Psychopharmacology最新文献

Background: In this study, we investigated transcranial magnetic stimulation (TMS)-derived markers of excitability and inhibition in methamphetamine (METH) use disorder.

Methods: Sixteen methamphetamine users and 20 matched controls underwent psychological assessments, revised form of Symptom Checklist-90-Revised, cognitive assessment, anxiety and depression scales and TMS measures, including resting and active motor thresholds (RMT and AMT), motor evoked potential amplitude (MEP-A), cortical silent period (CSP), and short-interval intracortical inhibition (SICI).

Results: METH users reported higher anxiety, depression, and somatization (p < 0.001), while cognition remained preserved. They exhibited reduced RMT and AMT (p < 0.001), indicating increased excitability, with no significant differences in MEP-A (p = 0.083). CSP onset latency was prolonged at 150% RMT (p = 0.042), suggesting impaired inhibition. Excitability thresholds correlated negatively with methamphetamine dose, while addiction duration was linked to CSP changes and obsessive-compulsive symptoms. Lower thresholds also correlated with greater interpersonal sensitivity and addiction severity.

Conclusion: Increased cortical excitability and decreased inhibitory control are linked to METH usage, and these factors may be underlying psychiatric symptoms. TMS-derived indices show potential as biomarkers for neurophysiological monitoring and targeted interventions in methamphetamine use disorder.

Rationale: Interoceptive sensations elicited by psychoactive substances can acquire incentive motivational properties via learned associations with other reinforcers. Moreover, interoceptive drug states have been linked to and can predict their own reinforcing action.

Objectives: Given these interactions between the interoceptive and reinforcing properties of drugs, the current study tested the hypothesis that the learned significance of an interoceptive drug stimulus can enhance its reinforcing action.

Methods: To investigate this, the interoceptive stimulus properties of morphine were trained as a positive or negative occasion setter that signaled the presence or absence of an appetitive (auditory stimulus-sucrose) association, respectively. Then, intravenous morphine self-administration was conducted to assess aspects of morphine reinforcement.

Results: When the interoceptive effects of morphine were learned to facilitate the activation of an appetitive Pavlovian association, it acquired reinforcing properties such that it promoted robust acquisition of lever discrimination, enhanced morphine-seeking under escalating response requirements, and maintained responding in the absence of reinforcement. Conversely, when the interoceptive properties of morphine were learned to facilitate the suppression of the appetitive association, it acquired inhibitory properties, such that it attenuated responding across extinction as well as during reinstatement assessment compared to controls.

Conclusions: Thus, through mechanisms of associative learning, in addition to resolving reward-predictive stimulus ambiguity, the interoceptive effects of morphine can acquire altered reinforcing properties. These findings highlight that the learned significance of a drug's interoceptive effects can alter its subsequent reinforcing efficacy, and that occasion setting serves as a mechanism of learning through which this can occur.

Rationale: Opioid addiction, including morphine use, is a major public health crisis in the U.S. It has been associated with brain volume changes in reward-related regions, neuronal loss, and neuroinflammation. While these alterations have been studied separately, it remains unclear whether structural changes co-occur with microglial adaptations at early stages of morphine use.

Objective: This study aimed to examine region-specific brain volume changes, cellular counts, and the emergence of distinct microglial phenotypes in addiction-related regions, using a model of morphine self-administration that simulates the early phase of morphine consumption.

Methods: Male Wistar rats were trained to self-administer morphine (0.01 mg/kg/inf) for 20 days in 3-hour daily sessions under operant conditioning. Structural MRI was conducted before and after the self-administration period, and brain volume was quantified using deformation-based morphometry. Brain tissue was immunolabeled for Iba1 and NeuN, and confocal microscopy images of microglia were analyzed using principal component analysis and K-means clustering.

Results: Morphine self-administration produced volume increases in the globus pallidus and reductions in the insular cortex. Microglial density was elevated in these regions and other addiction-related areas, including the caudate-putamen and dentate gyrus, without significant variations in neuronal count but with a marked reduction in neuronal soma size in these latter regions. Clustering revealed diverse microglial phenotypes, including intermediate morphologies, with region-dependent distributions indicative of diverse neuroinflammatory states.

Conclusions: These findings suggest that morphine-induced brain volume changes during the early stages of consumption are not attributable to neuronal loss but may reflect adaptive processes involving neuronal restructuring and microglial remodeling. Microglial phenotyping emerges as a sensitive approach for detecting neuroinflammatory patterns linked to addiction vulnerability.

Rationale: Nicotine addiction is characterized by escalated drug use, craving and a high relapse rate after abstinence. Recently, we showed that, compared to rats with a fixed moderate dose of nicotine, rats with access to increasing high doses of nicotine for self-administration progressively escalated their nicotine intake. Whether these animals with escalating patterns of nicotine self-administration also develop other behavioral signs of addiction remains to be investigated.

Results: Here we report that after escalation of nicotine intake, animals have a greater difficulty of abstaining from seeking the drug, a greater responsiveness to nicotine-induced craving-like behavior, and an increased vulnerability to re-escalate nicotine intake post-extinction than rats with stable patterns of nicotine intake. No substantial sex differences in the development of these different addiction-related phenomena were observed. Finally, after escalation, nicotine intake also became primarily dependent on nicotine reinforcement and less so on the nicotine-paired cue.

Conclusions: Overall, this study shows that most of the behavioral changes observed following escalation of nicotine self-administration are similar to those previously observed with other drugs of abuse.

