Addiction neuroscience最新文献

Background

Depression and attention deficit hyperactivity disorder are known to be comorbid. Treatment of these commonly coexisting diseases typically involves the combined prescription of methylphenidate (MP), a psychostimulant, and fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI). MP and cocaine have similar mechanisms of action and this study examined the effects of chronic treatment of MP combined with FLX on cocaine consumption in rats.

Methods

Four groups of rats received access to drinking solutions of water (control), MP (30/60 mg/kg/day), FLX (20 mg/kg/day), or the combination of MP (30/60 mg/kg/day) plus FLX (20 mg/kg/day), during 8 h per day for one month. Following these drug treatments, rats were allowed to self-administer cocaine for 14 days.

Results

Our results showed that, during the first week of cocaine self-administration, the MP-treated rats had significantly greater numbers of active lever presses (plus 127%) and increased consumption of cocaine compared to the control rats. In contrast, during week two of cocaine self-administration, the rats treated with the MP + FLX combination showed significantly more lever presses (plus 198%) and significantly greater cocaine consumption (plus 84%) compared to the water controls.

Conclusion

Chronic oral treatment during adolescence with the combination of MP plus FLX resulted in increased cocaine use after 2 weeks of cocaine self-administration in rats. These novel findings suggest that the combined exposure to these two drugs chronically, during adolescence, may produce increased vulnerability towards cocaine abuse during young adulthood.

Resumption of drug taking is a primary focus for substance use disorder research and can be triggered by drug-associated environmental stimuli. The Nucleus Accumbens (NAc) is a key brain region which guides motivated behavior and is implicated in resumption. Yet, there remains a pressing need to characterize NAc neurons’ responsiveness to drug associated stimuli during withdrawal and abstinence. We recorded discriminative stimulus (DS) induced NAc activity via in vivo single-unit electrophysiology in rats that self-administered cocaine. Male and female rats implanted with a jugular catheter and a microwire array in NAc Core and Shell self-administered cocaine under control of a 30s auditory DS for 6 hours per session across 14 consecutive days. Rats acquired tone discrimination within 4 sessions. To exclude pharmacological effects of circulating cocaine from all neuronal analyses, we studied changes in DS-induced firing only for trials preceding the first infusion of cocaine in each of the 14 sessions, which were defined as “pre-drug trials.” NAc neuron responses were assessed prior to tone-evoked movement onset. Responsiveness to the DS tone was exhibited throughout all sessions by the NAc Core population, but only during Early sessions by the NAc Shell population. Both Core and Shell responded selectively to the DS, i.e., more strongly on drug taking trials, or Hits, than on Missed opportunities. These findings suggest that NAc Core and Shell play distinct roles in initiating cocaine seeking prior to daily cocaine consumption, and align with reports suggesting that as drug use becomes chronic, cue-evoked activity shifts from NAc Shell to NAc Core.

Addiction is a disorder that can be characterized in part as the constant pursuit of a particular substance despite negative consequences. Although the orbitofrontal cortex (OFC) is known to regulate risk-taking more generally and be critical to the development of addiction, its role in regulating drug use under risk-taking conditions is unknown. To address this, we examined drug-taking and drug-seeking in male and female rats under conditions where cocaine infusions were paired with foot shock punishment 50% of the time and combined this paradigm with cFos immunohistochemistry. We found that rats that showed higher levels of drug-taking and drug-seeking prior to punishment showed decreased responding during self-administration sessions under risky conditions and lower levels of c-Fos expression in the lateral but not medial OFC. However, despite these initial differences in responses to infusions paired with foot shocks, all rats showed decreased responding with additional punishment sessions. We then used chemogenetic viral approaches to examine how altering activity of the lateral OFC affects drug-taking and drug-seeking during punished drug use. Although there was no effect of G_i/o DREADD-mediated inhibition of the lateral OFC on these behaviors, G_q DREADD-mediated activation increased drug-taking and drug-seeking when drug use was associated with foot shock 50% of the time. Interestingly, this manipulation had no effect on non-risky self-administration behavior. These results suggest that the involvement of lateral OFC in cocaine use is context-sensitive and influences decision-making based on negative outcomes.

