scholarly journals Sex-specific prefrontal cortex dysfunction underlying opioid-induced cognitive impairment

2019 ◽  
Author(s):  
Eden M. Anderson ◽  
Annabel Engelhardt ◽  
Skyler Demis ◽  
Elissa Porath ◽  
Matthew C. Hearing
Keyword(s):  
Cognitive Control ◽  
Pyramidal Neurons ◽  
Ex Vivo ◽  
Self Administration ◽  
Synaptic Regulation ◽  
Biological Sex ◽  
Prefrontal Function ◽  
Chronic Drug Use ◽  
Drug Naïve ◽  
Cortical Regions

AbstractWomen transition to addiction faster and experience greater difficulties remaining abstinent; however, what drives this is unknown. Although poorly understood, loss of cognitive control following chronic drug use has been linked to decreased activation of frontal cortical regions. We show that self-administration of the opioid, remifentanil, causes a long-lasting decrease inex vivoexcitability but augments firing capacity of pyramidal neurons in the prelimbic cortex. This phenomenon occurs faster in females, manifests from sex-specific changes in excitatory and inhibitory synaptic regulation and aligns with impairments in cognitive flexibility. Further, chemogenetic induction of a hypoactive pyramidal neuron state in drug-naïve mice produces deficits, while compensating for this hypoactive state protects against cognitive inflexibility resulting from opioid self-administration. These data define cellular and synaptic mechanisms by which opioids impair prefrontal function and cognitive control and indicate that interventions aimed at treating opioid addiction must be tailored based on biological sex.

scholarly journals Sex Differences in the Reward-Enhancing Effects of Nicotine on Ethanol Reinforcement: A Reinforcer Demand Analysis

2019 ◽  
Vol 22 (2) ◽  
pp. 238-247 ◽  
Author(s):  
Scott T Barrett ◽  
Brady M Thompson ◽  
Jessica R Emory ◽  
Chris E Larsen ◽  
Steven T Pittenger ◽  
...  
Keyword(s):  
Alcohol Abuse ◽  
Ethanol Solution ◽  
Female Rats ◽  
Demand Model ◽  
Self Administration ◽  
Biological Sex ◽  
Ethanol Reinforcement ◽  
Nicotine Abuse ◽  
Reinforcer Demand ◽  
Reinforcement Value

Abstract Background Alcohol is often consumed with tobacco, and dependence to alcohol and tobacco are highly comorbid. In addition, there are differences in the prevalence of nicotine- and alcohol-abuse between the sexes. Nicotine produces enhancing effects on the value of other reinforcers, which may extend to alcohol. Methods Male and female Wistar rats were trained to self-administer 15% ethanol solution in 30-minute sessions. Once ethanol self-administration was established, demand for ethanol was evaluated using an exponential reinforcer demand method, in which the response cost per reinforcer delivery was systematically increased over blocks of several sessions. Within each cost condition, rats were preinjected with nicotine (0.05, 0.1, 0.2, or 0.4 mg/kg base, SC) or saline 5 minutes before self-administration sessions. The effects of nicotine dose and biological sex were evaluated using the estimates generated by the reinforcer demand model. Results Under saline conditions, males showed greater sensitivity to ethanol reinforcement than females. Nicotine enhanced the reinforcement value of alcohol and this varied with sex. In both sexes, 0.4 mg/kg nicotine decreased intensity of ethanol demand. However, 0.05, 0.1, and 0.2 mg/kg nicotine decreased elasticity of ethanol demand in females, but not in males. Conclusions Nicotine enhances ethanol reinforcement, which may partially drive comorbidity between nicotine-abuse and alcohol-abuse. Males showed signs of greater ethanol reinforcement value than females under saline conditions, and nicotine attenuated this effect by increasing ethanol reinforcement value in the females. These findings highlight that a complete understanding of alcohol-abuse must include a thorough study of alcohol use in the context of other drug use, including nicotine. Implications Nicotine dose dependently enhances the alcohol reinforcement value in a manner that is clearly influenced by biological sex. Under saline baseline conditions, males show lower elasticity of demand for alcohol reinforcement than females, indicative of greater reinforcement value. However, nicotine attenuated this difference by enhancing alcohol reward in the females. Specifically, low-to-moderate doses (0.05–0.2 mg/kg) of nicotine decreased elasticity of alcohol demand in female rats, increasing the perseverance of their alcohol taking behavior. These data indicate that the well-documented reward-enhancing effects of nicotine on sensory reinforcement extend to alcohol reinforcement and that these vary with biological sex.

scholarly journals In utero MRI identifies consequences of early-gestation alcohol drinking on fetal brain development in rhesus macaques