The Incentive Sensitization Theory (IST) of addiction posits that repeated intermittent exposure to potentially addictive drugs can sensitize brain mesolimbic dopamine systems. Those systems normally attribute incentive salience to rewards and their cues, but when sensitized may produce compulsive cue-triggered 'wanting' for drugs that can persist long after the discontinuation of drug use and the cessation of withdrawal symptoms, thus contributing to an enduring propensity to relapse. Much of the original evidence for IST came from studies on psychostimulant drugs, such as amphetamine and cocaine. But can IST account for addiction to opioid drugs as well? Several serious objections have been raised as to whether pathological 'wanting' for opioids involves dopamine sensitization, as posited by IST, thus suggesting IST does not apply to opioid addiction. Here we assess those objections and provide a review of evidence from the opioid literature on both human and non-human animals relevant to IST. We first summarize the main tenets of IST and the major objections to IST regarding opioid use disorder and addiction. We then address the following specific questions. (1) Do opioid drugs engage mesolimbic systems, including dopamine? (2) Do opioid drugs sensitize those dopamine systems? (3) Do opioid drugs also sensitize the incentive motivational effects of drugs and their cues, to produce incentive-sensitization and excessive 'wanting'? (4) Is dopamine necessary for opioid self-administration. We conclude that the answer to the question posed in the title of this paper is 'yes', even though there remain significant gaps in this literature that need to be filled by future studies.

Background: Attention-deficit/hyperactivity disorder (ADHD), a highly prevalent neurodevelopmental disorder among children, is directly associated with impairments in cognition and memory. In the nervous system, autophagy is essential for the development of neurons, the formation and remodeling of synapses, and the transmission of neurotransmitters. The 3-methyladenine (3-MA), an autophagy inhibitor, mitigates cognitive and memory impairment in neurological disorders. This study aimed to investigate the potential role of 3-MA in ADHD.

Methods: An ADHD model was established in offspring mice by intraperitoneal injection of S-ketamine during mid-to-late gestation. Postnatal day 14 offspring received intraperitoneal 3-MA (15 mg/kg/day) or vehicle for 7 consecutive days. To assess behavioral, electrophysiological, and pathological changes in mice, several tests were employed, including the open field test (OFT), novel object recognition (NOR) test, fear conditioning (FC), local field potential recording, western blot, transmission electron microscopy and immunofluorescence assays.

Results: Compared to controls, ADHD model mice exhibited: Increased total distance in OFT, Decreased recognition index in NOR, Reduced context- and cue-related freezing time in FC and Attenuated theta oscillation power in the prefrontal cortex. RNA sequencing revealed significant enrichment of the PI3KC3 pathway and autophagy-related genes. ADHD model mice showed upregulated autophagy-related protein expression, elevated LC3II/I ratio, increased autophagosomes, and accumulated abnormal organelles in the mPFC. TH-positive neurities and PSD95-positive puncta were significantly reduced in the mPFC. 3-MA treatment partially reversed these alterations.

Conclusion: Cognitive and memory impairments in the mPFC due to ADHD are correlated with autophagy, and these impairments might be alleviated by 3-MA.

Rationale: While around 50% of the risk for developing Alcohol Use Disorder (AUD) has been determined to be genetic, examining predictors of addictive-like behavior and individual variance in models without a family history of addiction is also important. Impaired reward sensitivity and response to natural reward may play a role in an individual's propensity to develop alcohol addiction. Little research has been done on predictors of alcohol addiction without food or water deprivation to coax animals into addiction.

Objectives: This study seeks to examine psychological and behavioral predictors of alcohol addiction in non-food restricted rats and determine whether sucrose seeking, consumption, and reward sensitivity relates to later motivation and reward-sensitivity related functions for ethanol.

Methods: This study examined the appetitive and consummatory behavior of female Wistar rats in self-administration tasks using sucrose and ethanol solutions and ad-libitum access to food and water. Varying time of access for sucrose was utilized to evaluate reward sensitivity analyzing inter-session and intra-session measures.

Results: Operant sucrose consumption predicted both 15% and 30% ethanol consumption in the home cage during 30-min exposure. Animals expressed key differences in reward sensitivity between natural and drug reward including lack of reward discrimination for sucrose during consumption along with different profiles of responding for sucrose and ethanol during the anticipatory motivated actions.

Conclusions: Using more precise measures of natural reward sensitivity could provide key insight into vulnerability to develop substance use disorders.

Rationale: Prenatal exposure to infection is a risk factor for neuropsychiatric disorders that often co-occur with alcohol misuse. However, the mechanisms by which early exposure to infection might increase the risk of such disorders remains unclear. One hypothesis is that prenatal stressors interact with adolescent stressors (i.e., "two-hits") to promote alcohol misuse development.

Objectives: The current project tested whether maternal immune activation (MIA) combined with adolescent alcohol exposure (AA) increases the motivation to work for alcohol and negative affect in adulthood, and whether prenatal antioxidant treatment prevents these effects.

Methods: Pregnant Sprague-Dawley rats were exposed to poly(I: C) (4 mg/kg) or saline on gestational day 15, and the antioxidant n-acetylcysteine (NAC; 100 mg/kg) or saline 24 h before and after poly(I: C). Offspring had 24-hour access to 10% ethanol and water during adolescence. In adulthood, offspring were trained to self-administer 10% ethanol and tested on escalating schedules of reinforcement. Elevated plus maze (EPM) behavior was assessed on non-self-administration days.

Results: Poly(I: C) and NAC treatment independently led to an increased willingness to work for alcohol in males, but not females, relative to same-sex controls. NAC treatment suppressed the MIA-induced increase in alcohol-seeking. Poly(I: C) increased locomotor activity in the EPM in both sexes, independent of NAC, without altering open or closed arm time.

Conclusions: These data support the hypothesis that MIA-induced oxidative stress negatively influences development, leaving the brain more susceptible to the negative effects of AA, and increasing the risk of alcohol misuse in adulthood, particularly in males.