Glutamatergic imbalances are characteristic of SUDs. Astrocytic and neuronal transporters help regulate glutamate homeostasis and disruptions in this homeostasis engender SUD. The cysteine-glutamate exchanger (xCT) is primarily localized on astrocytes and maintains glutamate concentrations. This process is disrupted by cocaine use, and the therapeutic N-acetylcysteine (NAC) lowers cue-induced relapse to cocaine by restoring xCT function. However, little research has shown how these effects extend to other psychostimulants, such as amphetamine (AMP). Here, we assessed xCT expression following relapse to AMP cues, and if NAC can attenuate relapse via changes to astrocyte and xCT expression. We administered NAC (100 mg/kg ip) daily during a 14-day abstinence period following AMP (0.1 mg/kg/infusion; 2 h sessions) self-administration. Relapse was tested following one (WD 1) or 14 days (WD 14) of withdrawal. The overall number of astrocytes was also quantified within the medial prefrontal cortex (mPFC) and nucleus accumbens (ACb). NAC failed to lower cue-induced AMP craving via cue-induced relapse and reinstatement testing. Cue-induced craving did not increase from WD 1 to WD 14. AMP-exposed rats had greater astrocyte counts in the mPFC and ACb when compared AMP-naïve rats. Repeated injection with NAC decreased xCT expression within the mPFC and ACb. Overall, these results suggest that NAC may be an ineffective treatment option for lowering cue-induced relapse to AMP. Further, the results suggest that stimulating xCT via NAC may not be an effective therapeutic approach for decreasing cue-seeking for AMP.

Methadone is used for the treatment of opioid use disorder, including in pregnant patients. Research has established several consequences of prenatal opioid misuse, however little work has investigated the effects of prenatal methadone exposure (PME) on the offspring long-term, despite the continued prescription to pregnant individuals. The current study aimed to identify the long-term cognitive impairments arising from PME and assess hippocampal neurogenesis in these adult offspring. Pregnant Sprague Dawley rats were injected with methadone or sterile water twice daily from gestational day 3–20 or were left undisturbed as naïve controls. Adult offspring were tested in one of three behavioral tasks to assess pattern separation, spatial learning and memory, and contextual learning and memory, or were assigned to hippocampal tissue collection. For assessment of neurogenesis, offspring underwent injections of bromodeoxyuridine, and brains were collected at 24 h, 2wks, or 4wks for immunofluorescent staining. Methadone-exposed females, but not males, showed subtle impairments in pattern separation and heightened freezing during the extinction period in the fear conditioning task, and spatial memory in both sexes remained unaffected. Additionally, PME did not alter the rate of dentate granule cell proliferation but did significantly reduce the number of adult-born neuron surviving to a mature phenotype in the PME females at the 4wk timepoint. This work adds to the understanding of PME on offspring long-term and demonstrates female-specific sensitivity to these consequences. Future work is needed to fully investigate the neural disruptions arising from PME, with the goal of better supporting exposed individuals long-term.

The special issue on Biomarkers of Nicotine and Tobacco Dependence reviews the science for precision treatment of nicotine dependence and future opportunities for research on biomarkers for inclusion in tobacco product cessation and switching clinical trials to advance translation. This overview summarizes the articles contributed to the special issue by leading researchers in field of addiction.

Epidermal/brain fatty acid-binding protein 5 (FABP5) plays an integral role in the intracellular trafficking of bioactive lipids/endocannabinoids and the subsequent initiation of cellular cascades affecting cannabinoid and dopamine (DA) systems. Social isolation (SI) and environmental enrichment (EE) during adolescence have been shown to impact DA signaling, and, specifically, DA transporter (DAT) and receptor levels of DA type 1 (D1) and 2 (D2); however, the relationship between FABP5, environment and DA signaling remains unclear. The present study quantified DAT and DA receptor levels in male/female FABP5−/− and FABP5+/+ mice raised in either SI or EE. Results showed that FABP5−/− mice had 6.09–8.81% greater D1 levels in striatal sub-regions of the caudal brain, independent of sex or environment. D1 levels were 8.03% greater only in the olfactory tubercle of enrichment-reared animals. In summary, these results supported that FABP5 plays an important function in regulating striatal DA signaling, and this may have important implications as a target with therapeutic potential for various psychiatric disorders.

