Neuroadaptive Processes Research Articles

Long-term effects of marijuana use on the brain.

Questions surrounding the effects of chronic marijuana use on brain structure continue to increase. To date, however, findings remain inconclusive. In this comprehensive study that aimed to characterize brain alterations associated with chronic marijuana use, we measured gray matter (GM) volume via structural MRI across the whole brain by using voxel-based morphology, synchrony among abnormal GM regions during resting state via functional connectivity MRI, and white matter integrity (i.e., structural connectivity) between the abnormal GM regions via diffusion tensor imaging in 48 marijuana users and 62 age- and sex-matched nonusing controls. The results showed that compared with controls, marijuana users had significantly less bilateral orbitofrontal gyri volume, higher functional connectivity in the orbitofrontal cortex (OFC) network, and higher structural connectivity in tracts that innervate the OFC (forceps minor) as measured by fractional anisotropy (FA). Increased OFC functional connectivity in marijuana users was associated with earlier age of onset. Lastly, a quadratic trend was observed suggesting that the FA of the forceps minor tract initially increased following regular marijuana use but decreased with protracted regular use. This pattern may indicate differential effects of initial and chronic marijuana use that may reflect complex neuroadaptive processes in response to marijuana use. Despite the observed age of onset effects, longitudinal studies are needed to determine causality of these effects.

Assessing Alcohol Versus Baclofen Withdrawal Syndrome in Patients Treated With Baclofen for Alcohol Use Disorder

Baclofen is a γ-aminobutyric acid B (GABA-B) receptor agonist that is approved for spasticity. Recently, the off-label use of baclofen for alcohol use disorder (AUD) has increased. However, baclofen is known to induce a neuroadaptation process, which may be identified by the occurrence of a specific baclofen withdrawal syndrome (BWS), that is, confusion, agitation, seizures, and delirium. The same set of symptoms characterizes alcohol withdrawal syndrome (AWS), which could lead to mistaking BWS for AWS in some situations. We report the cases of 3 patients under a chronic baclofen treatment for AUD. The patients emergently presented with a clinical state of confusion that was initially diagnosed and treated as AWS, with limited effect of benzodiazepines. Retrospectively, using a validated algorithm for assessing drug-induced withdrawal, we determined that all of these clinical cases were consistent with BWS. Both AWS and BWS should be considered in the case of acute confusion or delirium occurring in patients treated with baclofen for AUD. Moreover, further research should investigate to what extent GABA-A and GABA-B induce shared or distinct neuroadaptation processes and withdrawal syndromes.

Neuroplastic changes in addiction

Neuroplastic changes in addiction

Haloperidol-induced striatalNur77expression in a non-human primate model of tardive dyskinesia

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication arising in patients chronically exposed to antipsychotic drugs. As several modern (so-called atypical) antipsychotic drugs are common offenders, combined with the widening clinical indications for prescription as well as exposure of vulnerable individuals, TD will remain a significant drug-induced unwanted side effect. In addition, the pathophysiology of TD remains elusive and therapeutics are difficult. Based on rodent experiments, we have previously shown that the transcriptional factor Nur77 (also known as nerve growth factor inducible gene B or Nr4a1) is induced in the striatum following antipsychotic drug exposure as part of a long-term neuroadaptive process. To confirm this, we exposed adult capuchin (Cebus apella) monkeys to prolonged treatments with haloperidol (median 18.5months, N=11) or clozapine (median 6months, N=6). Six untreated animals were used as controls. Five haloperidol-treated animals developed mild TD movements similar to those found in humans. No TD was observed in the clozapine group. Postmortem analysis of Nur77 expression measured by in situ hybridization revealed a stark contrast between the two drugs, as Nur77 mRNA levels in the caudate-putamen were strongly upregulated in animals exposed to haloperidol but were spared following clozapine treatment. Interestingly, within the haloperidol-treated group, TD-free animals showed higher Nur77 expression in putamen subterritories compared with dyskinetic animals. This suggests that Nur77 expression might be associated with a reduced risk of TD in this experimental model and could provide a novel target for drug intervention.

