Neuroadaptive Mechanisms Research Articles

Neuroadaptive Biochemical Mechanisms of Remote Ischemic Conditioning

This review summarizes the currently known biochemical neuroadaptive mechanisms of remote ischemic conditioning. In particular, it focuses on the significance of the pro-adaptive effects of remote ischemic conditioning which allow for the prevention of the neurological and cognitive impairments associated with hippocampal dysregulation after brain damage. The neuroimmunohumoral pathway transmitting a conditioning stimulus, as well as the molecular basis of the early and delayed phases of neuroprotection, including anti-apoptotic, anti-oxidant, and anti-inflammatory components, are also outlined. Based on the close interplay between the effects of ischemia, especially those mediated by interaction of hypoxia-inducible factors (HIFs) and steroid hormones, the involvement of the hypothalamic–pituitary–adrenocortical system in remote ischemic conditioning is also discussed.

Olfactive short-term habituation in children and young people with profound intellectual and multiple disabilities

BackgroundDespite its importance for learning, the existence of the habituation process and its characteristics in people with profound intellectual and multiple disabilities (PIMD) remains understudied. Habituation is, however, considered the simplest form of learning, and a significant neuroadaptive mechanism. Even though habituation occurs in all sensory modalities, the olfactory system is where it manifests itself very visibly. AimThis study explores the olfactory short-term habituation abilities of children and young people with PIMD. MethodTwenty children and young people with PIMD (7–18 years) were presented six times successively with a 30-second habituating olfactory stimulus. The interstimulus interval was 15 s. A new odour was presented on the seventh trial. The scenario was carried out two times with two pairs of stimuli. The participants’ head alignment duration on the odour was measured. ResultsSeventeen participants out of 20 manifested a decline in response, which reached about 50 % between the first and sixth presentation of the habituation odour. All habituators also showed a distinctive response when exposed to a novel odour. The participants who did not habituate showed a strong, non-fluctuating response to the stimulus throughout the presentations. Three participants only habituated to one of the two habituation stimuli. Conclusion and implicationsThe results raise theoretical, scientific, and practical issues. They question the factors explaining olfactory habituation mechanisms, namely the stimulus properties and the severity of impairment, reveal the need for points of comparison for interpreting this population’s responses, and point to the consequences of stimuli repetition and or variety in therapeutic or educational settings for these individuals’ learning and cognitive functioning.

Prolonged Alprazolam Treatment Alters Components of Glutamatergic Neurotransmission in the Hippocampus of Male Wistar Rats—The Neuroadaptive Changes following Long-Term Benzodiazepine (Mis)Use

Alprazolam (ALP), a benzodiazepine (BDZ) used to treat anxiety, panic, and sleep disorders, is one of the most prescribed psychotropic drugs worldwide. The side effects associated with long-term (mis)use of ALP have become a major challenge in pharmacotherapy, emphasizing the unmet need to further investigate their underlying molecular mechanisms. Prolonged BDZ exposure may induce adaptive changes in the function of several receptors, including the primary target, gammaaminobutyric acid receptor type A (GABAAR), but also other neurotransmitter receptors such as glutamatergic. The present study investigated the potential effects of prolonged ALP treatment on components of glutamatergic neurotransmission, with special emphasis on N-Methyl-D-aspartate receptor (NMDAR) in the hippocampus of adult male Wistar rats. The study revealed behavioral changes consistent with potential onset of tolerance and involvement of the glutamatergic system in its development. Specifically, an increase in NMDAR subunits (NR1, NR2A, NR2B), a decrease in vesicular glutamate transporter 1 (vGlut1), and differential modulation of excitatory amino acid transporters 1 and 2 (EAAT1/2, in vivo and in vitro) were observed, alongside a decrease in α1-containing GABAAR following the treatment. By describing the development of compensatory actions in the glutamatergic system, the present study provides valuable information on neuroadaptive mechanisms following prolonged ALP intake.

Application of gabapentinoids and novel compounds for the treatment of benzodiazepine dependence: the glutamatergic model.

