Neurobiology of Disease
March 22, 2021
Noelia Granado, Sara Ares-Santos, Idaira Oliva et al.
117 citations
The dopamine D2 receptor is necessary for the neurotoxic effects of methamphetamine and MDMA (ecstasy) in mice. In wild-type mice, both drugs caused hyperthermia, loss of dopamine markers (tyrosine hydroxylase and dopamine transporter) in the striatum, inflammation, and dopaminergic cell death in the substantia nigra pars compacta. In mice lacking the D2 receptor (D2R−/−), all these effects were blocked, including the loss of dopaminergic neurons. The neuroprotective effect of D2R inactivation was not solely due to preventing hyperthermia, as reserpine lowered body temperature in both genotypes but potentiated toxicity only in wild-type mice. These results indicate that D2R is essential for methamphetamine and MDMA neurotoxicity, independent of body temperature.
Neurobiology of Disease
November 7, 2019
Sriparna Ghosal, Catharine H. Duman, Rong-Jian Liu et al.
94 citations
Chronic unpredictable stress in male rodents reduces GABAergic proteins and the frequency of inhibitory postsynaptic currents in layer V pyramidal neurons of the medial prefrontal cortex, accompanied by depression-like behaviors. A single dose of ketamine reverses these stress-induced deficits in GABA markers and depressive-like behaviors. The findings indicate that impairments of GABAergic synapses are key determinants of depressive behavior and that ketamine restores both GABA inhibitory and glutamate neurotransmission.
Neurobiology of Disease
March 22, 2021
Robert E. Featherstone, Yuling Liang, John A. Saunders et al.
75 citations
Mice given repeated doses of ketamine and then tested after six months of abstinence showed lasting disruptions in brain function and cognition. The animals had reduced amplitude of later auditory event-related potential components (N40 and P80) and diminished stimulus-evoked theta oscillations, indicating impaired information processing. They also displayed deficits in reversal learning and spatial memory. Brain analysis revealed increased astrocyte proliferation and decreased expression of the glial glutamate transporter GLT-1, without signs of neuronal degeneration. These findings suggest that subchronic ketamine induces long-term adaptive or plastic brain changes that persist well beyond drug exposure, closely resembling cognitive impairments seen in human ketamine abusers.
Neurobiology of Disease
December 1, 2023
Youge Qu, Akifumi Eguchi, Li Ma et al.
26 citations
Pretreatment with MDMA for 14 days blocked anhedonia-like behavior and reduced synaptic proteins and brain-derived neurotrophic factor in the prefrontal cortex of mice exposed to chronic restraint stress. Cutting the subdiaphragmatic vagus nerve (vagotomy) blocked these beneficial effects. The gut microbiome showed differences in α-diversity between groups, and specific microbes varied between vehicle- and MDMA-treated stressed mice. Vagotomy prevented increases in three plasma compounds seen in MDMA-treated stressed mice, and two of those compounds correlated positively with several microbes. The data suggest that the gut-brain axis via the subdiaphragmatic vagus nerve may contribute to MDMA-induced stress resilience.
Neurobiology of Disease
September 1, 2024
Lijia Chang, Yan Wei, Youge Qu et al.
22 citations
In mice susceptible to chronic social defeat stress, removing the spleen reduces arketamine's antidepressant-like effects. RNA sequencing of the prefrontal cortex revealed that the oxidative phosphorylation (OXPHOS) pathway mediates this effect. Inhibiting OXPHOS with oligomycin A reversed the spleen removal's suppressive effect. Specific OXPHOS genes—COX11, UQCR11, and ATP5e—may be involved. Transforming growth factor β1 (TGF-β1) and COX11 appear to modulate the suppression; activating the TGF-β1 receptor with SRI-01138 alleviated it. Cutting the subdiaphragmatic vagus nerve also counteracted the inhibitory effect of splenectomy. These results suggest that arketamine's antidepressant-like effects involve the OXPHOS pathway and TGF-β1 in the prefrontal cortex, communicated through a spleen-brain axis via the vagus nerve.
Neurobiology of Disease
March 1, 2025
Liubov S. Kalinichenko, Iulia Zoicas, Anne-Marie Bienia et al.
4 citations
Overexpression of acid sphingomyelinase (ASM) in the forebrain affects addiction-related behaviors differently in male and female mice. In males, forebrain ASM overexpression increased alcohol consumption in a free-choice paradigm and reduced conditioned place preference (CPP) for alcohol and cocaine, but not for amphetamine, ketamine, or high-fat/carbohydrate food. In females, it increased binge-like alcohol drinking while moderate consumption remained unchanged, and enhanced CPP for amphetamine but not other substances. These findings suggest ASM plays a sex-specific role in the reinforcing effects of certain addictive substances, offering potential molecular targets for drug- and sex-specific therapies.
