Neuroadaptive Changes Research Articles

Disrupted iron regulation in the brain and periphery in cocaine addiction

Stimulant drugs acutely increase dopamine neurotransmission in the brain, and chronic use leads to neuroadaptive changes in the mesolimbic dopamine system and morphological changes in basal ganglia structures. Little is known about the mechanisms underlying these changes but preclinical evidence suggests that iron, a coenzyme in dopamine synthesis and storage, may be a candidate mediator. Iron is present in high concentrations in the basal ganglia and stimulant drugs may interfere with iron homeostasis. We hypothesised that morphological brain changes in cocaine addiction relate to abnormal iron regulation in the brain and periphery. We determined iron concentration in the brain, using quantitative susceptibility mapping, and in the periphery, using iron markers in circulating blood, in 44 patients with cocaine addiction and 44 healthy controls. Cocaine-addicted individuals showed excess iron accumulation in the globus pallidus, which strongly correlated with duration of cocaine use, and mild iron deficiency in the periphery, which was associated with low iron levels in the red nucleus. Our findings show that iron dysregulation occurs in cocaine addiction and suggest that it arises consequent to chronic cocaine use. Putamen enlargement in these individuals was unrelated to iron concentrations, suggesting that these are co-occurring morphological changes that may respectively reflect predisposition to, and consequences of cocaine addiction. Understanding the mechanisms by which cocaine affects iron metabolism may reveal novel therapeutic targets, and determine the value of iron levels in the brain and periphery as biomarkers of vulnerability to, as well as progression and response to treatment of cocaine addiction.

Interactions between cannabidiol and Δ9-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway

The evidence base for the use of medical cannabis preparations containing specific ratios of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) is limited. While there is abundant data on acute interactions between CBD and THC, few studies have assessed the impact of their repeated co-administration. We previously reported that CBD inhibited or potentiated the acute effects of THC dependent on the measure being examined at a 1:1 CBD:THC dose ratio. Further, CBD decreased THC effects on brain regions involved in memory, anxiety and body temperature regulation. Here we extend on these finding by examining over 15 days of treatment whether CBD modulated the repeated effects of THC on behaviour and neuroadaption markers in the mesolimbic dopamine pathway. After acute locomotor suppression, repeated THC caused rebound locomotor hyperactivity that was modestly inhibited by CBD. CBD also slightly reduced the acute effects of THC on sensorimotor gating. These subtle effects were found at a 1:1 CBD:THC dose ratio but were not accentuated by a 5:1 dose ratio. CBD did not alter the trajectory of enduring THC-induced anxiety nor tolerance to the pharmacological effects of THC. There was no evidence of CBD potentiating the behavioural effects of THC. However we demonstrated for the first time that repeated co-administration of CBD and THC increased histone 3 acetylation (H3K9/14ac) in the VTA and ΔFosB expression in the nucleus accumbens. These changes suggest that while CBD may have protective effects acutely, its long-term molecular actions on the brain are more complex and may be supradditive.

Increased expression of proenkephalin and prodynorphin mRNAs in the nucleus accumbens of compulsive methamphetamine taking rats.

Addiction is associated with neuroadaptive changes in the brain. In the present paper, we used a model of methamphetamine self-administration during which we used footshocks to divide rats into animals that continue to press a lever to get methamphetamine (shock-resistant) and those that significantly reduce pressing the lever (shock-sensitive) despite the shocks. We trained male Sprague-Dawley rats to self-administer methamphetamine (0.1 mg/kg/infusion) for 9 hours daily for 20 days. Control group self-administered saline. Subsequently, methamphetamine self-administration rats were punished by mild electric footshocks for 10 days with gradual increases in shock intensity. Two hours after stopping behavioral experiments, we euthanized rats and isolated nucleus accumbens (NAc) samples. Affymetrix Array experiments revealed 24 differentially expressed genes between the shock-resistant and shock-sensitive rats, with 15 up- and 9 downregulated transcripts. Ingenuity pathway analysis showed that these transcripts belong to classes of genes involved in nervous system function, behavior, and disorders of the basal ganglia. These genes included prodynorphin (PDYN) and proenkephalin (PENK), among others. Because PDYN and PENK are expressed in dopamine D1- and D2-containing NAc neurons, respectively, these findings suggest that mechanisms, which impact both cell types may play a role in the regulation of compulsive methamphetamine taking by rats.

