Microglial activation increases cocaine self-administration following adolescent nicotine exposure.
Ontology highlight
ABSTRACT:
SUBMITTER: Linker KE
PROVIDER: S-EPMC6965638 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Most people start experimenting with tobacco products or e-cigarettes in early adolescence and become habitual smokers in late adolescence or adulthood. These studies investigated if exposure to tobacco smoke or nicotine during early and mid-adolescence affects nicotine intake in late adolescence and early adulthood. Male and female rats were exposed to tobacco smoke from low- and high-nicotine SPECTRUM cigarettes or nicotine (0.3 mg/kg, twice a day) from postnatal day (P) 24-42. The self-administration sessions started at P55. The rats self-administered nicotine for 14-15 days under a fixed-ratio 1 schedule, and on the first day, the maximum number of infusions was twenty. Exposure to smoke from high, but not low, nicotine cigarettes during adolescence increased nicotine self-administration in female but not male rats. Adolescent treatment with nicotine facilitated nicotine self-administration. On the first day of nicotine self-administration, nicotine-treated rats reached the maximum number of infusions before the saline-treated control rats. Nicotine intake was also higher in the nicotine-treated female rats than in the saline-treated females. There was no sex difference in nicotine intake in controls when the data from the studies were combined. Smoke exposure led to a dose-dependent increase in plasma nicotine and cotinine levels in adolescent rats. Exposure to smoke from high-nicotine cigarettes and 0.3 mg/kg of nicotine led to plasma nicotine and cotinine levels that are similar to those in tobacco users. These findings indicate that in females, but not males, exposure to nicotine during adolescence may facilitate smoking and e-cigarette use later in life.
| S-EPMC7660018 | biostudies-literature
Project description:Drug addiction is characterized by compulsive drug-taking behaviors and a high propensity to relapse following drug cessation. Drug craving and seeking can increase during a period of abstinence, but this phenomenon is not observed in drug-induced reinstatement models. To investigate the effect of withdrawal on cocaine relapse, rats were exposed to extended-access cocaine self-administration and subjected to either 1 or 30 d of withdrawal. When tested during 12 h unlimited access to cocaine (binge), the duration of the withdrawal did not influence cocaine intake. However, using a histamine punishment procedure that greatly suppresses drug-taking behavior, we demonstrate that longer periods of abstinence from cocaine induce a greater persistence in responding for drug in the face of negative consequences.
| S-EPMC4217113 | biostudies-other
Project description:IntroductionDuring adolescence, exposure to nicotine or cannabis independently induces effects on neuromaturation and later cognitive function. However, the potential effect of both drugs under co-use conditions has become of increasing concern given the prevalence of e-cigarettes, legalization of cannabis, and availability of synthetic "spice" cannabinoid agonists.Aims and methodsThe current studies investigated the effects of exposure to a cannabinoid receptor agonist (WIN55,212-2) and/or nicotine over a discrete time period in mid-adolescence on later intravenous nicotine self-administration in adult male and female mice. We further examined whether cannabinoid agonist administration in adulthood would alter nicotine reinforcement, with either acute or chronic pairing across 7 days.ResultsWe found that adult males exhibited increased nicotine self-administration at a lower, rewarding nicotine dose following adolescent cannabinoid exposure, either alone or with nicotine coadministration. In contrast, adult females demonstrated an opposing effect in which adolescent cannabinoid and nicotine coexposure resulted in decreased nicotine intake compared with the nicotine only and control groups. Furthermore, after maintaining nicotine self-administration across sessions, pretreatment with a low dose of the cannabinoid agonist decreased nicotine intake in both male and female control mice, and this lowering effect was evidenced after both acute and chronic treatment. However, the cannabinoid agonist was ineffective in altering nicotine intake in mice previously exposed to nicotine, cannabinoid agonist, or both during adolescence.ConclusionsThese data provide evidence that adolescent drug exposure can alter later nicotine reinforcement in a sex-specific manner and can further modulate the effectiveness of interventions in reducing nicotine intake during adulthood.ImplicationsThese studies demonstrate a significant impact of nicotine, cannabinoids, or coexposure on developmental processes during adolescence. Differential effects were observed within each sex, with opposing results found for cannabinoid exposure on nicotine intake in males and females. Intriguingly, we also evidenced resistance to the lowering effects of a cannabinoid agonist on nicotine intake in adulthood based on adolescent drug exposure. Thus, these findings have important implications for our understanding of the impact of nicotine and cannabinoids (eg, Δ9-tetrahydrocannabinol (THC) and synthetic "spice" cannabinoids) during development, with further implications for the effectiveness of therapeutic interventions based on prior drug exposure in youth.