Neurobiology of Disease
February 1, 2025
Peihan J Huang, Jake J Son, Yasra Arif et al.
Heavy cannabis users show weaker alpha brain oscillations during the encoding phase of a working memory task, particularly in superior parietal and occipital regions, compared to nonusers. During memory maintenance, a group-by-condition interaction emerged: cannabis users exhibited weaker alpha and beta oscillations during maintain trials but stronger oscillations in the same regions during manipulate trials, alongside prolonged reaction times. Nonusers showed no such differences. Neurobehavioral relationships in prefrontal cortices appeared only in nonusers. Chronic cannabis use may impair initial memory encoding but prompt compensatory neural activity during more demanding memory manipulation.
Neurobiology of Disease
March 1, 2024
Yong Yang, Akifumi Eguchi, Chisato Mori et al.
Depression often accompanies liver cirrhosis, but the underlying reasons are unclear. In mice with cirrhosis induced by common bile duct ligation (CBDL), depression-like behaviors, inflammation, reduced synaptic proteins in the prefrontal cortex, gut microbiota imbalance, and altered blood metabolites were observed. These changes were reversed by severing the subdiaphragmatic vagus nerve, and a single injection of arketamine improved the depression-like behaviors. The findings suggest that the gut-liver-brain axis, via the vagus nerve, mediates depression in cirrhosis, and arketamine may offer a new treatment.
Neurobiology of Disease
January 1, 2023
Marta Barrera-Conde, Emma Veza-Estévez, Maria Gomis-Gonzalez et al.
CDK5, a kinase that regulates neurotransmission, and its partner PSD95 were studied in olfactory cells from first-episode psychosis patients with and without prior cannabis use, and in a mouse model. Patients who had used cannabis showed less social impairment, lower CDK5, and higher PSD95 than non-users. Treating cells from non-users with a cannabinoid agonist in vitro reduced CDK5. In mice, the NMDA blocker PCP caused social deficits and altered PSD95/CDK5, which were partly reversed by adding a cannabinoid agonist or by blocking CDK5 activity. Increased CDK5 may be an early marker of psychosis-related social deficits, modulated by cannabis.
Neurobiology of Disease
May 17, 2021
Zhaohong Qin, Li Zhang, Michael A. Zasloff et al.
In mice, subanesthetic doses of ketamine produce schizophrenia-like behaviors, including hyperlocomotion and deficits in working memory and sensorimotor gating. Ketamine increased the membrane resistance and excitability of pyramidal neurons in the prefrontal cortex and reduced endocannabinoid mobilization while unexpectedly decreasing inhibitory inputs. Pharmacological inhibition of the enzyme PTP1B with Trodusquemine restored normal neuronal properties and prevented the ketamine-induced deficits in memory and sensorimotor gating, but not hyperlocomotion. Ablation of PTP1B in glutamatergic neurons similarly prevented memory and sensorimotor gating deficits but not hyperlocomotion, suggesting PTP1B in different cell types mediates distinct effects. Trodusquemine may represent a new class of fast-acting antipsychotic drugs for schizophrenia-like symptoms.
Neurobiology of Disease
March 1, 2014
Erica Zamberletti, Sarah Beggiato, Luca Steardo et al.
Adolescent exposure to THC in female rats leads to long-lasting behavioral changes in adulthood, including memory deficits, social withdrawal, altered emotional reactivity, and heightened sensitivity to the effects of PCP. These changes are accompanied by reduced levels of the enzyme GAD67 and the neurotransmitter GABA in the prefrontal cortex, as well as increased glutamate and cFos activity in the prefrontal cortex and dorsal striatum. The findings suggest that adolescent THC exposure may contribute to the development of psychotic-like behaviors later in life.
Neurobiology of Disease
March 1, 2007
Colin Kehrer, Tamar Dugladze, Nino Maziashvili et al.
Exposure to the compound MK-801, which induces psychosis-like symptoms similar to those in acute schizophrenia, alters brain activity in an animal model. Gamma frequency oscillations in the hippocampus, evoked by kainate, were more powerful in animals that had received MK-801 than in controls. The resting membrane potential of pyramidal cells was more depolarized after MK-801, while other membrane properties remained unchanged. The authors suggest that changes in sodium-potassium pump activity and increased phasic inhibition may underlie these effects.