Alcohol use disorder (AUD) is a culturally pervasive and often treatment resistant disorder. Stress is a major trigger for relapse in AUD. Allostasis in response to stress is governed by the hypothalamic-pituitary-adrenal axis (HPA axis). Investigation into HPA axis functioning in response to stress in AUD may provide a novel drug target for AUD treatment. This systematic review found 46 studies concerning ongoing AUD, withdrawal from alcohol, early-abstinence (<6 months), and late-abstinence (>6 months). Cortisol responses were mixed in ongoing AUD and higher in withdrawal. In early abstinence, significantly lower responses to stress compared to healthy controls were found for ACTH (SMD = -1.47, p = < .001, I²: 35.68%) and cortisol (SMD = −1.32, p = < .001, I²: 38.97%). Baseline values did not significantly differ compared to healthy controls for ACTH (SMD = −0.39, p = < .001, I²: 81.11%) and cortisol (SMD = 0.74, p =  .015, I²: 88.66%). HPA axis functionality may normalise following 6 months of abstinence, though this may be confounded by selection bias. HPA axis hypoactivity was associated with a higher risk of relapse. Future research should aim to investigate all sexes and races, increase methodological consistency and participant follow up, and use HPA-sensitising drugs during early abstinence to assess their effects on relapse rates. Overall, the HPA axis presents strong potential as a novel treatment target in AUD.

A wealth of functional magnetic resonance imaging monetary incentive delay task (MIDT) research has shown alcohol dependency is associated with a hypoactive striatal response during gain anticipation (gain > neutral) and loss anticipation (loss > neutral). Electroencephalography (EEG) holds clinical advantages over fMRI (high temporal resolution, low cost, portable) however its use to study reward processing in alcohol dependence is limited.  We aimed to carry out the first EEG MIDT (eMIDT) study in alcohol dependence. 21 abstinent alcohol dependent individuals and 26 controls performed an MIDT while neural activity was recorded using 64-channel EEG. Trial averaged event-related potentials (ERPs) and single-trial machine learning discriminant analyses were applied to EEG data. Clinical variables related to severity of dependence were collected and relationships with ERP data explored.  Alcohol dependent individuals, compared with healthy controls, had blunted cue-P3 amplitudes for gain and loss anticipation (interaction: p = 0.019); and elevated contingent negative variation amplitudes for all conditions (gain, loss, neutral)(main effect: p < 0.001) which was associated with increased alcohol consumption (p = 0.002). The machine learning analyses demonstrated alcohol dependent individuals had reduced ability to discriminate between loss and neutral cues between 328 – 350 ms (p = 0.040), 354 – 367 ms (p = 0.047) and 525 – 572 ms (p = 0.022). The eMIDT approach is demonstrated to be a low-cost, sensitive measure of dysfunctional anticipatory reward processing in alcohol dependence, which we propose is ideal for big data approaches to prognostic psychiatry and translation into clinical practice.

Despite being aware of negative consequences and wanting to quit, long-term addicts find it difficult to quit seeking and consuming drugs. This inconsistency between the (often compulsive) behavioural patterns and the explicit knowledge of negative consequences represents a cognitive conflict which is a central characteristic of addiction. Neurobiologically, differential cue-induced activity in distinct striatal subregions, as well as the dopamine connectivity spiraling from ventral striatal regions to the dorsal regions, play critical roles in compulsive drug seeking. The focus of this work is to illustrate the mechanisms that lead to a cognitive conflict and it’s impact on actions taken i.e. addictive choices. We propose an algorithmic model that captures how the action choices that the agent makes when reinforced with drug-rewards become impervious to the presence of negative consequences that often follow those choices. We advance the understanding of having a decision hierarchy in representing “cognitive control” and how lack of such control at higher-level in the hierarchy could potentially lead to consolidated drug-seeking habits. We further propose a cost-benefit based arbitration scheme, which mediates the allocation of control across different levels of the decision-making hierarchy. Lastly, we discuss how our algorithmic model could help us understand how addictive drugs progressively hijack the dopamine-spiralling circuit at the neural implementation level.