Addiction neuroscience最新文献

Alcohol and other drug pharmacology, including acute effects and mechanisms leading to drug seeking and addiction, has been extensively studied. Glial cells are critical for the proper development and function of the brain, and their reactivity is often an early signature of neurodegenerative and psychiatric disorders. Alcohol and other drugs have an impact on glial cells and promote a reactive glial state with cross-talk between neurons and glia. In this review, we summarize the major findings on the involvement of glial cells, particularly astrocytes, microglia and oligodendrocytes, in the effects of alcohol and other drugs on the brain. We focus on the contribution of imaging modalities, particularly Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI), to understanding these mechanisms in the living brain. We analyze the role of glia in the cerebral effects of alcohol and other drugs through various ways including glutamate homeostasis, neuroinflammatory process, myelin and white matter integrity and blood-brain barrier permeability. A review of targets, radioligands, and methods used or needed in PET and MRI is presented and discussed. The analyze of PET and MRI studies confirms the need for more selective radioligands and more appropriate methods that selectively target different glial cell types.

Early life stress (ELS) is a major risk factor for alcohol use disorder (AUD) and comorbid neuropsychiatric conditions. We previously demonstrated that an adolescent social isolation (aSI) model of ELS significantly increased behavioral risk factors for these disorders (e.g. anxiety-like behaviors, alcohol drinking) in male, but not female rats. Since many neurodevelopmental milestones are accelerated in females, we investigated whether an earlier/shorter isolation window (PND 21-38) would yield comparable phenotypes in both sexes. In two experiments, Long Evans rats were socially isolated (SI) or group-housed (GH) on postnatal day (PND) 21 and locomotion was assessed in the open field test (OFT; PND 30). Experiment 1 also assessed behavior on the elevated plus-maze (EPM) (PND 32). In Experiment 2, all rats were single housed on PND 38 to assess home cage alcohol drinking. Experiment 1 revealed that SI females had increased locomotor activity in the OFT but did not differ from GH subjects on the EPM. The OFT results were replicated in both sexes in Experiment 2 and both male and female SI rats had significantly greater ethanol consumption during an eight day continuous access paradigm. In contrast, during subsequent intermittent two-bottle choice drinking, only SI females displayed greater ethanol intake and preference and increased consumption of a quinine-adulterated alcohol solution. These findings demonstrate that early life social isolation can promote AUD vulnerability-related phenotypes in female rats but that there are profound sex differences in the vulnerability window to this early life stressor. Uncovering the neural mechanisms responsible for these sexually dimorphic differences in sensitivity to ELS may shed light on the biological substrates associated with vulnerability to AUD and comorbid disorders of negative emotion in men and women.

The present study examined the effect of deep brain stimulation (DBS) in the nucleus accumbens shell on cocaine seeking and neuronal plasticity in rats. Electrical DBS of the accumbens shell attenuated cocaine primed reinstatement across a range of frequencies as low as 12 Hz in male rats. Nucleus accumbens medium spiny neurons (MSNs) can be differentiated by expression of dopamine D1 receptors (D1DRs) or D2DRs. Low-frequency optogenetic-DBS in D1DR- or D2DR-containing neurons attenuated cocaine seeking in male but not female rats. In slice electrophysiology experiments, 12 Hz electrical stimulation evoked long term potentiation (LTP) in D1DR-MSNs and D2DR-MSNs from cocaine naive male and female rats. However, in cocaine-experienced rats, electrical and optical DBS only elicited LTP in D2DR-MSNs from male rats. These results suggest that low frequency DBS in the nucleus accumbens shell effectively, but sex-specifically, suppresses cocaine seeking, which may be associated with the reversal of synaptic plasticity deficits in D2DR-MSNs.

Alcohol use disorders (AUDs) are common mental health issues worldwide and can lead to other chronic diseases. Stress is a major factor in the development and continuation of AUDs, and adolescent alcohol exposure can lead to enhanced stress-responsivity and increased risk for AUD development in adulthood. The exact mechanisms behind the interaction between adolescence, stress, and alcohol are not fully understood and require further research. In this regard, the nucleus of the tractus solitarius (NTS) provides dense norepinephrine projections to the extended amygdala, providing a key pathway for stress-related alcohol behaviors. While NTS norepinephrine neurons are known to be alcohol sensitive, whether adolescent alcohol disrupts NTS-norepinephrine neuron development and if this is related to altered stress-sensitivity and alcohol preference in adulthood has not previously been examined. Here, we exposed male and female C57Bl/6J mice to the commonly used adolescent intermittent ethanol (AIE) vapor model during postnatal day 28-42 and examined AIE effects on: 1) tyrosine hydroxylase (TH) mRNA expression in the NTS across various ages (postnatal day 21-90), 2) behavioral responses to acute stress in the light/dark box test in adulthood, 3) NTS TH neuron responses to acute stress and ethanol challenges in adulthood, and 4) ethanol conditioned place preference behavior in adulthood. Overall the findings indicate that AIE alters NTS TH mRNA expression and increases anxiety-like behaviors following acute stress exposure in a sex-dependent manner. These mRNA expression and behavioral changes occur in the absence of AIE-induced changes in NTS TH neuron sensitivity to either acute stress or acute alcohol exposure or changes to ethanol conditioned place preference.