Current approaches for managing benzodiazepine (BZD) withdrawal symptoms are daunting for clinicians and patients, warranting novel treatment and management strategies. This review discusses the pharmacodynamic properties of BZDs, gabapentinoids (GBPs), endozepines, and novel GABAergic compounds associated with potential clinical benefits for BZD-dependent patients. The objective of this study was to review the complex neuromolecular changes occurring within the GABAergic and glutamatergic systems during the BZD tolerance and withdrawal periods while also examining the mechanism by which GBPs and alternative pharmacological therapies may attenuate withdrawal symptoms. An elaborative literature review was conducted using multiple platforms, including the National Center for Biotechnology (NCBI), AccessMedicine, ScienceDirect, pharmacology textbooks, clinical trial data, case reports, and PubChem. Our literature analysis revealed that many distinctive neuroadaptive mechanisms are involved in the GABAergic and glutamatergic systems during BZD tolerance and withdrawal. Based on this data, we hypothesize that GBPs may attenuate the overactive glutamatergic system during the withdrawal phase by an indirect presynaptic glutamatergic mechanism dependent on the α2δ1 subunit expression. GBPs may benefit individuals undergoing BZD withdrawal, given that the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor current significantly increases during abrupt BZD withdrawal in animal studies. This may be a conceivable explanation for the effectiveness of GBPs in treating both alcohol withdrawal symptoms and BZD withdrawal symptoms in some recent studies. Finally, natural and synthetic GABAergic compounds with unique pharmacodynamic properties were found to exert potential clinical benefits as BZD substitutes in animal studies, though human studies are lacking.

Participation of HIF-1 in the mechanisms of neuroadaptation to acute stressful exposure

BACKGROUND: New laboratory and instrumental technologies for analyzing the adaptive capabilities of a biological organism to acute stressful effects including hypoxic ones have significantly facilitated the diagnosis and fixation of adaptive behavioral reactions, physiological and biochemical changes. Much attention has been paid to the phenomenon of preconditioning a positive effect from exposure to small doses of pathogenic factors. Hypoxia-inducible factor 1 (HIF-1) is one of the most promising markers for fixing the phenomenon of hypoxic preconditioning.
 AIM: To study the mechanisms of neuroadaptation to acute stressful effects.
 MATERIALS AND METHODS: Using models of immobilization, hypothermic exposure, and electrocutaneous irritation of rat paws were carried out for the assessment of the mechanisms of neuroadaptation. Changes in the HIF-1 concentration were recorded in the blood and in the structures of the brain.
 RESULTS: The maximum concentration of HIF-1 was found in the amygdala (230 pg / mg), in the prefrontal cortex it was 50.8 pg / mg in the control group. Hypothermal exposure increased the HIF-1 content in the amygdala by more than 4 times, while emotionally pain and immobilization showed a slight decrease in HIF-1 in the amygdala. All types of stressors significantly increased the concentration of HIF-1 in the prefrontal cortex of animals. The most pronounced changes were observed when using the model of emotional pain stress. The obtained experimental data allow us to draw with caution a conclusion about the universality and unity of multicomponent mechanisms of adaptation to acute stressful effects.

The Role of the Central Amygdala in Alcohol Dependence.

Alcohol dependence is a chronically relapsing disorder characterized by compulsive drug-seeking and drug-taking, loss of control in limiting intake, and the emergence of a withdrawal syndrome in the absence of the drug. Accumulating evidence suggests an important role for synaptic transmission in the central nucleus of the amygdala (CeA) in mediating alcohol-related behaviors and neuroadaptive mechanisms associated with alcohol dependence. Acute alcohol facilitates γ-aminobutyric acid (GABA)ergic transmission in the CeA via both pre- and postsynaptic mechanisms, and chronic alcohol increases baseline GABAergic transmission. Acute alcohol inhibits glutamatergic transmission via effects at N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the CeA, whereas chronic alcohol up-regulates NMDA receptor (NMDAR)-mediated transmission. Pro- (e.g., corticotropin-releasing factor [CRF]) and antistress (e.g., nociceptin/orphanin FQ, oxytocin) neuropeptides affect alcohol- and anxiety-related behaviors, and also alter the alcohol-induced effects on CeA neurotransmission. Alcohol dependence produces plasticity in these neuropeptide systems, reflecting a recruitment of those systems during the transition to alcohol dependence.

