumption. Conversely, VTA Ex-4 inhibited ethanol intake and antagonized the stimulatory effect of d-amphetamine and cocaine on ethanol consumption. In a final study we further demonstrated that VTA Ex-4 treatment significantly inhibited the combined stimulatory effects of ghrelin paired with d-amphetamine or ghrelin paired with cocaine. Overall our findings are consistent with a critical role for both ghrelin and GLP-1 receptor mechanisms in mesolimbic ethanol reward circuitry. Moreover, our results further suggest that ghrelin and GLP-1 modulate the stimulatory effect of psychostimulants on ethanol intake.

The abuse potential of prolintane in rodents: Behavioral pharmacology approaches.

Prolintane (1-Phenyl-2-pyrrolidinylpentane), a synthetic central nervous system (CNS) stimulant, is structurally similar to amphetamine but pharmacologically acts as a dopamine reuptake inhibitor like cocaine. While several case studies reported adverse effects and recreational use of prolintane, the abuse potential of the drug has not been systemically examined yet. In the present study, we evaluated the behavioral effects of prolintane regarding its abuse liability in rodents using locomotor activity, conditioned place preference (CPP), self-administration (SA), and drug discrimination paradigms, as well as in-vivo microdialysis experiment. First, acute prolintane (10 and 20 mg/kg, intraperitoneal injection) increased locomotor activity (distance traveled, cm) in mice but to a lesser degree than methamphetamine (as a positive control). We also found that a single and solitary injection of prolintane (20 mg/kg, IP) significantly increased extracellular dopamine in the striatum. The following result suggests that its stimulatory effects might be associated with the mesolimbic dopaminergic pathway. Further, prolintane produced a significant drug-paired place preference at doses of both 10 and 20 mg/kg. In the SA experiment, the mice that self-administered prolintane intravenously (4 mg/kg/inf) showed a higher infusion and active lever responses but not inactive lever responses. Additionally, cumulative doses of prolintane partially elicited cocaine-appropriate lever responses (38.57% at doses up to 10 mg/kg) in rats. These results implied that prolintane has not only rewarding and reinforcing effects but also interoceptive stimulus properties, which are similar to cocaine at a moderate level. Taken together, this study was the first to show, to our knowledge, that prolintane has a certain level of abuse potential and should be considered carefully as a valuable basis for legal restrictions on use.

Role of neuropeptide neuromedin U in the nucleus accumbens shell in cocaine self-administration in male rats.

The nucleus accumbens shell (NAcSh) and its afferent and efferent neuronal projections control key aspects of motivation for cocaine. A recently described regulator of γ-aminobutyric acid (GABA) projections from the dorsal raphe nucleus (DRN) to the NAcSh (DRN → NAcSh) is the neuropeptide neuromedin U (NMU). Here, we find that systemic administration of NMU decreases breakpoint for cocaine on a progressive ratio schedule of reinforcement in male rats. Employing a retrograde adeno-associated virus (AAV), we found that RNAi-mediated knockdown of the NMU receptor 2 (NMUR2) in afferent DRN projections to the NAcSh increases the breakpoint for cocaine. Our previous studies demonstrated that NMU regulates GABA release in the NAcSh, and our current investigation found that systemic NMU administration suppresses cocaine-evoked GABA release in the NAcSh and increases phosphorylated c-Fos expression in neurons projecting from the NAcSh to the ventral pallidum (VP). To further probe the impact of NMU/NMUR2 on neuroanatomical pathways regulating motivation for cocaine, we employed multi-viral transsynaptic studies. Using a combination of rabies virus and retrograde AAV helper virus, we mapped the impact of NMU across three distinct brain regions simultaneously and found a direct connection of GABAergic DRN neurons to the NAcSh → VP pathway. Together, these data reveal that NMU/NMUR2 modulates a direct connection within the GABAergic DRN → NAcSh → VP circuit that diminishes breakpoints for cocaine. These findings importantly advance our understanding of the neurochemical underpinnings of pathway-specific regulation of neurocircuitry that may regulate cocaine self-administration, providing a unique therapeutic perspective.

Sex differences in inflammatory cytokine levels following synthetic cathinone self-administration in rats.

Synthetic cathinones are used as stimulants of abuse. Many abused drugs, including stimulants, activate nuclear factor-κB (NF-κB) transcription leading to increases in NF-κB-regulated pro-inflammatory cytokines, and the level of inflammation appears to correlate with length of abuse. The purpose of this study was to measure the profile of IL-1α, IL-1ß, IL-6, CCL2 and TNF-α in brain and plasma to examine if drug exposure alters inflammatory markers. Male and female Sprague-Dawley rats were trained to self-administer α-pyrrolidinopentiophenone (α-PVP) (0.1 mg/kg/infusion), 4-methylmethcathinone (4MMC) (0.5 mg/kg/infusion), or saline through autoshaping, and then self-administered for 21 days during 1 h (short access; ShA) or 6 h (long access; LgA) sessions. Separate rats were assigned to a naïve control group. Cytokine levels were examined in amygdala, hippocampus, hypothalamus, prefrontal cortex, striatum, thalamus, and plasma. Rats acquired synthetic cathinone self-administration, and there were no sex differences in drug intake. Synthetic cathinone self-administration produced sex differences in IL-1α, IL-1ß, IL-6, CCL2 and TNF-α levels. There were widespread increases in inflammatory cytokines in the brains of male rats compared to females, particularly for 4MMC, whereas females were more likely to show increased inflammatory cytokines in plasma compared to saline groups than males. Furthermore, these sex differences in cytokine levels were more common after LgA access to synthetic cathinones than ShA. These results suggest that synthetic cathinone use likely produces sex-selective patterns of neuroinflammation during the transition from use to abuse. Consequently, treatment need may differ depending on the progression of synthetic cathinone abuse and based on sex.