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Methamphetamine (METH) is a potent psychostimulant that disrupts cognitive and neurobiological functions in brain regions such as the prefrontal cortex (PFC) and hippocampus. Chronic METH use leads to altered synaptic plasticity, neuroinflammation, and mitochondrial dysfunction, contributing to methamphetamine use disorder (MUD). This study investigates gene expression changes following long-access intravenous METH self-administration in a rodent model. RNA sequencing (RNA-Seq) was conducted on PFC and hippocampal tissue to identify differentially expressed genes (DEGs) between METH-treated and control groups. We identified 41 DEGs in the PFC and 32 in the hippocampus, many involved in synaptic plasticity, immune response, and energy metabolism. Key findings included downregulation of mitochondrial function genes and upregulation of genes related to neural development and extracellular matrix organization, highlighting the profound transcriptional effects of METH. As a proof-of-concept, we explored individual gene expression variability in relation to economic demand for METH. Rats exhibiting higher demand showed distinct molecular profiles, including upregulation of genes linked to neural signaling and transcription regulation, such as Foxd1 and Cdh1. This preliminary analysis demonstrates that individual differences in drug-seeking correlate with unique gene expression patterns. These findings suggest that both group-level and individual molecular changes contribute to the neurobiological mechanisms of METH use. A better understanding of these individual differences could potentially inform the development of personalized therapeutic approaches for MUD.

Methamphetamine (meth) addicts often exhibit enduring cognitive and neural deficits that likely contribute to persistent drug seeking and the high rates of relapse. These deficits may be related to changes in the prefrontal cortex (PFC) and its glutamatergic projections to the nucleus accumbens (NAc). Here, we performed in vivo microdialysis in the PFC and NAc in rats following either meth self-administration or yoked-saline control histories to assess baseline glutamate (GLU) levels, or reinstatement-evoked GLU and dopamine (DA) efflux in both regions simultaneously under cue-induced, meth-primed, or combined cues+meth reinstatement conditions. Our results show that meth self-administration (1) reduced basal GLU levels in both the dmPFC and NAc, (2) concurrently increased dmPFC and NAc GLU efflux during reinstatement, and (3) increased DA efflux in the dmPFC, but not in the NAc, under all reinstatement conditions when compared with yoked-saline controls. These data demonstrate for the first time that a history of psychostimulant self-administration alters GLU homeostasis not only in the NAc, but also in the dmPFC, its primary GLU projection source. Furthermore, combined cues+meth-primed reinstatement conditions produced the most pronounced increases in mPFC and NAc extracellular GLU, suggesting that the cue and meth prime conditions are additive in promoting reinstatement. Finally, increased efflux of DA in the dmPFC, but not in the NAc, across reinstatement conditions suggests that DA release in the dmPFC may be an important mediator of drug seeking initiated by multiple relapse triggers.

Methamphetamine (METH) is an extremely addictive drug which continues to cause significant harm to individuals and communities. In the present study we trained male rats to self-administer METH for 20 days, followed by 9 days of foot shock exposure. All rats escalated their METH intake during the first 20 days. The rats that continued to self-administer METH in the presence of aversive stimuli were termed shock-resistant (SR), while those that reduced their intake were shock-sensitive (SS). RNA sequencing showed numerous differentially expressed genes (DEGs) in the prefrontal cortex, nucleus accumbens, dorsal striatum, and midbrain. Ingenuity pathway analysis linked DEGs to addiction-related mechanisms. We identified shared genes with similar expression patterns across four brain regions (SR: Fos and Ahsp; SS: Tet1, Cym, and Tmem30c). The identified genes play key roles in addiction-related brain functions, such as neuronal activity, stress response, and epigenetic regulation, and their importance in METH addiction is highlighted. These genes represent promising targets for developing new treatments aimed at reversing neuroadaptations caused by METH use.

Neural complexity correlates with one's level of consciousness. During coma, anesthesia, and sleep, complexity is reduced. During altered states, including after lysergic acid diethylamide (LSD), complexity is increased. In the present analysis, we examined whether low doses of LSD (13 and 26 µg) were sufficient to increase neural complexity in the absence of altered states of consciousness. In addition, neural complexity was assessed after doses of two other drugs that significantly altered consciousness and mood: delta-9-tetrahydrocannabinol (THC; 7.5 and 15 mg) and methamphetamine (MA; 10 and 20 mg). In three separate studies (N = 73; 21, LSD; 23, THC; 29, MA), healthy volunteers received placebo or drug in a within-subjects design over three laboratory visits. During anticipated peak drug effects, resting state electroencephalography (EEG) recorded Limpel-Ziv complexity and spectral power. LSD, but not THC or MA, dose-dependently increased neural complexity. LSD also reduced delta and theta power. THC reduced, and MA increased, alpha power, primarily in frontal regions. Neural complexity was not associated with any subjective drug effect; however, LSD-induced reductions in delta and theta were associated with elation, and THC-induced reductions in alpha were associated with altered states. These data inform relationships between neural complexity, spectral power, and subjective states, demonstrating that increased neural complexity is not necessary or sufficient for altered states of consciousness. Future studies should address whether greater complexity after low doses of LSD is related to cognitive, behavioral, or therapeutic outcomes, and further examine the role of alpha desynchronization in mediating altered states of consciousness.