Transtornos relacionados ao uso de álcool e as mulheres: impacto nos circuitos integrativos e de neurorregulação do estresse

Dysfunctional stress response can play a key role in some mental disorders. An increasing number of studies have demonstrated sex differences in the prevalence of stress-related disorders. In particular, women with alcohol use disorders (AUDs) present different negative outcomes whe compared to men in terms of brain function e neuroadaptative mechanisms. Alcohol consumption has been associated with subtle, long-term hypothalamic-hypophysis-adrenal (HPA) axis alterations, affecting the adaptive response of stress neuroregulatorycircuits. Future research in this field may positively influence the development of treatment strategies.

Acute and residual effects in adolescent rats resulting from exposure to the novel synthetic cannabinoids AB-PINACA and AB-FUBINACA.

Synthetic cannabinoids (SCs) have rapidly proliferated as recreational drugs, and may present a substantial health risk to vulnerable populations. However, information on possible effects of long-term use is sparse. This study compared acute and residual effects of the popular indazole carboxamide SC compounds AB-PINACA and AB-FUBINACA in adolescent rats with ∆9-tetrahydrocannabinol (THC) and control treatments. Albino Wistar rats were injected (i.p.) with AB-PINACA or AB-FUBINACA every second day (beginning post-natal day (PND) 31), first at a low dose (0.2 mg/kg on 6 days) followed by a higher dose (1 mg/kg on a further 6 days). THC-treated rats received equivalent doses of 6 × 1 mg/kg and 6 × 5 mg/kg. During drug treatment, THC, AB-PINACA, and AB-FUBINACA decreased locomotor activity at high and low doses, increased anxiety-like behaviours and audible vocalisations, and reduced weight gain. Two weeks after dosing was completed, all cannabinoid pre-treated rats exhibited object recognition memory deficits. These were notably more severe in rats pre-treated with AB-FUBINACA. However, social interaction was reduced in the THC pre-treated group only. Six weeks post-dosing, plasma levels of cytokines interleukin (IL)-1α and IL-12 were reduced by AB-FUBINACA pre-treatment, while cerebellar endocannabinoids were reduced by THC and AB-PINACA pre-treatment. The acute effects of AB-PINACA and AB-FUBINACA were broadly similar to those of THC, suggesting that acute SC toxicity in humans may be modulated by dose factors, including inadvertent overdose and product contamination. However, some lasting residual effects of these different cannabinoid receptor agonists were subtly different, hinting at recruitment of different mechanisms of neuroadaptation.

Role of Estradiol in the Regulation of Prolactin Secretion During Late Pregnancy.

Estrogen action is necessary for evidencing the stimulatory action of mifepristone and naloxone on prolactin (PRL) secretion during late pregnancy. Our aim is to determine the mechanism mediating this facilitator action of estrogens. To investigate the hypothalamic mechanisms involved in estrogen actions in PRL secretion at the end of pregnancy, we measured the effect of pretreatment with the estrogen antagonist tamoxifen on the expression of tyrosine hydroxylase (TH), hormone receptors (ERα and β, PRs, PRLR(long)), and μ- and κ- opioid receptors (ORs) at mRNA (by semiquantitative RT-PCR) and protein (by western blot for TH, PRLR(long), ERα, PRs, μ- and ORs) levels in extracts of medial basal hypothalamus (MBH) and serum PRL, E2 and P4 levels (by RIA) in mifepristone- and naloxone-treated rats. Tamoxifen administration partially prevented PRL release induced by the combined treatment. TH expression diminished and ERα expression increased in mifepristone-treated rats at mRNA and protein levels and tamoxifen partially prevented these changes with no effect on PRs expression. Mifepristone increased PRLR(long) mRNA levels; this increase was blocked by tamoxifen. Combined tamoxifen and mifepristone treatment decreased μ- and k-ORs mRNA but not protein levels. In conclusion, E2 induces neuroadaptive mechanisms necessary to facilitate PRL release preceding delivery. Acting through ERα, E2 modulates hypothalamic dopaminergic neurons activity, regulating TH, μ- and κ-ORs and PRLR(long) expression, and is necessary for evidencing the effects of P4 withdrawal. Its presence on days 14 and 15 of pregnancy is crucial to facilitate the opioid system modulation of PRL secretion at the end of pregnancy in the rat.