FMRP regulates an ethanol-dependent shift in GABABR function and expression with rapid antidepressant properties.

Alcohol promotes lasting neuroadaptive changes that may provide relief from depressive symptoms, often referred to as the self-medication hypothesis. However, the molecular/synaptic pathways that are shared by alcohol and antidepressants are unknown. In the current study, acute exposure to ethanol produced lasting antidepressant and anxiolytic behaviours. To understand the functional basis of these behaviours, we examined a molecular pathway that is activated by rapid antidepressants. Ethanol, like rapid antidepressants, alters γ-aminobutyric acid type B receptor (GABABR) expression and signalling, to increase dendritic calcium. Furthermore, new GABABRs are synthesized in response to ethanol treatment, requiring fragile-X mental retardation protein (FMRP). Ethanol-dependent changes in GABABR expression, dendritic signalling, and antidepressant efficacy are absent in Fmr1-knockout (KO) mice. These findings indicate that FMRP is an important regulator of protein synthesis following alcohol exposure, providing a molecular basis for the antidepressant efficacy of acute ethanol exposure.

Anandamide reverses depressive-like behavior, neurochemical abnormalities and oxidative-stress parameters in streptozotocin-diabetic rats: Role of CB1 receptors

The pathophysiology associated with increased prevalence of depression in diabetics is not completely understood, although studies have pointed the endocannabinoid system as a possible target. Then, we aimed to investigate the role of this system in the pathophysiology of depression associated with diabetes. For this, diabetic (DBT) male Wistar rats were intraperitoneally treated with cannabinoid CB1 (AM251, 1mg/kg) or CB2 (AM630, 1mg/kg) receptor antagonists followed by anandamide (AEA, 0.005mg/kg) and then submitted to the forced swimming test (FST). Oxidative stress parameters, CB1 receptor expression and serotonin (5-HT) and noradrenaline levels in the hippocampus (HIP) and prefrontal cortex (PFC) were also performed. It was observed that DBT animals presented a more pronounced depressive-like behavior and increase of CB1 receptor expression in the HIP. AEA treatment induced a significant improvement in the depressive-like behavior, which was reversed by the CB1 antagonist AM251, without affecting the hyperglycemia or weight gain. AEA was also able to restore the elevated CB1 expression and also to elevate the reduced level of 5-HT in the HIP from DBT animals. In addition, AEA restored the elevated noradrenaline levels in the PFC and induced a neuroprotective effect by restoring the decreased reduced glutathione and increased lipid hydroperoxides levels along with the decreased superoxide dismutase activity observed in HIP or PFC. Together, our data suggest that in depression associated with diabetes, the endocannabinoid anandamide has a potential to induce neuroadaptative changes able to improve the depressive-like response by its action as a CB1 receptor agonist.

Tip60 HAT Action Mediates Environmental Enrichment Induced Cognitive Restoration.

Environmental enrichment (EE) conditions have beneficial effects for reinstating cognitive ability in neuropathological disorders like Alzheimer’s disease (AD). While EE benefits involve epigenetic gene control mechanisms that comprise histone acetylation, the histone acetyltransferases (HATs) involved remain largely unknown. Here, we examine a role for Tip60 HAT action in mediating activity- dependent beneficial neuroadaptations to EE using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model. We show that flies raised under EE conditions display enhanced MB axonal outgrowth, synaptic marker protein production, histone acetylation induction and transcriptional activation of cognition linked genes when compared to their genotypically identical siblings raised under isolated conditions. Further, these beneficial changes are impaired in both Tip60 HAT mutant flies and APP neurodegenerative flies. While EE conditions provide some beneficial neuroadaptive changes in the APP neurodegenerative fly MB, such positive changes are significantly enhanced by increasing MB Tip60 HAT levels. Our results implicate Tip60 as a critical mediator of EE-induced benefits, and provide broad insights into synergistic behavioral and epigenetic based therapeutic approaches for treatment of cognitive disorder.

Nucleus incertus corticotrophin-releasing factor 1 receptor signalling regulates alcohol seeking in rats.

