cocaine

Nr4a1 and chromatin bivalency in cocaine pathophysiology

Epigenetic regulation of alternative splicing in the context of cocaine reward

Neuronal alternative splicing is a key gene regulatory mechanism in the brain. However, the spliceosome machinery is insufficient to fully specify splicing complexity. In considering the role of the epigenome in activity-dependent alternative splicing, we and others find the histone modification H3K36me3 to be a putative splicing regulator. In this study, we found that mouse cocaine self-administration caused widespread differential alternative splicing, concomitant with the enrichment of H3K36me3 at differentially spliced junctions. Importantly, only targeted epigenetic editing can distinguish between a direct role of H3K36me3 in splicing and an indirect role via regulation of splice factor expression elsewhere on the genome. We targeted Srsf11, which was both alternatively spliced and H3K36me3 enriched in the brain following cocaine self-administration. Epigenetic editing of H3K36me3 at Srsf11 was sufficient to drive its alternative splicing and enhanced cocaine self-administration, establishing the direct causal relevance of H3K36me3 to alternative splicing of Srsf11 and to reward behavior.

Addiction to cocaine: How you take the drug is more important than how much

Nr4a1-mediated morphological adaptations in Ventral Pallidal projections to Mediodorsal Thalamus support cocaine intake and relapse-like behaviors

Growing evidence suggests the ventral pallidum (VP) is critical for drug intake and seeking behaviors. Receiving dense projections from the nucleus accumbens as well as dopamine inputs from the midbrain, the VP plays a central role in the control of motivated behaviors. Repeated exposure to cocaine is known to alter VP neuronal firing and neurotransmission. Surprisingly, there is limited information on the molecular adaptations occurring in VP neurons following cocaine intake.To provide insights into cocaine-induced transcriptional alterations we performed RNA-sequencing on VP of mice following cocaine self-administration. Gene Ontology analysis pointed toward alterations in dendrite- and spinerelated genes. Subsequent transcriptional regulator analysis identified the transcription factor Nr4a1 as a common regulator for these sets of morphology-related genes.Consistent with the central role of the VP in reward, its neurons project to several key regions associated with cocaine-mediated behaviors. We thus assessed Nr4a1 expression levels in various projection populations.Following cocaine self-administration, VP neurons projecting to the mediodorsal thalamus (MDT) showed significantly increased Nr4a1 levels. To further investigate the role of Nr4a1 in cocaine intake and relapse, we bidirectionally manipulated its expression levels selectively in VP neurons projecting to the MDT. Increasing Nr4a1 levels resulted in enhanced relapse-like behaviors accompanied by a blockage of cocaine-induced spinogenesis.However, decreasing Nr4a1expression levels completely abolished cocaine intake and consequential relapse-like behaviors. Together, our preliminary findings suggest that drug-induced neuronal remodeling in pallido-thalamic circuits is critical for cocaine intake and relapse-like behaviors.

The anterior insular cortex in the rat exerts an inhibitory influence over the loss of control of heroin intake and subsequent propensity to relapse

The anterior insular cortex (AIC) has been implicated in addictive behaviour, including the loss of control over drug intake, craving and the propensity to relapse. Evidence suggests that the influence of the AIC on drug-related behaviours is complex as in rats exposed to extended access to cocaine self-administration, the AIC was shown to exert a state-dependent, bidirectional influence on the development and expression of loss of control over drug intake, facilitating the latter but impairing the former. However, it is unclear whether this influence of the AIC is confined to stimulant drugs that have marked peripheral sympathomimetic and anxiogenic effects or whether it extends to other addictive drugs, such as opiates, that lack overt acute aversive peripheral effects. We investigated in outbred rats the effects of bilateral excitotoxic lesions of AIC induced both prior to or after long-term exposure to extended access heroin self-administration, on the development and maintenance of escalated heroin intake and the subsequent vulnerability to relapse following abstinence. Compared to sham surgeries, pre-exposure AIC lesions had no effect on the development of loss of control over heroin intake, but lesions made after a history of escalated heroin intake potentiated escalation and also enhanced responding at relapse. These data show that the AIC inhibits or limits the loss of control over heroin intake and propensity to relapse, in marked contrast to its influence on the loss of control over cocaine intake.

Neuronal encoding of drug choices and preference in the orbitofrontal cortex

Human neuroimaging research has consistently shown that drug addiction is associated with structural and functional changes within the orbitofrontal cortex (OFC). In view of the important role of the OFC in value-based decision-making, these changes have been hypothesised to bias choice towards drug use despite and at the expense of other competing pursuits, thereby explaining drug addiction. Here I will present in vivo recording data in the OFC supporting this hypothesis in a choice-based model of addiction where rats could choose between two actions, one rewarded by a drug (cocaine or heroin), the other by a nondrug alternative (saccharin).

