Psychopharmacology最新文献

Pigeons show a suboptimal choice for probabilistic reinforcement in the presence of informative stimuli, which has been proposed as an animal model of gambling. However, this behaviour has been difficult to replicate in rats. In our study, rats responded on alternatives that provided 50% or 100% reinforcement with half of the sessions reliably signalled and half un-signalled. Contrary to expectation, rats preferred the optimal alternative to a greater extent in the signalled sessions compared to the un-signalled sessions. Acute methamphetamine increased preference for the 50% alternative exclusively in signalled sessions. These results suggest that rats, unlike pigeons, are able to use the information provided by the stimulus correlated with non-reinforcement to shift preference away from the suboptimal alternative, and that the influence of methamphetamine on rats' probabilistic choice is context dependent.

Rationale: Dopamine and opioids modulate the "wanting" and "liking" components of reward processes, yet their specific roles in social and human-animal interactions (HAIs) remain unclear.

Objectives: In this pilot study, we aimed to disentangle the roles of dopamine and opioids during HAIs, contrasting them with food reward and novel object test scenarios. We investigated these neurotransmitter systems as proximate mechanisms for "wanting" and "liking" behaviours in domesticated pigs. Additionally, there is a significant knowledge gap on the optimal dosage for the dopamine D2/D3 receptor antagonist amisulpride and mu-opioid receptor antagonist naloxone.

Methods: We administered amisulpride orally and naloxone intranasally at three dosage levels to 30 female pigs using a within-subject design. Each treatment (drug × dose level) was administered prior to 10-min interaction sessions with a familiar human.

Results: Both the high doses of amisulpride (800 mg) and naloxone (80 mg/ml) significantly increased pigs' latency to first contact with the human compared to pre-test, suggesting both systems modulate the motivation ("wanting") to interact. However, neither influenced the time pigs spent in contact with the human, contrary to our prediction that blocking opioids would decrease this behaviour as an indicator of the pleasurability ("liking") of the interaction.

Conclusion: These altered reward-related behaviours along with the absence of side-effects are the first indicators for the safe and effective use of amisulpride and naloxone to non-invasively study reward mechanisms in domesticated animals.

Rationale: Fear memories are essential for survival, but their inappropriate expression can contribute to anxiety disorders, phobias, and post-traumatic stress disorders that can present differently between the sexes. Memory reconsolidation is a process through which previously stored memories can be modified upon reactivation. The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway regulates neuronal gene transcription and is involved in synaptic plasticity and memory formation. Evidence suggests possible sex differences in the neurobiological mechanisms underlying fear responses and memory processes. However, its involvement in the reconsolidation of contextual fear conditioning (CFC) memory in male and female rats remains unclear.

Objective: To investigate the involvement of the MAPK/ERK pathway in the CA1 region of the dorsal hippocampus during CFC memory reconsolidation in male and female Wistar rats.

Methods: The role of the MAPK/ERK pathway was evaluated by infusing the selective inhibitor U0126 (0.04 µg/side) into the hippocampus at different time points after the reactivation session.

Results: The results demonstrated that, in both male and female rats, the inhibition of the MAPK/ERK pathway in the CA1 region impaired the CFC memory reconsolidation when administered immediately and 3 h after the reactivation session. However, this effect was not observed when administered 6 h later.

Conclusions: These findings indicate the involvement of the MAPK/ERK signaling pathway in the CA1 region of the hippocampus in the reconsolidation of contextual fear conditioning memory in male and female rats and provide new insights into the molecular mechanisms underlying memory reconsolidation, highlighting a common molecular mechanism across sexes.

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.