The Extracellular Matrix Protein Brevican Limits Time-Dependent Enhancement of Cocaine Conditioned Place Preference.

Cocaine-associated environmental cues sustain relapse vulnerability by reactivating long-lasting memories of cocaine reward. During periods of abstinence, responding to cocaine cues can time-dependently intensify a phenomenon referred to as 'incubation of cocaine craving'. Here, we investigated the role of the extracellular matrix protein brevican in recent (1 day after training) and remote (3 weeks after training) expression of cocaine conditioned place preference (CPP). Wild-type and Brevican heterozygous knock-out mice, which express brevican at ~50% of wild-type levels, received three cocaine-context pairings using a relatively low dose of cocaine (5 mg/kg). In a drug-free CPP test, heterozygous mice showed enhanced preference for the cocaine-associated context at the remote time point compared with the recent time point. This progressive increase was not observed in wild-type mice and it did not generalize to contextual-fear memory. Virally mediated overexpression of brevican levels in the hippocampus, but not medial prefrontal cortex, of heterozygous mice prevented the progressive increase in cocaine CPP, but only when overexpression was induced before conditioning. Post-conditioning overexpression of brevican did not affect remote cocaine CPP, suggesting that brevican limited the increase in remote CPP by altering neuro-adaptive mechanisms during cocaine conditioning. We provide causal evidence that hippocampal brevican levels control time-dependent enhancement of cocaine CPP during abstinence, pointing to a novel substrate that regulates incubation of responding to cocaine-associated cues.

Resting-state functional connectivity and presynaptic monoamine signaling in Alcohol Dependence.

Alcohol Dependence (AD) is a chronic relapsing disorder with high degrees of morbidity and mortality. While multiple neurotransmitter systems are involved in the complex symptomatology of AD, monoamine dysregulation and subsequent neuroadaptations have been long postulated to play an important role. Presynaptic monoamine transporters, such as the vesicular monoamine transporter 1 (VMAT1), are likely critical as they represent a key common entry point for monoamine regulation and may represent a shared pathway for susceptibility to AD. Excessive monoaminergic signaling as mediated by genetic variation in VMAT1 might affect functional brain connectivity in particular in alcoholics compared to controls. We conducted resting-state fMRI functional connectivity (FC) analysis using the independent component analysis (ICA) approach in 68 AD subjects and 72 controls. All subjects were genotyped for the Thr136Ile (rs1390938) variant in VMAT1. Functional connectivity analyses showed a significant increase of resting-state FC in 4 networks in alcoholics compared to controls (P < 0.05, corrected). The FC was significantly positively correlated with Alcohol Dependence Scale (ADS). The hyperfunction allele 136Ile was associated with a significantly decreased FC in the Default Mode Network, Prefrontal Cortex Network, and Executive Control Network in alcohol dependent participants (P < 0.05, corrected), but not in controls. Our data suggest that increased FC might represent a neuroadaptive mechanism relevant to AD that is furthermore mediated by genetic variation in VMAT1. The hyperfunction allele Thr136Ile might have a protective effect that is, in particular, relevant in AD by mechanism of increased monoamine transport into presynaptic storage vesicles.

Neurobiological research on addiction: What value has it added to the concept?

Kalant, H. (2015). Neurobiological research on addiction: What value has it added to the concept?. The International Journal Of Alcohol And Drug Research, 4(1), 53-59. doi:http://dx.doi.org/10.7895/ijadr.v4i1.196The initial goal of neurobiological research on addiction was to identify the neural mechanisms involved in the mediation and expression of addictive behavior. More recently, however, it has attributed causal roles to these mechanisms, as illustrated by the definition of addiction as a brain disease caused by chronic exposure to a drug. This concept carries a number of implications that can be assessed experimentally and clinically. None of these implications is borne out by the currently available evidence. The interactions of neuronal systems involved in addiction are also involved in adaptation to experience and environmental change. Much of the neurobiological research to date has not differentiated between causes of addiction, neuronal mechanisms that are activated by them, and risk factors that contribute to individual vulnerability. It has largely ignored the important experiential and environmental influences known to affect the prevalence of addiction in different populations or different times, and it has so far directed much less attention to other forms of addiction-like behavior that do not involve drugs. These failures are not inherent in neurobiological research but require reorientation of objectives, including more emphasis on the study of mechanisms by which environment and experience, including drug experience, can determine whether genetic risk factors are expressed or remain dormant and can direct neuroadaptive mechanisms toward alternative outcomes.