Cocaine-Sensitive Orbitofrontal Circuits Encode Action Variables for Flexible Decision Making

Neuroimaging in human drug addiction: an eye towards intervention development

Drug addiction is a chronically relapsing disorder characterized by compulsive drug use despite catastrophic personal consequences (e.g., loss of family, job) and even when the substance is no longer perceived as pleasurable. In this talk, I will present results of human neuroimaging studies, utilizing a multimodal approach (neuropsychology, functional magnetic resonance imaging, event-related potentials recordings), to explore the neurobiology underlying the core psychological impairments in drug addiction (impulsivity, drive/motivation, insight/awareness) as associated with its clinical symptomatology (intoxication, craving, bingeing, withdrawal). The focus of this talk is on understanding the role of the dopaminergic mesocorticolimbic circuit, and especially the prefrontal cortex, in higher-order executive dysfunction (e.g., disadvantageous decision-making such as trading a car for a couple of cocaine hits) in drug addicted individuals. The theoretical model that guides the presented research is called iRISA (Impaired Response Inhibition and Salience Attribution), postulating that abnormalities in the orbitofrontal cortex and anterior cingulate cortex, as related to dopaminergic dysfunction, contribute to the core clinical symptoms in drug addiction. Specifically, our multi-modality program of research is guided by the underlying working hypothesis that drug addicted individuals disproportionately attribute reward value to their drug of choice at the expense of other potentially but no-longer-rewarding stimuli, with a concomitant decrease in the ability to inhibit maladaptive drug use. In this talk I will also explore whether treatment (as usual) and 6-month abstinence enhance recovery in these brain-behavior compromises in treatment seeking cocaine addicted individuals. Promising neuroimaging studies, which combine pharmacological (i.e., oral methylphenidate, or RitalinTM) and salient cognitive tasks or functional connectivity during resting-state, will be discussed as examples for using neuroimaging for empirically guiding the development of effective neurorehabilitation strategies (encompassing cognitive reappraisal and transcranial direct current stimulation) in drug addiction.

Activating Neuronal Ensembles in the Nucleus Accumbens Enhances Cocaine-Conditioned Place Preference

Anxiety levels after vicarious social defeat stress are associated with vulnerability and resilience to cocaine-induced conditioned place preference in female mice

Attenuation of the appetitive response to a cocaine-associated context after an escalating-dose drug regimen is associated with maladaptive changes in the prefrontal cortex

Capturing, tracking, and profiling cocaine-recruited neuronal ensembles in the nucleus accumbens

Cellular mechanism of silent synapses formation in central amygdala in cocaine-induced locomotor sensitization

Impact of a highly potent and long-acting cocaine hydrolase on recovery of dopaminergic system after cocaine exposure

FENS Forum 2024

A cross-network oscillatory motif underpinning cocaine-paired memory retrieval

Dopamine D3 receptor antagonism blocked the Akt/mTOR pathway downregulation in the dentate gyrus after the reinstatement of cocaine induced CPP evoked by physiological stress

The effect of cocaine and alcohol poly-consumption on drug seeking behavior in young adult rats

Effect of cocaine self-administration on cerebellar perineuronal nets components

Effects of the activation of the noradrenergic system on reconsolidation, extinction, and subsequent reinstatement of conditioned memories associated with the administration of cocaine

Effects of S-ketamine on cocaine-seeking behavior in rats

Elevation of anandamide by URB597 mitigates cocaine-seeking behaviour during abstinence

Epigenetic priming underlies latent gene dysregulation in cocaine withdrawal

Impact of astrocyte reactivity in cocaine addiction

Individual differences in DNA methylation associated with sensitivity and resistance to the extinction of cocaine memories

Influence of neurogenic improvement strategies on extinction and reinstatement of cocaine-induced Conditioned Place Preference

Involvement of nucleus accumbens parvalbumin interneurons in cocaine seeking behavior

Lack of the Sez6 protein, or inhibition of ectodomain shedding, attenuates cocaine relapse

Modulating the effects of a lesion in LVIII of the cerebellar vermis on cocaine-induced CPP through chemogenetic inhibition of the interposed nucleus activity

Molecular candidates in the nucleus accumbens shell involved in the protective effect of social interaction when available as an alternative to cocaine

Noradrenergic stimulation modulates extinction of conditioned memories induced by cocaine in mice

Optogenetic neural plasticity in Somatostatin-expressing interneurons to suppress cocaine-seeking behaviour

A rare variant of VGLUT3 (p.T8I) identified in patients with psychiatric disorders induces excessive habits, cocaine addiction-like and maladaptive eating in a mouse model

Progressive hyperpolarization-activated cation current (Ih) reduction: a response mechanism to decrease cocaine-induced excitability in VTA DA neurons

Reversing escalated cocaine intake with social contact and optogenetic modulation of the subthalamic nucleus

Role of CYFIP2 on medial prefrontal cortex to nucleus accumbens pathway in regulation of cocaine reward

Role of a hypothalamus-habenula circuit in acupuncture inhibition of cocaine addiction-like behaviors

Role of a lateral hypothalamus-lateral habenula pathway in cocaine-induced psychomotor responses

The role of Microglia in synaptic adaptations in the nucleus accumbens after cocaine-induced conditioned place preference

Striatal modulation of brain cholesterol metabolism during abstinence reduces cocaine seeking in rats

Structural plasticity of dendritic spines within cocaine-seeking neuronal ensembles

TRPA1 can modulate cocaine addiction within glutamatergic neurons extending from medial frontal cortex to nucleus accumbens

Unique gene expression profiles in the extinction of cocaine and nicotine self-administration

Voluntary alcohol consumption alters the neurobiology underlying cocaine-seeking

Ayahuasca prevents the expression of cocaine-induced conditioned place preference in C57BL/6 mice

FENS Forum 2024

LDT cholinergic inputs to the nucleus accumbens neurons facilitate cocaine reinforcing properties

FENS Forum 2024

Chronic cocaine exposure modulates decision-making in mice in a sex-dependent manner

FENS Forum 2024

Cocaine detrimentally affects mitochondrial functionality and cell viability in dopaminergic neurons

FENS Forum 2024

Compulsive-like seeking behavior correlates with AMPA receptor rectification in synapses of the subthalamic nucleus in a rat model of cocaine addiction

FENS Forum 2024