Differential regulation of accumbal dopamine transmission in rats following cocaine, heroin and speedball self‐administration

Cocaine/heroin combinations (speedball) exert synergistic neurochemical and behavioral effects that are thought to contribute to the increased abuse potential and subjective effects reported by polydrug users. In vivo fast-scan cyclic voltammetry was used to examine the effects of chronic intravenous self-administration (25 consecutive sessions) of cocaine (250 μg/inf), heroin (4.95 μg/inf) and speedball (250/4.95 μg/inf cocaine/heroin) on changes in electrically evoked dopamine (DA) efflux, maximal rate of DA uptake (V(max)) and the apparent affinity (K(m)) of the DA transporter in the nucleus accumbens. The increase in electrically evoked DA was comparable following cocaine and speedball injection; however, heroin did not increase evoked DA. DA transporter K(m) values were similarly elevated following cocaine and speedball, but unaffected by heroin. However, speedball self-administration significantly increased baseline V(max), while heroin and cocaine did not change baseline V(max), compared with the baseline V(max) values of drug-naïve animals. Overall, elevated DA clearance is a likely consequence of synergistic elevations of nucleus accumbens extracellular DA concentrations by chronic speedball self-administration, as reported previously in microdialysis studies. The present results indicate neuroadaptive processes that are unique to cocaine/heroin combinations and cannot be readily explained by simple additivity of changes observed with cocaine and heroin alone.

Serum brain‐derived neurotrophic factor levels were reduced during methamphetamine early withdrawal

Methamphetamine (METH) abuse is an increasing public health problem worldwide. Many of the METH-induced physical and mental problems are associated with the neurotoxic effects of METH. Animal studies have shown that brain-derived neurotrophic factor (BDNF) decreased after repeated amphetamine administration and increased at 30 and 90 days from psychostimulant withdrawal, suggesting that there might be a psychostimulant-induced neuroprotective dysfunction followed by a neuroadaptive process in the brain. However, current research on the role of BDNF in human METH addiction is limited, particularly during early withdrawal. The aim of this study was to assess the serum BDNF levels in METH abusers during the early withdrawal stage. Two groups of subjects were enrolled: (1) 59 DSM-IV METH abusers confirmed by board-certified psychiatrists during the first 3 weeks of withdrawal; (2) 59 age- and sex-matched healthy controls. We found that serum BDNF levels were significantly and constantly lower in the METH abusers during early withdrawal than those of the healthy controls. This indicates that METH abusers might have severe BDNF dysfunction and an impaired neuroprotective function after repetitive METH misuse.

Learning to cope with stress: psychobiological mechanisms of stress resilience

Stress is the main non-genetic source of psychopathology. Therefore, the identification of neurobiological bases of resilience, the resistance to pathological outcomes of stress, is a most relevant topic of research. It is an accepted view that resilient individuals are those who do not develop helplessness, or other depression-like phenotypes, following a history of stress. In the present review, we discuss the phenotypic differences between mice of the inbred C57BL/6J and DBA/2J strains that could be associated with the strain-specific resistance to helplessness observable in DBA/2J mice. The reviewed results support the hypothesis that resilience to stress-promoted helplessness develops through interactions between a specific genetic makeup and a history of stress, and is associated with an active coping style, a bias toward the use of stimulus-response learning, and specific adaptive changes of mesoaccumbens dopamine transmission under stress. Finally, evidence that compulsivity represents a side effect of the neuroadaptive processes fostering resistance to develop depressive-like phenotypes under stress is discussed.

Effects of simultaneous exposure to stress and nicotine on nicotine-induced locomotor activation in adolescent and adult rats

Preclinical studies have shown that repeated stress experiences can result in an increase in the locomotor response to the subsequent administration of drugs of abuse, a phenomenon that has been termed behavioral cross-sensitization. Behavioral sensitization reflects neuroadaptive processes associated with drug addiction and drug-induced psychosis. Although crosssensitization between stress- and drug-induced locomotor activity has been clearly demonstrated in adult rats, few studies have evaluated this phenomenon in adolescent rats. In the present study, we determined if the simultaneous exposure to stress and nicotine was capable of inducing behavioral sensitization to nicotine in adolescent and adult rats. To this end, adolescent (postnatal day (P) 28-37) and adult (P60-67) rats received nicotine (0.4 mg/kg, sc) or saline (0.9% NaCl, sc) and were immediately subjected to restraint stress for 2 h once a day for 7 days. The control group for stress was undisturbed following nicotine or saline injections. Three days after the last exposure to stress and nicotine, rats were challenged with a single dose of nicotine (0.4 mg/kg, sc) or saline and nicotine-induced locomotion was then recorded for 30 min. In adolescent rats, nicotine caused behavioral sensitization only in animals that were simultaneously exposed to stress, while in adult rats nicotine promoted sensitization independently of stress exposure. These findings demonstrate that adolescent rats are more vulnerable to the effects of stress on behavioral sensitization to nicotine than adult rats.

