Biology subjects

Kruyer, A.

Publications and source records attributed to Kruyer, A..

4 recordsLinked to original sources

bioRxiv2026

Reward Circuit Adaptations After Chronic Antipsychotic Treatment Confer Addiction Vulnerability

ObjectiveAntipsychotics are widely used chronically to treat several psychiatric conditions and off-label indications, but their clinical utility is often accompanied by motor and/or metabolic side effects. Antipsychotics can also alter the brains reward circuitry, and we recently showed that upon abrupt discontinuation, chronic treatment with the first-generation antipsychotic haloperidol increases cocaine relapse in a rodent model of i.v. cocaine self-administration. Here, we examined whether chronic treatment with second-generation antipsychotics was also associated with increased addiction vulnerability in rodents and humans, and sought to further characterize the cellular substrate linking antipsychotic exposure to substance use disorder (SUD). MethodsAdult rats received subcutaneous infusion of risperidone, olanzapine, or vehicle for 14 days. Rats were then trained to self-administer i.v. cocaine or oral sucrose pellets for 10 days and active lever presses were paired with compound cue exposure. After a period of extinction training, reward seeking was reinstated by restoration of cues to active lever pressing for 20 minutes. To enable quantification of dendritic spine morphology and manipulation of MSNs during relapse, viral approaches were used to label D1- or D2-MSNs in the nucleus accumbens core (NAcore), a region that encodes reward-related responses and regulates symptoms associated with addiction and other psychiatric disorders, including schizophrenia. To assess the clinical relationship between chronic antipsychotic use and SUD, we conducted a systematic review and meta-analysis of studies identified through PubMed, CENTRAL, Scopus, and Embase that examined the effects of antipsychotic treatment on addictive substance use or craving in patients with SUD. ResultsIn rats, chronic risperidone or olanzapine treatment delayed extinction learning and increased cue-induced cocaine seeking, but did not alter seeking of the natural reward sucrose or its extinction. Cued relapse increased spine head diameter in NAcore D2-MSNs, but not D1-MSNs after antipsychotic treatment relative to vehicle-treated controls. Chemogenetic inhibition of D2-MSNs reversed addiction vulnerability conferred by antipsychotic treatment. In patients whose SUDs were treated with antipsychotics, duration of treatment (>4 months) strongly predicted addictive substance use or craving independent of antipsychotic type (first- vs. second-generation) or misused substance (psychostimulant, opioid, alcohol, or cannabis). ConclusionsChronic antipsychotic treatment, regardless of drug class, was associated with increased vulnerability to addictive substance use and relapse-like behavior in a rat model, and was linked to potentiation of D2-MSNs in the ventral striatum. In humans, systematic review and meta-analytic findings supported this pattern in patients maintained on antipsychotic treatment.

neuroscience↗

bioRxiv2024

Central Amygdala Astrocyte Plasticity Underlies GABAergic Dysregulation in Ethanol Dependence

Dependence is a hallmark of alcohol use disorder characterized by excessive alcohol intake and withdrawal symptoms. The central nucleus of the amygdala (CeA) is a key brain structure underlying the synaptic and behavioral consequences of ethanol dependence. While accumulating evidence suggests that astrocytes regulate synaptic transmission and behavior, there is a limited understanding of the role astrocytes play in ethanol dependence. The present study used a combination of viral labeling, super resolution confocal microscopy, 3D image analysis, and slice electrophysiology to determine the effects of chronic intermittent ethanol (CIE) exposure on astrocyte plasticity in the CeA. During withdrawal from CIE exposure, we observed increased GABA transmission, an upregulation in astrocytic GAT3 levels, and an increased proximity of astrocyte processes near CeA synapses. Furthermore, GAT3 levels and synaptic proximity were positively associated with voluntary ethanol drinking in dependent rats. Slice electrophysiology confirmed that the upregulation in astrocytic GAT3 levels was functional, as CIE exposure unmasked a GAT3-sensitive tonic GABA current in the CeA. A causal role for astrocytic GAT3 in ethanol dependence was assessed using viral-mediated GAT3 overexpression and knockdown approaches. However, GAT3 knockdown or overexpression had no effect on somatic withdrawal symptoms, dependence-escalated ethanol intake, aversion-resistant drinking, or post-dependent ethanol drinking in male or female rats. Moreover, intra-CeA pharmacological inhibition of GAT3 also did not alter dependent ethanol drinking. Together, these findings indicate that ethanol dependence induces GABAergic dysregulation and astrocyte plasticity in the CeA. However, astrocytic GAT3 does not appear necessary for the drinking related phenotypes associated with dependence.

neuroscience↗

bioRxiv2020

Accumbens D2-MSN hyperactivity drives behavioral supersensitivity

Antipsychotic-induced behavioral supersensitivity is a problematic consequence of long-term treatment with antipsychotic drugs and is characterized by emergence of refractory symptoms and dyskinesias. The underlying mechanisms are unknown, and no rational approaches exist to prevent or reverse antipsychotic-induced supersensitivity. Here we describe major adaptations impacting populations of striatal medium spiny neurons (MSNs) during the development of behavioral supersensitivity and reveal a prominent role played by D2 receptor expressing MSNs. We show that enhanced D2-MSN activity underlies several symptoms spanning from psychostimulant sensitization, to antipsychotic treatment resistance and drug addiction. Our data warn against severe adverse events following antipsychotic treatment discontinuation and offer insight that may inform therapeutic approaches to overcome antipsychotic-induced supersensitivity.

neuroscience↗

bioRxiv2020

Heroin Cues Reveal Astroglial Heterogeneity in the Nucleus Accumbens Core

Opioid use disorder (OUD) produces detrimental personal and societal consequences. Astrocytes are a major cell group in the brain that receives little attention in mediating OUD. We determined how astrocytes and the astroglial glutamate transporter, GLT-1, in the nucleus accumbens core adapt and contribute to heroin seeking in rats. Seeking heroin, but not sucrose, produced two transient forms of plasticity in different astroglial subpopulations. Increased morphological proximity to synapses occurred in one subpopulation and increased extrasynaptic GLT-1 expression in another. Augmented synapse proximity by astroglia occurred selectively at D2-dopamine receptor expressing dendrites, while changes in GLT-1 were not neuron-subtype specific. Importantly, mRNA-antisense inhibition of either morphological or GLT-1 plasticity promoted cue-induced heroin seeking. We show that heroin cues induce two distinct forms of transient plasticity in separate astroglial subpopulations that dampen heroin relapse. TEASERDifferent subpopulations of astrocytes engage with accumbens synapses to dampen heroin relapse.

animal behavior and cognition↗