2020 ◽  
Vol 117 (18) ◽  
pp. 10035-10044
Author(s):  
Xiaojie Wang ◽  
Verginia C. Cuzon Carlson ◽  
Colin Studholme ◽  
Natali Newman ◽  
Matthew M. Ford ◽  
...  
Keyword(s):  
White Matter ◽  
Brain Development ◽  
Ex Vivo ◽  
Early Recognition ◽  
Brain Mri ◽  
Fetal Brain ◽  
Fetal Mri ◽  
Diffusion Anisotropy ◽  
Self Administration ◽  
White Matter Tracts

One factor that contributes to the high prevalence of fetal alcohol spectrum disorder (FASD) is binge-like consumption of alcohol before pregnancy awareness. It is known that treatments are more effective with early recognition of FASD. Recent advances in retrospective motion correction for the reconstruction of three-dimensional (3D) fetal brain MRI have led to significant improvements in the quality and resolution of anatomical and diffusion MRI of the fetal brain. Here, a rhesus macaque model of FASD, involving oral self-administration of 1.5 g/kg ethanol per day beginning prior to pregnancy and extending through the first 60 d of a 168-d gestational term, was utilized to determine whether fetal MRI could detect alcohol-induced abnormalities in brain development. This approach revealed differences between ethanol-exposed and control fetuses at gestation day 135 (G135), but not G110 or G85. At G135, ethanol-exposed fetuses had reduced brainstem and cerebellum volume and water diffusion anisotropy in several white matter tracts, compared to controls. Ex vivo electrophysiological recordings performed on fetal brain tissue obtained immediately following MRI demonstrated that the structural abnormalities observed at G135 are of functional significance. Specifically, spontaneous excitatory postsynaptic current amplitudes measured from individual neurons in the primary somatosensory cortex and putamen strongly correlated with diffusion anisotropy in the white matter tracts that connect these structures. These findings demonstrate that exposure to ethanol early in gestation perturbs development of brain regions associated with motor control in a manner that is detectable with fetal MRI.

scholarly journals Non-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA-Driven Intractable Epilepsy

2021 ◽  
Vol 14 ◽  
Author(s):  
Achira Roy ◽  
Victor Z. Han ◽  
Angela M. Bard ◽  
Devin T. Wehle ◽  
Stephen E. P. Smith ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Genetic Model ◽  
Ex Vivo ◽  
Significant Proportion ◽  
Intractable Epilepsy ◽  
Therapeutic Interventions ◽  
Hippocampal Pyramidal Neurons ◽  
Phosphoinositide 3 Kinase

Patients harboring mutations in the PI3K-AKT-MTOR pathway-encoding genes often develop a spectrum of neurodevelopmental disorders including epilepsy. A significant proportion remains unresponsive to conventional anti-seizure medications. Understanding mutation-specific pathophysiology is thus critical for molecularly targeted therapies. We previously determined that mouse models expressing a patient-related activating mutation in PIK3CA, encoding the p110α catalytic subunit of phosphoinositide-3-kinase (PI3K), are epileptic and acutely treatable by PI3K inhibition, irrespective of dysmorphology. Here we report the physiological mechanisms underlying this dysregulated neuronal excitability. In vivo, we demonstrate epileptiform events in the Pik3ca mutant hippocampus. By ex vivo analyses, we show that Pik3ca-driven hyperactivation of hippocampal pyramidal neurons is mediated by changes in multiple non-synaptic, cell-intrinsic properties. Finally, we report that acute inhibition of PI3K or AKT, but not MTOR activity, suppresses the intrinsic hyperactivity of the mutant neurons. These acute mechanisms are distinct from those causing neuronal hyperactivity in other AKT-MTOR epileptic models and define parameters to facilitate the development of new molecularly rational therapeutic interventions for intractable epilepsy.

Isradipine inhibits nicotine intravenous self-administration in drug-naive mice

1995 ◽  
Vol 52 (2) ◽  
pp. 271-274 ◽  
Author(s):  
M.Cristina Martellotta ◽  
Alexander Kuzmin ◽  
Edwin Zvartau ◽  
Gregorio Cossu ◽  
Gian Luigi Gessa ◽  
...  
Keyword(s):  
Self Administration ◽  
Drug Naïve

Self-administration of the cannabinoid receptor agonist WIN 55,212-2 in drug-naive mice