Proteomic analysis of the nucleus accumbens in rhesus monkeys of morphine dependence and withdrawal intervention

It has been known that the reinforcing effects and long-term consequences of morphine are closely associated with nucleus accumbens (NAc) in the brain, a key region of the mesolimbic dopamine pathway. However, the proteins involved in neuroadaptive processes and withdrawal symptom in primates of morphine dependence have not been well explored. In the present study, we performed proteomes in the NAc of rhesus monkeys of morphine dependence and withdrawal intervention with clonidine or methadone. Two-dimensional electrophoresis was used to compare changes in cytosolic protein abundance in the NAc. We found a total of 46 proteins differentially expressed, which were further identified by mass spectrometry analysis. The identified proteins can be classified into 6 classes: metabolism and mitochondrial function, synaptic transmission, cytoskeletal proteins, oxidative stress, signal transduction and protein synthesis and degradation. Importantly, we discovered 14 proteins were significantly but similarly altered after withdrawal therapy with clonidine or methadone, revealing potential pharmacological strategies or targets for the treatment of morphine addiction. Our study provides a comprehensive understanding of the neuropathophysiology associated with morphine addiction and withdrawal therapy in primate, which is helpful for the development of opiate withdrawal pharmacotherapies.

Differential Patterns of Serum Brain-Derived Neurotrophic Factor Levels in Alcoholic Patients With and Without Delirium Tremens During Acute Withdrawal

Brain-derived neurotrophic factor (BDNF) is associated with alcohol addiction and withdrawal-related neurotoxicity. Delirium tremens (DT) is the most serious complication of alcohol withdrawal syndrome (AWS). In this study, we explored the differences in serum BDNF levels, measured at baseline and 1 week after alcohol withdrawal among alcoholic patients with and without DT. Sixty-five inpatients, fulfilling the DSM-IV criteria of alcohol dependence and admitted for alcohol detoxification, as well as 39 healthy control subjects were enrolled. The alcoholic patients were divided by the appearance of DTs into the DT group (n = 25) and non-DT group (n = 40). We collected blood samples of the patient groups on the first and seventh days of alcohol withdrawal and measured serum BDNF levels by sandwich enzyme-linked immunosorbent assay. Serum BDNF levels differed significantly among the three groups: (i) control group 14.8 ± 4.7 ng/ml; (ii) non-DT group 12.3 ± 3.3 ng/ml; (iii) DT group 6.2 ± 2.6 ng/ml (p < 0.001). One week after alcohol withdrawal, the BDNF levels increased significantly for both alcoholic groups. While non-DT group had comparable BDNF levels (13.4 ± 3.5 ng/ml) with controls, the DT group still exhibited lower levels (8.9 ± 4.4 ng/ml). This study suggests chronic drinking leads to a reduction in BDNF levels, and patients with more deficient BDNF expression are vulnerable to the development of DTs. Additionally, BDNF levels elevated after prompt alcohol detoxification treatment. These findings indicate that BDNF could involve modifying the phenotypes of AWS as well as the pertinent neuroadaptive processes of alcohol dependence.