| S-EPMC7364841 | biostudies-literature
Project description:Adolescent smoking is associated with pathological drinking later in life, but the biological basis for this vulnerability is unknown. To examine how adolescent nicotine exposure influences subsequent ethanol intake, nicotine was administered during adolescence or adulthood, and responses to alcohol were measured 1 month later. We found that adolescent, but not adult, nicotine exposure altered GABA signaling within the ventral tegmental area (VTA) and led to a long-lasting enhancement of alcohol self-administration. We detected depolarizing shifts in GABAA reversal potentials arising from impaired chloride extrusion in VTA GABA neurons. Alterations in GABA signaling were dependent on glucocorticoid receptor activation and were associated with attenuated dopaminergic neuron responses to alcohol in the lateral VTA. Importantly, enhancing chloride extrusion in adolescent nicotine-treated animals restored VTA GABA signaling and alcohol self-administration to control levels. Taken together, this work suggests that adolescent nicotine exposure increases the risk profile for increased alcohol drinking in adulthood.
| S-EPMC5983379 | biostudies-literature
Project description:Nicotine, the main psychoactive ingredient of tobacco, induces negative emotional symptoms during abstinence that contribute to a profound craving for nicotine. However, the neurobiological mechanisms underlying how nicotine produces dependence remains poorly understood. We demonstrate one mechanism for both the anxiety-like symptoms of withdrawal and excessive nicotine intake observed after abstinence, through recruitment of the extrahypothalamic stress peptide corticotropin-releasing factor (CRF) system and activation of CRF(1) receptors. Overactivation of the CRF-CRF(1) system may contribute to nicotine dependence and may represent a prominent target for investigating the vulnerability to tobacco addiction.
| S-EPMC2040467 | biostudies-literature
Project description:It has been shown that exposure to cocaine can result in neuroinflammatory responses. Microglia, the resident CNS immune cells, undergo a transition to an activated state when challenged. In rodents, and possibly humans, cocaine exposure activates microglia. The goal of this study was to assess the extent and magnitude of microglial activation in rhesus monkeys with an extensive history of cocaine self-administration. Male rhesus monkeys (N?=?4/group) were trained to respond on a fixed-interval 3-min schedule of food or 0.3 mg/kg/injection cocaine presentation (30 reinforcers/session) for 300 sessions. At the end of the final session, monkeys were administered 2-[14C]deoxyglucose intravenously and 45 min later euthanized. Brain sections were used for autoradiographic assessments of glucose utilization and for microglia activation with [3H]PK11195, a marker for the microglial 18-kDa translocator protein. There were no group differences in gray matter [3H]PK11195 binding, while binding was significantly greater in cocaine self-administration animals as compared to food controls in 8 of the 11 white matter tracts measured at the striatal level. Binding did not differ from control at other levels. There were also significant increases in white matter local cerebral glucose utilization at the striatal level, which were positively correlated with [3H]PK11195 binding. The present findings demonstrate an elevation in [3H]PK11195 binding in forebrain white matter tracts of nonhuman primates with a prolonged history of cocaine self-administration. These elevations were also associated with greater cerebral metabolic rates. These data suggest that white matter deficits may contribute to behavioral, motivational, and cognitive impairments observed in cocaine abusers.
| S-EPMC6510647 | biostudies-literature
Project description:We previously showed that after repeated exposure to cocaine, D1-like dopamine receptor (D1DR) stimulation reverses plastic changes of AMPA receptor-mediated signaling in the nucleus accumbens shell. However, there is little information on the impact of cocaine self-administration on D1-NMDA receptor interactions in this brain region. Here, using whole-cell patch-clamp recordings, we assessed whether cocaine self-administration alters the effects of D1DR stimulation on synaptic and extrasynaptic NMDA receptors (NMDARs). In slices from cocaine-naive rats, pretreatment with a D1DR agonist decreased synaptic NMDAR-mediated currents and increased the contribution of extrasynaptic NMDARs. In contrast, neither cocaine self-administration alone nor cocaine experience followed by D1DR stimulation had an effect on synaptic or extrasynaptic NMDAR signaling. Activation of extrasynaptic NMDARs relies on the availability of extracellular glutamate, which is regulated primarily by glutamate transporters. In cocaine-experienced animals, relative to cocaine-naive rats, administration of a glutamate reuptake blocker, DL-threo-β-benzyloxyaspartic acid, revealed increased extrasynaptic NMDAR activity and stronger baseline activity of glutamate uptake transporters. In cocaine-naive rats, the D1DR-mediated increase in extrasynaptic NMDAR signaling was independent of the activity of glutamate reuptake transporters. Together, these results indicate that cocaine experience blunts the influence of D1DRs on synaptic and extrasynaptic NMDAR signaling. Additionally, prior cocaine self-administration limits activation of the extrasynaptic NMDAR pool by increasing glutamate reuptake. These findings outline a pattern of adaptive interactions between D1DRs and NMDARs in the nucleus accumbens shell and demonstrate upregulation of extrasynaptic NMDAR signaling as a novel consequence of cocaine self-administration.