Background Monitoring the scale of pharmaceuticals, illicit and licit drugs consumption is important to assess the needs of law enforcement and public health, and provides more information about the different trends within different countries. Community drug use patterns are usually described by national surveys, sales and seizure data. Wastewater-based epidemiology (WBE) has been shown to be a reliable approach complementing such surveys. Method This study aims to compare and correlate the consumption estimates of pharmaceuticals, illicit drugs, alcohol, nicotine and caffeine from wastewater analysis and other sources of information. Wastewater samples were collected in 2015 from 8 different European cities over a one week period, representing a population of approximately 5 million people. Published pharmaceutical sale, illicit drug seizure and alcohol, tobacco and caffeine use data were used for the comparison. Results High agreement was found between wastewater and other data sources for pharmaceuticals and cocaine, whereas amphetamines, alcohol and caffeine showed a moderate correlation. methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) and nicotine did not correlate with other sources of data. Most of the poor correlations were explained as part of the uncertainties related with the use estimates and were improved with other complementary sources of data. Conclusions This work confirms the promising future of WBE as a complementary approach to obtain a more accurate picture of substance use situation within different communities. Our findings suggest further improvements to reduce the uncertainties associated with both sources of information in order to make the data more comparable.

We recently reported that social choice-induced voluntary abstinence prevents incubation of methamphetamine craving in rats. This inhibitory effect was associated with activation of protein kinase-Cδ (PKCδ)-expressing neurons in central amygdala lateral division (CeL). In contrast, incubation of craving after forced abstinence was associated with activation of CeL-expressing somatostatin (SOM) neurons. Here we determined the causal role of CeL PKCδ and SOM in incubation using short-hairpin RNAs against PKCδ or SOM that we developed and validated. We injected two groups with shPKCδ or shCtrlPKCδ into CeL and trained them to lever press for social interaction (6 d) and then for methamphetamine infusions (12 d). We injected two other groups with shSOM or shCtrlSOM into CeL and trained them to lever press for methamphetamine infusions (12 d). We then assessed relapse to methamphetamine seeking after 1 and 15 abstinence days. Between tests, the rats underwent either social choice-induced abstinence (shPKCδ groups) or homecage forced abstinence (shSOM groups). After test day 15, we assessed PKCδ and SOM, Fos, and doublelabeled expression in CeL and central amygdala medial division (CeM). shPKCδ CeL injections decreased Fos in CeL PKCδ- expressing neurons, increased Fos in CeM output neurons, and reversed the inhibitory effect of social choice-induced abstinence on incubated drug seeking on day 15. In contrast, shSOM CeL injections decreased Fos in CeL SOM-expressing neurons, decreased Fos in CeM output neurons, and decreased incubated drug seeking after 15 forced abstinence days. Our results identify dissociable central amygdala mechanisms of abstinence-dependent expression or inhibition of incubation of craving.

We recently introduced an animal model of incubation of methamphetamine craving after choice-based voluntary abstinence in male rats. Here we studied the generality of this phenomenon to (1) female rats, and (2) male and female rats with a history of heroin self-administration. We first trained rats to self-administer palatable food pellets for 6 days (6 h per day) for either methamphetamine (0.1 mg/kg/infusion) or heroin (0.1 mg/kg/infusion) for 12 days (6 h/day). We then assessed relapse to drug seeking under extinction conditions after 1 and 21 abstinence days. Between tests, the rats underwent either voluntary abstinence (achieved via a discrete choice procedure between drug and palatable food; 20 trials/day) or home-cage forced abstinence. We found no sex differences in methamphetamine self-administration or in the strong preference for the palatable food over methamphetamine during the choice-based voluntary abstinence. In both sexes, methamphetamine seeking in the relapse tests was higher after 21 days of either voluntary or forced abstinence than after 1 day (incubation of methamphetamine craving). We also found no sex differences in heroin self-administration or the strong preference for the palatable food over heroin during the choice-based voluntary abstinence. However, male and female rats with a history of heroin self-administration showed incubation of heroin craving after forced but not voluntary abstinence. Our results show that incubation of methamphetamine craving after voluntary abstinence generalizes to female rats. Unexpectedly, prolonged voluntary abstinence prevented the emergence of incubation of heroin craving in both sexes.