Nicotine increases neural response to unpleasant stimuli and anxiety in non‐smokers

Studies in smokers suggest that nicotine might exert anxiolytic, stress-dampening and mood-enhancing effects and beneficially influences neural processing of affective information. Regarding non-smokers, results are inconsistent, and no data exist on the effect of nicotine on neural emotion processing. We applied functional magnetic resonance imaging (fMRI) to assess the influence of nicotine on brain activation during processing of emotional stimuli in 31 non-smokers with a maximum lifetime cigarette consumption of 20 cigarettes. Participants were subjected to two fMRI scans with event-related presentations of images taken from the International Affective Picture System, receiving nicotine (2 mg) and placebo gums in a double-blinded, randomized cross-over design. Furthermore, subjective affect was assessed. Nicotine increased brain activity in response to unpleasant stimuli in the amygdala, anterior cingulate cortex (ACC) and basal ganglia, whereas processing of pleasant stimuli was not altered. Psychophysiological interaction (PPI) analyses revealed that nicotine increased connectivity between the amygdala and the perigenual ACC (pACC) during processing of unpleasant stimuli and decreased connectivity between those structures during processing of pleasant stimuli. Participants reported higher state anxiety under nicotine than placebo. A single dose of nicotine acted as a stressor in non-smokers, leading to increased anxiety and neural activation elicited by unpleasant stimuli as well as altered connectivity within the amygdala-pACC circuit. Besides the possibility that reactions to nicotine may differ between non-smokers and smokers due to tolerance and neuroadaptive processes that occur during prolonged nicotine use, a priori differences in smokers and non-smokers might potentially explain diverse effects of nicotine on affect and emotional reactivity.

Bildgebung in der Diagnostik der Alkoholabhängigkeit

Neuroimaging provides insight into the main biological mechanisms underlying alcohol dependence. This article discusses results from brain imaging studies on neurobiological correlates of alcohol dependence. Cardinal symptoms of alcohol dependence are the development of tolerance, withdrawal symptoms, drug craving, loss of control on alcohol intake, and harmful consequences of alcohol consumption. Brain imaging studies support the hypothesis that tolerance can be understood as a neuroadaptive mechanism to ensure homeostasis during chronic alcohol intake. When alcohol consumption is suddenly interrupted during detoxification, the loss of homeostasis typically manifests as withdrawal syndrome. While tolerance reduces the effects of chronic alcohol intake, sensitization is a neuroadaptive process that increases the effects of alcohol and raises incentive salience. Brain imaging studies indicate that sensitization and drug craving are associated with neuroadaptive processes in the brain reward system. Harmful consequences of alcohol intake also include neurotoxic effects on the central nervous system characterized by local and global atrophy. These findings can be best diagnosed with neuroimaging.

The Site Specific Demethylation in the 5′-Regulatory Area of NMDA Receptor 2B Subunit Gene Associated with CIE-Induced Up-Regulation of Transcription

BackgroundThe NMDA receptor represents a particularly important site of ethanol action in the CNS. We recently reported that NMDA receptor 2B (NR2B) gene expression was persistently up-regulated following chronic intermittent ethanol (CIE) treatment. Increasing evidence that epigenetic mechanisms are involved in dynamic and long-lasting regulation of gene expression in multiple neuroadaptive processes prompted us to investigate the role of DNA methylation in mediating CIE-induced up-regulation of NR2B gene transcription. To dissect the changes of DNA methylation in the NR2B gene, we have screened a large number of CpG sites within its 5′-regulatory area following CIE treatment.MethodsPrimary cortical cultured neurons were subjected to ethanol treatment in a CIE paradigm. Bisulfite conversion followed by pyrosequencing was used for quantitative measurement and analysis of CpG methylation status within the 5′-regulatory area of the NR2B gene; chromatin immunoprecipitation (ChIP) assay was used to examine DNA levels associated with methylation and transcription factor binding. Electrophoretic mobility shift assay (EMSA) and in vitro DNA methylation assays were performed to determine the direct impact of DNA methylation on the interaction between DNA and transcription factor and promoter activity.ResultsAnalysis of individual CpG methylation sites within the NR2B 5′regulatory area revealed three regions with clusters of site-specific CpG demethylation following CIE treatment and withdrawal. This was confirmed by ChIP showing similar decreases of methylated DNA in the same regions. The CIE-induced demethylation is characterized by being located near certain transcription factor binding sequences, AP-1 and CRE, and occurred during treatment as well as after ethanol withdrawal. Furthermore, the increase in vitro of methylated DNA decreased transcription factor binding activity and promoter activity. An additional ChIP assay indicated that the CIE-induced DNA demethylation is accompanied by increased occupation by transcription factors.ConclusionsThese results suggest an important role of DNA demethylation in mediating CIE-induced NR2B gene up-regulation, thus implicating a novel molecular site of alcohol action.