Neuroscience ◽  
1998 ◽  
Vol 85 (2) ◽  
pp. 327-330 ◽  
Author(s):  
M.C. Martellotta ◽  
G. Cossu ◽  
L. Fattore ◽  
G.L. Gessa ◽  
W. Fratta
Keyword(s):  
Receptor Agonist ◽  
Cannabinoid Receptor ◽  
Self Administration ◽  
Drug Naïve

scholarly journals The antihelminthic moxidectin enhances tonic GABA currents in rodent hippocampal pyramidal neurons

2018 ◽  
Vol 119 (5) ◽  
pp. 1693-1698
Author(s):  
Jay Spampanato ◽  
Anne Gibson ◽  
F. Edward Dudek
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Gaba Receptors ◽  
Pyramidal Neurons ◽  
Ex Vivo ◽  
Companion Animals ◽  
Brain Slices ◽  
Dependent Manner ◽  
Hippocampal Pyramidal Neurons ◽  
Mammalian Central Nervous System

Macrocyclic lactones (MLs) are commonly used treatments for parasitic worm and insect infections in humans, livestock, and companion animals. MLs target the invertebrate glutamate-activated chloride channel that is not present in vertebrates. MLs are not entirely inert in vertebrates, though; they have been reported to have activity in heterologous expression systems consisting of ligand-gated ion channels that are present in the mammalian central nervous system (CNS). However, these compounds are typically not able to reach significant concentrations in the CNS because of the activity of the blood-brain barrier P-glycoprotein extrusion system. Despite this, these compounds are able to reach low levels in the CNS that may be useful in the design of novel “designer” ligand-receptor systems that can be used to directly investigate neuronal control of behavior in mammals and have potential for use in treating human neurological diseases. To determine whether MLs might affect neurons in intact brains, we investigated the activity of the ML moxidectin (MOX) at native GABA receptors. Specifically, we recorded tonic and phasic miniature inhibitory postsynaptic currents (mIPSCs) in ex vivo brain slices. Our data show that MOX potentiated tonic GABA currents in a dose-dependent manner but had no concomitant effects on phasic GABA currents (i.e., MOX had no effect on the amplitude, frequency, or decay kinetics of mIPSCs). These studies indicate that behavioral experiments that implement a ML-based novel ligand-receptor system should take care to control for potential effects of the ML on native tonic GABA receptors.NEW & NOTEWORTHY We have identified a novel mechanism of action in the mammalian central nervous system for the antihelminthic moxidectin, commonly prescribed to animals worldwide and currently being evaluated for use in humans. Specifically, moxidectin applied to rodent brain slices selectively enhanced the tonic GABA conductance of hippocampal pyramidal neurons.

scholarly journals Cognitive Control, Goal Maintenance, and Prefrontal Function in Healthy Aging

2007 ◽  
Vol 18 (5) ◽  
pp. 1010-1028 ◽  
Author(s):  
Jessica L. Paxton ◽  
Deanna M. Barch ◽  
Caroline A. Racine ◽  
Todd S. Braver
Keyword(s):  
Cognitive Control ◽  
Healthy Aging ◽  
Goal Maintenance ◽  
Prefrontal Function ◽  
Control Goal

scholarly journals Acute effects of cocaine on the neurobiology of cognitive control

2008 ◽  
Vol 363 (1507) ◽  
pp. 3267-3276 ◽  
Author(s):  
Hugh Garavan ◽  
Jacqueline N Kaufman ◽  
Robert Hester
Keyword(s):  
Cognitive Control ◽  
Cognitive Processes ◽  
Impulse Control ◽  
Control Function ◽  
Brain Regions ◽  
Acute Effects ◽  
Neurocognitive Dysfunction ◽  
Action Monitoring ◽  
Motor Response Inhibition ◽  
Drug Naïve

Compromised ability to exert control over drug urges and drug-seeking behaviour is a characteristic of addiction. One specific cognitive control function, impulse control, has been shown to be a risk factor for the development of substance problems and has been linked in animal models to increased drug administration and relapse. We present evidence of a direct effect of cocaine on the neurobiology underlying impulse control. In a laboratory test of motor response inhibition, an intravenous cocaine administration improved task performance in 13 cocaine users. This improvement was accompanied by increased activation in right dorsolateral and inferior frontal cortex, regions considered critical for this cognitive function. Similarly, for both inhibitory control and action monitoring processes, cocaine normalized activation levels in lateral and medial prefrontal regions previously reported to be hypoactive in users relative to drug-naive controls. The acute amelioration of neurocognitive dysfunction may reflect a chronic dysregulation of those brain regions and the cognitive processes they subserve. Furthermore, the effects of cocaine on midline function suggest a dopaminergically mediated intersection between cocaine's acute reinforcing effects and its effects on cognitive control.

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