Rodent models and mechanisms of voluntary binge-like ethanol consumption: Examples, opportunities, and strategies for preclinical research.

Binge ethanol consumption has widespread negative consequences for global public health. Rodent models offer exceptional power to explore the neurobiology underlying and affected by binge-like drinking as well as target potential prevention, intervention, and treatment strategies. An important characteristic of these models is their ability to consistently produce pharmacologically-relevant blood ethanol concentration. This review examines the current available rodent models of voluntary, pre-dependent binge-like ethanol consumption and their utility in various research strategies. Studies have demonstrated that a diverse array of neurotransmitters regulate binge-like drinking, resembling some findings from other drinking models. Furthermore, repeated binge-like drinking recruits neuroadaptive mechanisms in mesolimbocortical reward circuitry. New opportunities that these models offer in the current context of mechanistic research are also discussed.

SY07-3 * MEDICATIONS FOR TREATMENT OF ALCOHOLISM THAT DERIVE FROM THE DARK SIDE OF ADDICTION

Drug addiction is a disorder characterized by compulsive drug intake, loss of control over intake and emergence of a negative emotional state during withdrawal. Addiction involves elements of impulsivity and compulsivity which when combined form an addiction cycle that provides heuristic framework with which to identify the neurobiological and neuroadaptive mechanisms involved in addiction, and as a result treatments for addiction. Based on this framework 3 stages of the addiction cycle have been identified that are relevant to alcoholism. These three stages: Binge-intoxication, withdrawal-negative affect and preoccupation-anticipation (“craving”) are reflected in key neuroadaptations that drive and maintain addiction. The binge-intoxication stage includes enhanced habit (stimulus- response) activity in the dorsal striatum. The withdrawal-negative affect stage reflects reward deficits in the ventral striatum (nucleus accumbens) such as dopamine and opioid peptides, but also stress surfeit in the amygdala such as recruitment of the brain stress systems including corticotropin releasing factor, dynorphin and norepinephrine. The preoccupation-anticipation stage reflects impairments in self-regulation mediated by dysregulation of executive function in the frontal cortex. Each of these stages provides a heuristic framework for treatment and can be targeted by existing and novel pharmaceuticals. Both naltrexone and acamprosate are effective medications for the treatment of alcoholism and are approved by the Food and Drug Administration of the USA. Naltrexone acts on the binge-intoxication state to block endogenous opioids and acamprosate acts on the preoccupation-anticipation stage to block glutamatergic activation. Future medications that focus on the withdrawal-afffect stage and preoccupation- anticipation stage to restore the stress surfeit dysregulation characterizing these stages of the addiction cycle may have high potential as novel approaches to medications development for alcoholism.

Synapse density and dendritic complexity are reduced in the prefrontal cortex following seven days of forced abstinence from cocaine self-administration.

Chronic cocaine exposure in both human addicts and in rodent models of addiction reduces prefrontal cortical activity, which subsequently dysregulates reward processing and higher order executive function. The net effect of this impaired gating of behavior is enhanced vulnerability to relapse. Previously we have shown that cocaine-induced increases in brain-derived neurotrophic factor (BDNF) expression in the medial prefrontal cortex (PFC) is a neuroadaptive mechanism that blunts the reinforcing efficacy of cocaine. As BDNF is known to affect neuronal survival and synaptic plasticity, we tested the hypothesis that abstinence from cocaine self-administration would lead to alterations in neuronal morphology and synaptic density in the PFC. Using a novel technique, array tomography and Golgi staining, morphological changes in the rat PFC were analyzed following 14 days of cocaine self-administration and 7 days of forced abstinence. Our results indicate that overall dendritic branching and total synaptic density are significantly reduced in the rat PFC. In contrast, the density of thin dendritic spines are significantly increased on layer V pyramidal neurons of the PFC. These findings indicate that dynamic structural changes occur during cocaine abstinence that may contribute to the observed hypo-activity of the PFC in cocaine-addicted individuals.