BDNF levels are not related with levodopa‐induced dyskinesias in MPTP monkeys

Levodopa-induced dyskinesias (LIDs) are frequent in parkinsonian patients and may result from an aberrant plasticity. Brain-derived neurotrophic factor (BDNF) represents a likely candidate to subserve neuroadaptive processes encountered in LIDs. We compared striatal BDNF levels measured by ELISA in levodopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys having developed LIDs compared with animals where LIDs were prevented by the addition of CI-1041 (NR1A/2B NMDA receptor antagonist) or low doses of cabergoline (dopamine D2 receptor agonist). We observed reduced striatal BDNF concentrations in levodopa-treated MPTP monkeys with or without LIDs, suggesting that levodopa treatment is associated with reduced striatal BDNF levels and is independent of dyskinesias.

Altered white matter microstructure in adolescent substance users

Chronic marijuana use during adolescence is frequently comorbid with heavy alcohol consumption and associated with CNS alterations, yet the influence of early cannabis and alcohol use on microstructural white matter integrity is unclear. Building on evidence that cannabinoid receptors are present in myelin precursors and affect glial cell processing, and that excessive ethanol exposure is associated with persistently impaired myelination, we used diffusion tensor imaging (DTI) to characterize white matter integrity in heavy substance using and non-using adolescents. We evaluated 36 marijuana and alcohol-using (MJ + ALC) adolescents (ages 16–19) and 36 demographically similar non-using controls with DTI. The diffusion parameters fractional anisotropy (FA) and mean diffusivity (MD) were subjected to whole-brain voxelwise group comparisons using tract-based spatial statistics (Smith, S.M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T.E., Mackay, C.E., Watkins, K.E., Ciccarelli, O., Cader, M.Z., Matthews, P.M., Behrens, T.E., 2006. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31, 1487-1505). MJ + ALC teens had significantly lower FA than controls in 10 regions, including left superior longitudinal fasciculus (SLF), left postcentral gyrus, bilateral crus cerebri, and inferior frontal and temporal white matter tracts. These diminutions occurred in the context of increased FA in right occipital, internal capsule, and SLF regions. Changes in MD were less distributed, but increased MD was evident in the right occipital lobe, whereas the left inferior longitudinal fasciculus showed lower MD in MJ + ALC users. Findings suggest that fronto-parietal circuitry may be particularly impacted in adolescent users of the most prevalent intoxicants: marijuana and alcohol. Disruptions to white matter in this young group could indicate aberrant axonal and myelin maturation with resultant compromise of fiber integrity. Findings of increased anisotropic diffusion in alternate brain regions suggest possible neuroadaptive processes and can be examined in future studies of connectivity to determine how aberrancies in specific tracts might influence efficient cognitive processing.

Corneal multifocality with excimer laser for presbyopia correction

To offer a comprehensive perspective on corneal multifocality created by excimer laser surgery, with the different approaches used for the purpose and its reported outcomes. Three different approaches have been used for corneal multifocality: transitional multifocality, central presbyLasik (center for near) and peripheral presbyLasik (peripheral cornea for near). Although central presbyLasik creates a bifocal cornea, the other techniques increase the depth of focus based on the ablation of the peripheral cornea. Transitional multifocality creates intentionally an increase in coma aberration. According to the reported results, both central and peripheral presbyLasik obtain adequate spectacle independence simultaneously for far and for near. A neuroadaptation process is necessary for peripheral presbyLasik. Transitional techniques have a very limited use and very few outcomes reported. The level of scientific evidence from the literature is enough to consider that presbyLasik is a useful tool in the correction of presbyopia. However, most of the techniques are still under development in clinical investigations and further clinical data will validate the outcomes reported for the different techniques.