| S-EPMC3715961 | biostudies-literature
Project description:Poor decision making and elevated risk taking, particularly during adolescence, have been strongly linked to drug use; however the causal relationships among these factors are not well understood. To address these relationships, a rat model (the Risky Decision-making Task; RDT) was used to determine whether individual differences in risk taking during adolescence predict later propensity for cocaine self-administration and/or whether cocaine self-administration causes alterations in risk taking. In addition, the RDT was used to determine how risk taking is modulated by dopamine signaling, particularly in the striatum. Results from these experiments indicated that greater risk taking during adolescence predicted greater intake of cocaine during acquisition of self-administration in adulthood, and that adult cocaine self-administration in turn caused elevated risk taking that was present following 6 weeks of abstinence. Greater adolescent risk taking was associated with lower striatal D2 receptor mRNA expression, and pharmacological activation of D2/3 receptors in the ventral, but not dorsal, striatum induced a decrease in risk taking. These findings indicate that the relationship between elevated risk taking and cocaine self-administration is bi-directional, and that low striatal D2 receptor expression may represent a predisposing factor for both maladaptive decision making and cocaine use. Furthermore, these findings suggest that striatal D2 receptors represent a therapeutic target for attenuating maladaptive decision making when choices include risk of adverse consequences.
| S-EPMC3924529 | biostudies-literature
Project description:Addictive drugs produce neuroadaptations in dopamine neurons of the ventral tegmental area. It is unknown if individual differences in these neuroadaptive responses can account for naturally occurring differences in drug addiction liability.To study this question, we took advantage of high-responder (HR) and low-responder (LR) rats, a population that exhibits spontaneous differences in several models of addiction. High-responder and LR rats were allowed to self-administer saline or a high dose of cocaine (500 microg/kg/infusion) over a brief period, to normalize drug intake across individuals. Drug-induced changes in the baseline activity of ventral tegmental area dopamine neurons were recorded after various periods of withdrawal.All rats developed self-administration behavior and showed similar levels of drug intake. Withdrawal from cocaine self-administration increased dopamine cell firing and bursting in all animals. However, these changes in firing rates and patterns were more persistent in HR than in LR rats.These results demonstrate individual differences in the duration of drug-induced neuroadaptations in dopamine neurons of the ventral tegmental area. More persistent elevation of dopamine cell activity and reduced capacity to return to baseline levels may be an important factor contributing to the development of addiction in "at-risk" individuals.
| S-EPMC2767203 | biostudies-literature
Project description:RationaleAlcohol and nicotine co-dependence is common in humans, and nicotine increases alcohol drinking in humans without alcohol use disorder (AUD). Nevertheless, there is little basic research on the interactions between the reinforcing effects of these two drugs.ObjectivesThe aim of this study was to investigate the effects of chronic nicotine injections on oral alcohol self-administration in alcohol non-dependent rats.MethodsAfter stable alcohol self-administration was reached (baseline) and a period without alcohol access, adult male rats were treated with chronic nicotine or saline injections for 105 days during which time they were tested intermittently for alcohol self-administration. There were 3 experimental groups: (1) saline, rats treated with saline for 105 days; (2) early nicotine, rats treated with nicotine for 70 days, and then with saline for 35 days; and (3) late nicotine: rats treated with saline for 35 days, and then with nicotine for 70 days.ResultsOur results indicate that (1) chronic nicotine increases alcohol consumption regardless of whether exposure to alcohol was interrupted (early nicotine) or not (late nicotine) before the start of nicotine treatment, (2) the number of alcohol reinforcements correlates to blood-alcohol levels, and (3) alcohol self-administration rapidly decreases when nicotine is no longer available (early nicotine).ConclusionsThese discoveries may have clinical implications in social drinkers that use nicotine products, in that chronic nicotine can escalate alcohol drinking and cessation of nicotine exposure may decrease alcohol use.
| S-EPMC7796964 | biostudies-literature