Alpha‐melanocyte stimulating hormone modulates ethanol self‐administration in posterior ventral tegmental area through melanocortin‐4 receptors

Although the role of alpha-melanocyte stimulating hormone (α-MSH) in alcohol seeking behaviour in rats has been demonstrated, the underlying mechanisms are not understood. Herein, we test the hypothesis that α-MSH might have a permissive effect in promoting the reward action of ethanol. Rats were implanted with cannulae targeted at the posterior ventral tegmental area (pVTA), because the site is sensitive to reinforcing effects of ethanol. These rats were trained to self-administer ethanol in standard two-lever (active/inactive) operant chamber test. Each active lever press resulted in self-administration of 100 nl of ethanol (100-300 mg%) containing solution. Over a period of 7 days, ethanol significantly increased the number of lever presses, which was considered as a measure of reward. Because ethanol at 200 mg% resulted in maximum number of lever presses (∼18-20 lever presses/30-minute session), the dose was employed in further studies. While prior administration of melanocortin (MC) agonists, α-MSH or [Nle4,D-Phe7]-alpha-MSH into pVTA, resulted in an 89% increase in lever presses, the response was attenuated following pre-treatment with MC4 receptors (MC4R) antagonist, HS014. In an immunohistochemical study, the brains of rats that were trained to self-infuse ethanol showed significantly increased α-MSH immunoreactivity in the nucleus accumbens shell, bed nucleus of stria terminalis and arcuate nucleus of the hypothalamus. In the pVTA, α-MSH fibres were found to run close to the dopamine cells, labelled with tyrosine hydroxylase antibodies. We suggest that α-MSH-MC4R system in the pVTA might be a part of the neuroadaptive mechanism underlying ethanol addiction.

Anatomical specificity in the modulation of activity-regulated genes after acute or chronic lurasidone treatment

Lurasidone is a novel second generation antipsychotic drug characterized by a multi-receptor profile. Besides the high affinity for 5-HT2A and D2 receptors, it is also characterized by potent 5-HT7 receptor antagonism, which may be beneficial for mood and cognition. Considering that dose-dependent changes in receptor occupancy may differentially impact gene transcription, we aimed at investigating the effects of acute and chronic treatments with different doses of lurasidone (1, 3 and 10mg/kg) in rats on the expression of the activity-regulated genes Arc, Zif268 and Npas4, which are markers of neuronal activation and are also associated with neuroadaptive mechanisms. Our results show dose-dependent and anatomically-selective differences after acute and chronic lurasidone treatment. Indeed, the effects produced by acute treatment seem to reflect the modulatory activity of lurasidone at selected neurotransmitter receptors. In fact, low doses of the drug acted in the hippocampus, while high doses acted in the striatum, reflecting the high predominance of D2 receptor expression in this brain region. On the contrary, chronic treatment with lurasidone revealed a different profile of IEGs modulation, possibly reflecting neuroadaptive changes set in motion in response to repetitive drug exposure. In summary, the multi-receptor profile of lurasidone leads to the recruitment of different brain structures in a dose-related manner and this may be important for its therapeutic properties, particularly with respect to antidepressant activity and cognition.

Ethanol Reduces Neuronal Excitability of Lateral Orbitofrontal Cortex Neurons Via a Glycine Receptor Dependent Mechanism