Phosphorylation of the homer‐binding domain of group I metabotropic glutamate receptors by cyclin‐dependent kinase 5

Phosphorylation of neurotransmitter receptors can modify their activity and regulate neuronal excitability. Cyclin-dependent kinase 5 (cdk5) is a proline-directed serine/threonine kinase involved not only in neuronal development, but also in synaptic function and plasticity. Here we demonstrate that group I metabotropic glutamate receptors (mGluRs), which modulate post-synaptic signaling by coupling to intracellular signal transduction pathways, are phosphorylated by cdk5. In vitro kinase assays reveal that cdk5 phosphorylates mGluR5 within the domain of the receptor that interacts with the scaffolding protein homer. Using a novel phosphospecific mGluR antibody, we show that the homer-binding domain of both mGluR1 and mGluR5 are phosphorylated in vivo, and that inhibition of cdk5 with siRNA decreases the amount of phosphorylated receptor. Furthermore, kinetic binding analysis, by surface plasmon resonance, indicates that phosphorylation of mGluR5 enhances its association with homer. Homer protein complexes in the post-synaptic density, and their disruption by an activity-dependent short homer 1a isoform, have been shown to regulate the trafficking and signaling of the mGluRs and impact many neuroadaptive processes. Phosphorylation of the mGluR homer-binding domain, in contrast to homer 1a induction, provides a novel mechanism for potentially regulating a subset of homer interactions.

S65-03 Neurobiological effects of opioids - data from brain imaging

Neuroimaging provides insight into the main biological mechanisms underlying drug and alcohol dependence. Cardinal symptoms of drug dependence are the development of tolerance against drug effects, withdrawal symptoms, drug craving, reduced control over drug intake and harmful consequences of drug consumption. Brain imaging studies support the hypothesis that tolerance development can be understood as a neuroadaptive mechanism to ensure homeostasis during chronic drug intake. When drug consumption is suddenly interrupted during detoxification, the loss of homeostasis can manifest as a withdrawal syndrome. While tolerance development reduces the effects of chronic drug intake, sensitization is a neuroadaptive process that increases the effects of a drug dose. Brain imaging studies indicate that sensitisation and drug craving are associated with neuroadaptive processes in the brain reward system. This lecture gives a short review about the neurobiological background of opioid addiction

Repeated morphine exposure decreased the nucleus accumbens excitability during short‐term withdrawal

It is well known that the nucleus accumbens plays an important role in drug reinforcing effect and relapse. However, the cellular neuroadaptations that take place in accumbens neurons after repeated drug exposure are still not well understood, especially for opioids. Here, we examined how nucleus accumbens neuronal excitability becomes affected in rats exposed to morphine using whole-cell patch-clamp recordings. Medium spiny neurons recorded from brain slices of repeated morphine treated rats exhibited a significant decrease in the intrinsic excitability after 3-4 days withdrawal, compared to that of neurons from saline treated animals, which was indicated by the increase of current to evoke the first spike and the decrease of spike number induced by depolarizing current steps in the morphine group. Moreover, the excitability decrease was accompanied by related membrane property changes, such as resting membrane potential hyperpolarization, input resistance, and membrane time constant decrease, inward rectification increase, and action potential duration decrease. Taken together, repeated morphine exposure and short-term withdrawal may reduce nucleus accumbens activity and output by modulating intrinsic membrane properties of its output neurons, which could be an important neuroadaptation process that mediates morphine addictive effect.

Neurobiologie stoffgebundener Abhängigkeitserkrankungen - Befunde bildgebender Verfahren

Neuroimaging provides insight into the main biological mechanisms underlying drug and alcohol dependence. Cardinal symptoms of drug dependence are the development of tolerance against drug effects, withdrawal symptoms, drug craving, reduced control over drug intake and harmful consequences of drug consumption. Brain imaging studies support the hypothesis that tolerance development can be understood as a neuroadaptive mechanism to ensure homeostasis during chronic drug intake. When drug consumption is suddenly interrupted during detoxification, the loss of homeostasis can manifest as a withdrawal syndrome. While tolerance development reduces the effects of chronic drug intake, sensitization is a neuroadaptive process that increases the effects of a drug dose. Brain imaging studies indicate that sensitisation and drug craving are associated with neuroadaptive processes in the brain reward system. Harmful consequences of drug intake include neurotoxic effects on the central nervous system. Besides discussing brain imaging studies on the neurobiological correlates of drug dependence, this review also presents studies on vulnerability factors that predispose individuals to excessive drug intake.