The medical psychostimulant methylphenidate (MP) is used to treat attention-deficit hyperactivity disorder and recreationally as a “cognitive enhancer”. MP is a dopamine reuptake inhibitor, but does not affect serotonin. Serotonin contributes to addiction-related gene regulation and behavior. Previously, we showed that enhancing serotonin action by adding a selective serotonin reuptake inhibitor, fluoxetine (FLX), to MP potentiates MP-induced gene regulation in striatum and nucleus accumbens, mimicking cocaine effects. Here, we investigated the behavioral consequences of MP+FLX treatment. Young adult male rats received MP (5 mg/kg, i.p.) or MP+FLX (5 mg/kg each) daily for 6-8 days. Behavioral effects were assessed in an open-field test during the repeated treatment. Two weeks later the motor response to a cocaine challenge (25 mg/kg) and the rate of acquisition of cocaine self-administration behavior were determined. Our results demonstrate that FLX potentiates effects of MP on open-field behavior. However, we found differential behavioral responses to MP+FLX treatment, as approximately half of the rats developed high rates of focal stereotypies (termed “MP+FLX/high reactivity” group), whereas the other half did not, and only showed increased locomotion (“MP+FLX/low reactivity” group). Two weeks later, cocaine-induced locomotion and stereotypies were positively correlated with MP+FLX-induced behavior seen at the end of the repeated MP+FLX treatment. Moreover, the MP+FLX/high reactivity group, but not the low reactivity group, showed facilitated acquisition of cocaine self-administration. These results demonstrate that repeated MP+FLX treatment can facilitate subsequent cocaine taking behavior in a subpopulation of rats. These findings suggest that MP+FLX exposure in some individuals may increase the risk for psychostimulant use later in life.

This study investigates whether spermidine (SPD), an endogenous polyamine, alters extinction and reinstatement of alcohol-induced conditioned place preference (CPP) in adult female Swiss mice. CPP was induced by injecting alcohol (1.8 g/kg, i.p.) and placing the animals in the drug-associated compartment for 10 min in four alternate days. During extinction, animals received vehicle or SPD (3, 10 or 30 mg/kg), and were placed in the drug-associated compartment for 10 min in 4 alternate days. Alcohol re-exposure was performed in the alcohol-paired compartment. In a second experiment, after conditioning, animals received vehicle, the N-methyl-d-aspartate (NMDA) receptor polyamine binding site antagonist arcaine (ARC, 0.1 mg/kg), SPD (10 mg/kg) or the association of both (ARC+SDP) in the drug-associated compartment. Animals were then sequentially subjected to alcohol re-exposure and a post-reexposure test. Spermidine did not alter CPP extinction, but prevented the reinstatement of CPP induced by alcohol reexposure. Arcaine prevented the effect of spermidine on alcohol-induced CPP reinstatement. The results suggest that SPD may facilitate the reconsolidation of conditioning memory, disrupting CPP. This effect seems to involve the polyamine binding site at the NMDA receptor, because it is prevented by ARC.

Alcohol Use Disorder (AUD) can induce long lasting alterations to executive function. This includes altered action control, which can manifest as dysfunctional goal-directed control. Cortical and striatal circuits mediate goal-directed control over behavior, and prior research has found chronic alcohol disrupts these circuits. In particular, prior in vivo and ex vivo work have identified alterations to function and activity of dorsal medial striatum (DMS), which is necessary for goal-directed control. However, unknown is whether these alterations manifest as altered activity of select DMS populations during behavior. Here we examine effects of prior chronic alcohol exposure on calcium activity modulation during action-related behaviors via fiber photometry of genetically-identified DMS populations including the direct and indirect output pathways, and fast-spiking interneurons. We find that prior chronic alcohol exposure leads to increased calcium modulation of the direct pathway during action related behavior. In contrast, prior chronic alcohol exposure led to decreased calcium activity modulation of the indirect pathway and the fast-spiking interneuron population around action-related events. Together, our findings suggest an imbalance in striatal activity during action control. This disruption may contribute to the altered goal-directed control previously reported.

This study sought to assess the association between illicit opioid use and accelerated epigenetic aging (A.K.A. DNAm Age) among people of African ancestry who use heroin. DNA was obtained from participants with opioid use disorder (OUD) who confirmed heroin as their primary drug of choice. Clinical inventories of drug use included: the Addiction Severity Index (ASI) Drug-Composite Score (range: 0–1), and Drug Abuse Screening Test (DAST-10; range: 0–10). A control group of participants of African ancestry who did not use heroin was recruited and matched to heroin users on sex, age, socioeconomic level, and smoking status. Methylation data were assessed in an epigenetic clock to determined and compare Epigenetic Age to Chronological Age (i.e., age acceleration or deceleration). Data were obtained from 32 controls [mean age 36.3 (±7.5) years] and 64 heroin users [mean age 48.1 (±6.6) years]. The experimental group used heroin for an average of 18.1 (±10.6) years, reported use of 6.4 (±6.1) bags of heroin/day, with a mean DAST-10 score of 7.0 (±2.6) and ASI Score of 0.33 (±0.19). Mean age acceleration for heroin users [+0.56 (± 9.5) years] was significantly (p< 0.05) lower than controls [+5.19 (± 9.1) years]. This study did not find evidence that heroin use causes epigenetic age acceleration.