Alcoholism is a chronic relapsing disorder, and stress is a key precipitant of relapse. The nucleus incertus (NI) is highly responsive to corticotrophin-releasing factor (CRF) and psychological stressors, receives a CRF innervation and expresses CRF1 and CRF2 receptor mRNA. Furthermore, the ascending NI relaxin-3 system is implicated in alcohol seeking in rats. Therefore, in alcohol-preferring rats, we examined the effect of bilateral injections into the NI of the CRF1 receptor antagonist, CP376395 or the CRF2 receptor antagonist, astressin-2B on yohimbine-induced reinstatement of alcohol seeking. Using quantitative PCR analysis of NI micropunches, we assessed the effects of chronic alcohol consumption on gene expression profiles for components of the relaxin-3 and CRF systems. Bilateral intra-NI injections of CP376395 (500 ng/0.25 µl) attenuated yohimbine-induced reinstatement of alcohol seeking. In contrast, intra-NI injections of astressin-2B (200 ng/0.25 µl) had no significant effect. In line with these data, CRF1 , but not CRF2 , receptor mRNA was upregulated in the NI following chronic ethanol intake. Relaxin family peptide 3 receptor mRNA was also increased in the NI following chronic ethanol. Our quantitative PCR analysis also identified CRF mRNA within the rat NI, and the existence of a newly identified population of CRF-containing neurons was subsequently confirmed by detection of CRF immunoreactivity in rat and mouse NI. These data suggest that NI neurons contribute to reinstatement of alcohol seeking, via an involvement of CRF1 signalling. Furthermore, chronic ethanol intake leads to neuroadaptive changes in CRF and relaxin-3 systems within rat NI.

Sir2/Sirt1 Links Acute Inebriation to Presynaptic Changes and the Development of Alcohol Tolerance, Preference, and Reward.

Acute ethanol inebriation causes neuroadaptive changes in behavior that favor increased intake. Ethanol-induced alterations in gene expression, through epigenetic and other means, are likely to change cellular and neural circuit function. Ethanol markedly changes histone acetylation, and the sirtuin Sir2/SIRT1 that deacetylates histones and transcription factors is essential for the rewarding effects of long-term drug use. The molecular transformations leading from short-term to long-term ethanol responses mostly remain to be discovered. We find that Sir2 in the mushroom bodies of the fruit fly Drosophila promotes short-term ethanol-induced behavioral plasticity by allowing changes in the expression of presynaptic molecules. Acute inebriation strongly reduces Sir2 levels and increases histone H3 acetylation in the brain. Flies lacking Sir2 globally, in the adult nervous system, or specifically in the mushroom body α/β-lobes show reduced ethanol sensitivity and tolerance. Sir2-dependent ethanol reward is also localized to the mushroom bodies, and Sir2 mutants prefer ethanol even without a priming ethanol pre-exposure. Transcriptomic analysis reveals that specific presynaptic molecules, including the synaptic vesicle pool regulator Synapsin, depend on Sir2 to be regulated by ethanol. Synapsin is required for ethanol sensitivity and tolerance. We propose that the regulation of Sir2/SIRT1 by acute inebriation forms part of a transcriptional program in mushroom body neurons to alter presynaptic properties and neural responses to favor the development of ethanol tolerance, preference, and reward. We identify a mechanism by which acute ethanol inebriation leads to changes in nervous system function that may be an important basis for increasing ethanol intake and addiction liability. The findings are significant because they identify ethanol-driven transcriptional events that target presynaptic properties and direct behavioral plasticity. They also demonstrate that multiple forms of ethanol behavioral plasticity that are relevant to alcoholism are initiated by a shared mechanism. Finally, they link these events to the Drosophila brain region that associates context with innate approach and avoidance responses to code for reward and other higher-order behavior, similar in aspects to the role of the vertebrate mesolimbic system.

Episodic Social Stress-Escalated Cocaine Self-Administration: Role of Phasic and Tonic Corticotropin Releasing Factor in the Anterior and Posterior Ventral Tegmental Area.

Corticotropin releasing factor (CRF) within the ventral tegmental area (VTA) has emerged as a likely candidate molecule underlying the fundamental link between stress history and escalated drug self-administration. However, the nature of CRF release in the VTA during acute and repeated stress, as well as its role in enduring neuroadaptations driving later drug taking and seeking, are poorly understood. These experiments explore how CRF is released and interacts with its receptors in specific regions of the VTA both during and after stress to fuel later escalated cocaine taking and seeking behavior. Understanding these acute and persistent changes to the VTA CRF system may lead to better therapeutic interventions for addiction.