Although inhaled exposure to drugs is a prevalent route of administration for human substance abusers, preclinical models that incorporate inhaled exposure to psychomotor stimulants are not commonly available. Using a novel method that incorporates electronic cigarette-type technology to facilitate inhalation, male Wistar rats were exposed to vaporized methamphetamine (MA), 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone (4-methylmethcathinone) in propylene glycol vehicle using concentrations ranging from 12.5 to 200 mg/ml. Rats exhibited increases in spontaneous locomotor activity, measured by implanted radiotelemetry, following exposure to methamphetamine (12.5 and 100 mg/ml), MDPV (25, 50, and 100 mg/ml), and mephedrone (200 mg/ml). Locomotor effects were blocked by pretreatment with the dopamine D1-like receptor antagonist SCH23390 (10 μg/kg, intraperitoneal (i.p.)). MA and MDPV vapor inhalation also altered activity on a running wheel in a biphasic manner. An additional group of rats was trained on a discrete trial intracranial self-stimulation (ICSS) procedure interpreted to assess brain reward status. ICSS-trained rats that received vaporized MA, MDPV, or mephedrone exhibited a significant reduction in threshold of ICSS reward compared with vehicle. The effect of vapor inhalation of the stimulants was found comparable to the locomotor and ICSS threshold-reducing effects of i.p. injection of mephedrone (5.0 mg/kg), MA (0.5-1.0 mg/kg), or MDPV (0.5-1.0 mg/kg). These data provide robust validation of e-cigarette-type technology as a model for inhaled delivery of vaporized psychostimulants. Finally, these studies demonstrate the potential for human use of e-cigarettes to facilitate covert use of a range of psychoactive stimulants. Thus, these devices pose health risks beyond their intended application for the delivery of nicotine.

Objectives. To evaluate trends and correlates of methamphetamine use in the United States. Methods. Data are from 15 747 334 drug-related treatment admissions among persons aged 12 years or older in the 2008–2017 Treatment Episode Data Set. We analyzed trends and used multivariable logistic regression. Results. Methamphetamine-related admissions increased from 15.1% of drug-related treatment admissions in 2008 to 23.6% in 2017. Increases occurred among nearly all demographic groups. Methamphetamine injection increased from 17.5% of admissions in 2008 to 28.4% in 2017. Among methamphetamine-related admissions, heroin use increased from 5.3% of admissions in 2008 to 23.6% in 2017. Characteristics associated with increased odds of reporting methamphetamine use at admission included female sex; admissions aged 35 to 44 years; admissions in the Midwest, South, and West; unemployment; not in labor force; living dependent; living homeless; and having a referral from criminal justice, a health care provider, or other community treatment source. Conclusions. Treatment admissions involving methamphetamine use increased significantly over the past decade and appear to be linked to the ongoing opioid crisis in the United States. Efforts to mobilize public health prevention, treatment, and response strategies to address rising methamphetamine use and overdose are needed.

ObjectivesThere is considerable public health concern about the combining of sex and illicit drugs (chemsex) among gay men. With a view to inform supportive therapeutic and clinical interventions, we sought to examine the motivations for engaging in chemsex among gay men living in South London.MethodsCommunity advertising recruited 30 gay men for qualitative semi-structured interview. Aged between 21 and 53 years, all lived in South London in the boroughs of Lambeth, Southwark and Lewisham and all had combined crystal methamphetamine, mephedrone and/or γ-hydroxybutyric acid/γ-butyrolactone with sex in the past 12 months. Transcripts were subjected to a thematic analysis.ResultsWe broadly distinguished two groups of reasons for combining sex and drugs, within which we described eight distinct motivations. The first major group of motivations for combining drugs with sex was that drugs provide the means by which men can have the sex they desire by increasing libido, confidence, disinhibition and stamina. The second major group of motivations for chemsex was that drugs enhance the qualities of the sex that men value. Drugs made other men seem more attractive, increased physical sensations, intensified perceptions of intimacy and facilitated a sense of sexual adventure.ConclusionAnalysis revealed that sexualised drug use provides both motivation and capability to engage in the kinds of sex that some gay men value: sex that explores and celebrates adventurism. Those services providing (talking) interventions to men engaging in chemsex should consider these benefits of sexualised drug use alongside the harms arising.