Trauma-induced damage to the orbitofrontal cortex (OFC) often results in behavioral inflexibility and impaired judgment. Human alcoholics exhibit similar cognitive deficits suggesting that OFC neurons are susceptible to alcohol-induced dysfunction. A previous study from this laboratory examined OFC mediated cognitive behaviors in mice and showed that behavioral flexibility during a reversal learning discrimination task was reduced in alcohol-dependent mice. Despite these intriguing findings, the actions of alcohol on OFC neuron function are unknown. To address this issue, slices containing the lateral OFC (lOFC) were prepared from adult C57BL/6J mice and whole-cell patch clamp electrophysiology was used to characterize the effects of ethanol (EtOH) on neuronal function. EtOH (66 mM) had no effect on AMPA-mediated EPSCs but decreased those mediated by NMDA receptors. EtOH (11-66 mM) also decreased current-evoked spike firing and this was accompanied by a decrease in input resistance and a modest hyperpolarization. EtOH inhibition of spike firing was prevented by the GABAA antagonist picrotoxin, but EtOH had no effect on evoked or spontaneous GABA IPSCs. EtOH increased the holding current of voltage-clamped neurons and this action was blocked by picrotoxin but not the more selective GABAA antagonist biccuculine. The glycine receptor antagonist strychnine also prevented EtOH's effect on holding current and spike firing, and western blotting revealed the presence of glycine receptors in lOFC. Overall, these results suggest that acutely, EtOH may reduce lOFC function via a glycine receptor dependent process and this may trigger neuroadaptive mechanisms that contribute to the impairment of OFC-dependent behaviors in alcohol-dependent subjects.

Nicotine content and abstinence state have different effects on subjective ratings of positive versus negative reinforcement from smoking

Despite the well-known adverse health consequences of smoking, approximately 20% of US adults smoke tobacco cigarettes. Much of the research on smoking reinforcement and the maintenance of tobacco smoking behavior has focused on nicotine; however, a number of other non-nicotine factors are likely to influence the reinforcing effects of smoked tobacco. A growing number of studies suggest that non-nicotine factors, through many pairings with nicotine, are partially responsible for the reinforcing effect of smoking. Additionally, both clinical studies and preclinical advances in our understanding of nicotinic receptor regulation suggest that abstinence from smoking may influence smoking reinforcement. These experiments were conducted for 2 reasons: to validate a MRI-compatible cigarette smoking device; and to simultaneously investigate the impact of nicotine, smoking-associated conditioned reinforcers, and smoking abstinence state on subjective ratings of smoking reinforcement. Participants smoked nicotine and placebo cigarettes through an fMRI compatible device in an overnight-abstinent state or in a nonabstinent state, after having smoked a cigarette 25minutes prior. Outcome measures were within-subject changes in physiology and subjective ratings of craving and drug effect during the smoking of nicotine or placebo cigarettes on different days in both abstinence states. Cigarette type (nicotine vs. placebo) had a significant effect on positive subjective ratings of smoking reinforcement (“High”, “Like Drug”, “Feel Drug”; nicotine>placebo). In contrast, abstinence state was found to have significant effects on both positive and negative ratings of smoking reinforcement (“Crave”, “Anxiety”, “Irritability”; abstinence>nonabstinence). Interaction effects between abstinence and nicotine provide clues about the importance of neuroadaptive mechanisms operating in dependence, as well as the impact of conditioned reinforcement on subjective ratings of smoking-induced high.

Lower cognitive reserve in the aging human immunodeficiency virus-infected brain

More HIV-infected individuals are living longer; however, how their brain function is affected by aging is not well understood. One hundred twenty-two men (56 seronegative control [SN] subjects, 37 HIV subjects with normal cognition [HIV+NC], 29 with HIV-associated neurocognitive disorder [HAND]) performed neuropsychological tests and had acceptable functional magnetic resonance imaging scans at 3 Tesla during tasks with increasing attentional load. With older age, SN and HIV+NC subjects showed increased activation in the left posterior (reserve, “bottom-up”) attention network for low attentional-load tasks, and further increased activation in the left posterior and anterior (“top-down”) attention network on intermediate (HIV+NC only) and high attentional-load tasks. HAND subjects had only age-dependent decreases in activation. Age-dependent changes in brain activation differed between the 3 groups, primarily in the left frontal regions (despite similar brain atrophy). HIV and aging act synergistically or interactively to exacerbate brain activation abnormalities in different brain regions, suggestive of a neuroadaptive mechanism in the attention network to compensate for declined neural efficiency. While the SN and HIV+NC subjects compensated for their declining attention with age by using reserve and “top-down” attentional networks, older HAND subjects were unable to compensate which resulted in cognitive decline.