Convergent evidence from alcohol-dependent humans and rats for a hyperdopaminergic state in protracted abstinence

A major hypothesis in addiction research is that alcohol induces neuroadaptations in the mesolimbic dopamine (DA) system and that these neuroadaptations represent a key neurochemical event in compulsive drug use and relapse. Whether these neuroadaptations lead to a hypo- or hyperdopaminergic state during abstinence is a long-standing, unresolved debate among addiction researchers. The answer is of critical importance for understanding the neurobiological mechanism of addictive behavior. Here we set out to study systematically the neuroadaptive changes in the DA system during the addiction cycle in alcohol-dependent patients and rats. In postmortem brain samples from human alcoholics we found a strong down-regulation of the D1 receptor- and DA transporter (DAT)-binding sites, but D2-like receptor binding was unaffected. To gain insight into the time course of these neuroadaptations, we compared the human data with that from alcohol-dependent rats at several time points during abstinence. We found a dynamic regulation of D1 and DAT during 3 wk of abstinence. After the third week the rat data mirrored our human data. This time point was characterized by elevated extracellular DA levels, lack of synaptic response to D1 stimulation, and augmented motor activity. Further functional evidence is given by a genetic rat model for hyperdopaminergia that resembles a phenocopy of alcohol-dependent rats during protracted abstinence. In summary, we provide a new dynamic model of abstinence-related changes in the striatal DA system; in this model a hyperdopaminergic state during protracted abstinence is associated with vulnerability for relapse.

Brain Derived Neurotrophic Factor: From Neurobiology to Sexual Risk Prevention

Objective: The authors’ draw on neurobiological theory to posit that sexual risks might be associated with neurological changes, specifically, those neuro-adaptive changes associated with addictions. We propose that low levels of brain-derived neurotrophic factor (BDNF), a signaling molecule involved in cognitive, emotional, and addiction behaviors, may play a key role in the expression of high-risk sexual behaviors. Methods: In a prospective cohort of 400 people living with HIV (PLWH), information was collected regarding smoking (Fagerstrom Test for Nicotine Dependence), hazardous alcohol use (men >14 and women >7 drinks/week), sexual behaviors. To assess the role of BDNF, platelet poor plasma was obtained to measure BDNF levels and participants were dichotomized into Groups 1 (BDNF ≤ 5000 pg/mL) and 2 (BDNF >5000 pg/mL). Results: Over two-thirds of the participants reported multiple risk behaviors, confirming our hypothesis that Group 1 would have a general risk-taking tendency. Individuals in Group 1 were more likely to smoke (p=0.0001) and to drink alcohol hazardously (HAU) more days per week (p=0.04), particularly hard liquor (p=0.001). In support of our hypothesis, Group 1 was also more likely to report sex under the influence of drugs/alcohol (p=0.003) and to exchange sex for money (p=0.03). Men from Group 1 had multiple partners (p=0.09), and engaged in unprotected anal sex (p=0.08) more than those in Group 2. The results from regressions showed that BDNF (p=0.05), use of antidepressants (p=0.003), hazardous alcohol use (p=0.0001) and the BDNF x gender interaction (p=0.022) were significant predictors of high-risk sexual behaviors. Further supporting our postulate, participants with low BDNF showed triple the risk of herpes (p=0.05). Conclusion: This innovative approach demonstrated for the first time that substance abuse disorders (especially alcohol abuse), high-risk sexual behaviors, and sexually transmitted diseases occur more frequently in individuals with low BDNF levels. These findings suggest the importance of using BDNF modifiers in preventive interventions concerning people living with HIV. Given the limitations of the design, new studies among the general population are needed to confirm the generalizability of the findings.

The Effect of Chronic Alcohol Abuse on the Benzodiazepine Receptor System in Various Areas of the Human Brain

Objective: Alcohol abuse induces neuroadaptive changes in the functioning of neurotransmitter systems in the brain. Decrease of GABAergic neurotransmission found in alcoholics and persons with a high risk of alcohol dependence. Benzodiazepine receptor (BzDR) is allosterical modulatory site on GABA type A receptor complex (GABAAR), that modulate GABAergic function and may be important in mechanisms regulating the excitability of the brain processes involved in the alcohol addiction. The purpose of this study was to investigate the effects of chronic alcohol abuse on the BzDR in various areas of the human brain. Materials and Methods: Investigation of BzDR properties were studied in synaptosomal and mitochondrial membrane fractions from different brain areas of alcohol abused patients and non-alcoholic persons by radioreceptor assay with using selective ligands: [3H] flunitrazepam and [3H] PK-11195. Brain samples obtained at autopsy urgent. In total 126 samples of human brain areas were obtained to study radioreceptor binding, including a study group and control group. Results: Comparative study of kinetic parameters (Kd, Bmax) of [3H] flunitrazepam and [3H] PK-11195 binding with membrane fractions in studding brain samples was showed that affinity of BzDR was decreased and capacity increased in different areas of human brain under influence of alcohol abuse. More alters of synaptic BzDR “central” type (CBR) appeared in prefrontal cortex, mitochondrial BzDR “peripheral” type (PBR) – in n.caudatus and cerebella cortex. These results showed that alcohol addiction induce more expressive alterations in PBR than CBR in the brain structures that agree with maintaining function of glial cells in CNS under influence of different toxic factors. Conclusion: Chronic exposure to ethanol results in harmful effects on the human brain: causing nonuniform adaptive changes of BzDR in various areas of the brain, which can modulate GABAAR and reduce neuromediation GABA in various areas of the brain which can cause alcohol addiction. Graphical Abstract: Alcohol abuse induces neuroadaptive alters of benzodiazepine receptor system in various areas of the brain in patients with alcoholism that can modulate GABAAR and mediation of GABA in the brain, which can cause alcohol addiction.

Altered subjective reward valuation among drug-deprived heavy marijuana users: Aversion to uncertainty.

Marijuana is the most commonly used illicit drug in the United States and its use is rising. Nonetheless, scientific efforts to clarify the risk for addiction and other harm associated with marijuana use have been lacking. Maladaptive decision-making is a cardinal feature of addiction that is likely to emerge in heavy users. In particular, distorted subjective reward valuation related to homeostatic or allostatic processes has been implicated for many drugs of abuse. Selective changes in responses to uncertainty have been observed in response to intoxication and deprivation from various drugs of abuse. To assess for these potential neuroadaptive changes in reward valuation associated with marijuana deprivation, we examined the subjective value of uncertain and certain rewards among deprived and nondeprived heavy marijuana users in a behavioral economics decision-making task. Deprived users displayed reduced valuation of uncertain rewards, particularly when these rewards were more objectively valuable. This uncertainty aversion increased with increasing quantity of marijuana use. These results suggest comparable decision-making vulnerability from marijuana use as other drugs of abuse, and highlights targets for intervention.

Neurobiology of Alcohol Dependence and Implications on Treatment

The process of alcohol dependence has been conceptualized as a progress from controlled alcohol intake to compulsive alcohol consumption or a shift from alcohol intake for pleasure to compulsory alcohol seeking behavior. Hereditary and physical factors and the interaction of individuals with their environment, as well as permanent changes in the neurotransmitter and neurohormonal systems in the brain due to alcohol use, play the most important role in the etiology of alcohol dependence. The effects of ethanol on the neurotransmitter, neuropeptide and neuroendocrine systems not only account for its acute physiological and euphoric/reinforcing effects but also seem to be responsible for the development of dependence. While the motivation for alcohol use is mainly positive reinforcement in the earlier phases of alcohol consumption, both positive and negative reinforcements are involved in the process once dependence has developed. This event is caused by neuroadaptive process due to chronic alcohol consumption and also called as "allostasis". It seems that the most important neuroadaptive changes in progression from occasional alcohol intake to dependence are the down-regulation of the dopamine and gamma aminobutyric acid systems, permanent upregulation in the glutamate system and dysregulation in the stress systems (corticotropin-releasing hormone and serotonin) of the brain. In this paper, we will review the adaptive changes caused by chronic alcohol consumption which are important in the development of dependence and address the potential therapeutic contributions of interventions to these changes in alcohol dependence.

Transgenic mice with increased astrocyte expression of IL-6 show altered effects of acute ethanol on synaptic function

A growing body of evidence has revealed that resident cells of the central nervous system (CNS), and particularly the glial cells, comprise a neuroimmune system that serves a number of functions in the normal CNS and during adverse conditions. Cells of the neuroimmune system regulate CNS functions through the production of signaling factors, referred to as neuroimmune factors. Recent studies show that ethanol can activate cells of the neuroimmune system, resulting in the elevated production of neuroimmune factors, including the cytokine interleukin-6 (IL-6). Here we analyzed the consequences of this CNS action of ethanol using transgenic mice that express elevated levels of IL-6 through increased astrocyte expression (IL-6-tg) to model the increased IL-6 expression that occurs with ethanol use. Results show that increased IL-6 expression induces neuroadaptive changes that alter the effects of ethanol. In hippocampal slices from non-transgenic (non-tg) littermate control mice, synaptically evoked dendritic field excitatory postsynaptic potential (fEPSP) and somatic population spike (PS) at the Schaffer collateral to CA1 pyramidal neuron synapse were reduced by acute ethanol (20 or 60 mM). In contrast, acute ethanol enhanced the fEPSP and PS in hippocampal slices from IL-6 tg mice. Long-term synaptic plasticity of the fEPSP (i.e., LTP) showed the expected dose-dependent reduction by acute ethanol in non-tg hippocampal slices, whereas LTP in the IL-6 tg hippocampal slices was resistant to this depressive effect of acute ethanol. Consistent with altered effects of acute ethanol on synaptic function in the IL-6 tg mice, EEG recordings showed a higher level of CNS activity in the IL-6 tg mice than in the non-tg mice during the period of withdrawal from an acute high dose of ethanol. These results suggest a potential role for neuroadaptive effects of ethanol-induced astrocyte production of IL-6 as a mediator or modulator of the actions of ethanol on the CNS, including persistent changes in CNS function that contribute to cognitive dysfunction and the development of alcohol dependence.

Brain Angiotensin II AT1 receptors are involved in the acute and long-term amphetamine-induced neurocognitive alterations.

Angiotensin II, by activation of its brain AT1-receptors, plays an active role as neuromodulator in dopaminergic transmission. These receptors participate in the development of amphetamine-induced behavioral and dopamine release sensitization. Dopamine is involved in cognitive processes and provides connectivity between brain areas related to these processes. Amphetamine by its mimetic activity over dopamine neurotransmission elicits differential responses after acute administration or after re-exposure following long-term withdrawal periods in different cognitive processes. The purpose of this study is to evaluate the AT1-receptor involvement in the acute and long-term amphetamine-induced alterations in long-term memory and in cellular-related events. Male Wistar rats (250-300g) were used in this study. Acute effects: Amphetamine (0.5/2.5mg/kgi.p.) was administered after post-training in the inhibitory avoidance (IA) response. The AT1-receptor blocker Losartan was administered i.c.v. before a single dose of amphetamine (0.5mg/kgi.p.). Long-term effects: The AT1-receptors blocker Candesartan (3mg/kg p.o.) was administered for 5days followed by 5 consecutive days of amphetamine (2.5mg/kg/day, i.p.). The neuroadaptive changes were evidenced after 1week of withdrawal by an amphetamine challenge (0.5mg/kgi.p.). The IA response, the neuronal activation pattern, and the hippocampal synaptic transmission were evaluated. The impairing effect in the IA response of post-training acute amphetamine was partially prevented by Losartan. The long-term changes induced by repeated amphetamine (resistance to acute amphetamine interference in the IA response, neurochemical altered response, and increased hippocampal synaptic transmission) were prevented by AT1-receptors blockade. AT1-receptors are involved in the acute alterations and in the neuroadaptations induced by repeated amphetamine associated with neurocognitive processes.

Stable immediate early gene expression patterns in medial prefrontal cortex and striatum after long-term cocaine self-administration.

The transition from casual to compulsive drug use is thought to occur as a consequence of repeated drug taking leading to neuroadaptive changes in brain circuitry involved in emotion and cognition. At the basis of such neuroadaptations lie changes in the expression of immediate early genes (IEGs) implicated in transcriptional regulation, synaptic plasticity and intracellular signalling. However, little is known about how IEG expression patterns change during long-term drug self-administration. The present study, therefore, compares the effects of 10 and 60-day self-administration of cocaine and sucrose on the expression of 17 IEGs in brain regions implicated in addictive behaviour, i.e. dorsal striatum, ventral striatum and medial prefrontal cortex (mPFC). Increased expression after cocaine self-administration was found for 6 IEGs in dorsal and ventral striatum (c-fos, Mkp1, Fosb/ΔFosb, Egr2, Egr4, and Arc) and 10 IEGs in mPFC (same 6 IEGs as in striatum, plus Bdnf, Homer1, Sgk1 and Rgs2). Five of these 10 IEGs (Egr2, Fosb/ΔFosb, Bdnf, Homer1 and Jun) and Trkb in mPFC were responsive to long-term sucrose self-administration. Importantly, no major differences were found between IEG expression patterns after 10 or 60 days of cocaine self-administration, except Fosb/ΔFosb in dorsal striatum and Egr2 in mPFC, whereas the amount of cocaine obtained per session was comparable for short-term and long-term self-administration. These steady changes in IEG expression are, therefore, associated with stable self-administration behaviour rather than the total amount of cocaine consumed. Thus, sustained impulses to IEG regulation during prolonged cocaine self-administration may evoke neuroplastic changes underlying compulsive drug use.

Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects.

Addiction to psychostimulants has been considered as a chronic psychiatric disorder characterized by craving and compulsive drug seeking and use. Over the past two decades, accumulating evidence has demonstrated that repeated drug exposure causes long-lasting neurochemical and cellular changes that result in enduring neuroadaptation in brain circuitry and underlie compulsive drug consumption and relapse. Through intercellular signaling cascades, drugs of abuse induce remodeling in the rewarding circuitry that contributes to the neuroplasticity of learning and memory associated with addiction. Here, we review the role of the extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase, and its related intracellular signaling pathways in drug-induced neuroadaptive changes that are associated with drug-mediated psychomotor activity, rewarding properties and relapse of drug seeking behaviors. We also discuss the neurobiological and behavioral effects of pharmacological and genetic interferences with ERK-associated molecular cascades in response to abused substances. Understanding the dynamic modulation of ERK signaling in response to drugs may provide novel molecular targets for therapeutic strategies to drug addiction.

HIV-1 transgenic rats display an increase in [(3)H]dopamine uptake in the prefrontal cortex and striatum.

HIV viral proteins within the central nervous system are associated with the development of neurocognitive impairments in HIV-infected individuals. Dopamine transporter (DAT)-mediated dopamine transport is critical for normal dopamine homeostasis. Abnormal dopaminergic transmission has been implicated as a risk determinant of HIV-induced neurocognitive impairments. Our published work has demonstrated that transactivator of transcription (Tat)-induced inhibition of DAT is mediated by allosteric binding site(s) on DAT, not the interaction with the dopamine uptake site. The present study investigated whether impaired DAT function induced by Tat exposure in vitro can be documented in HIV-1 transgenic (HIV-1Tg) rats. We assessed kinetic analyses of [(3)H]dopamine uptake into prefrontal and striatal synaptosomes of HIV-1Tg and Fisher 344 rats. Compared with Fisher 344 rats, the capacity of dopamine transport in the prefrontal cortex (PFC) and striatum of HIV-1Tg rats was increased by 34 and 32%, respectively. Assessment of surface biotinylation indicated that DAT expression in the plasma membrane was reduced in PFC and enhanced in striatum, respectively, of HIV-1Tg rats. While the maximal binding sites (B max) of [(3)H]WIN 35,428 was decreased in striatum of HIV-1Tg rats, an increase in DAT turnover proportion was found, relative to Fisher 344 rats. Together, these findings suggest that neuroadaptive changes in DAT function are evidenced in the HIV-1Tg rats, perhaps compensating for viral-protein-induced abnormal dopaminergic transmission. Thus, our study provides novel insights into understanding mechanism underlying neurocognitive impairment evident in neuroAIDS.

The relationship between brain-derived neurotrophic factor and cognitive functions in alcohol-dependent patients: a preliminary study.

BackgroundAs a neurotoxic substance, alcohol can induce neurodegenesis in the brain. Alcohol-dependent patients’ cognitive functioning can be affected by chronic alcohol use. In addition, brain-derived neurotrophic factor (BDNF) is known to reflect the status of neuroadaptive changes. The purpose of this study was to investigate the relationship between cognitive functions and BDNF in alcohol-dependent patients.MethodsThe subjects were 39 alcohol-dependent patients. BDNF was measured using an enzyme-linked immunosorbent assay kit. We examined clinical features and administered the Korean version of Alcohol Dependence Scale. We also used the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) to measure cognitive functioning. Then, we determined the relationships between BDNF and various parts of the CERAD.ResultsThe performance of alcohol-dependent patients proved stable in most parts of the CERAD. Within the different parts of the CERAD, only Trail Making Test B correlated with BDNF. Trail Making Test specifically assesses executive functions.ConclusionsBDNF might play an important role in the detection of neurocognitive function among individuals with alcohol dependence.