Repeated cocaine use produces adaptations in brain function that contribute to long-lasting behaviors associated with cocaine use disorder (CUD). In rodents, the activity-regulated cytoskeleton-associated protein (Arc) can regulate glutamatergic synaptic transmission, and cocaine regulates Arc expression and subcellular localization in multiple brain regions, including the nucleus accumbens (NAc)-a brain region linked to CUD-related behavior. We show here that repeated, non-contingent cocaine administration in global Arc KO male mice produced a dramatic hypersensitization of cocaine locomotor responses and drug experience-dependent sensitization of conditioned place preference (CPP).
View Article and Find Full Text PDFFragile X syndrome (FXS), a leading monogenic cause of autism spectrum disorders (ASDs), typically occurs as the result of a mutation silencing the Fmr1 gene, preventing production of the fragile X messenger ribonucleoprotein (FMRP). FXS is characterized, in part, by hyperactivity, impaired behavioral flexibility, and the development of repetitive, or stereotyped, behaviors. While these phenotypes are influenced by striatal activity, few studies have examined FXS or FMRP in the context of striatal function.
View Article and Find Full Text PDFIntravenous self-administration (IVSA) is a behavioral method of voluntary drug intake in animal models which is used to study the reinforcing effects of drugs of abuse. It is considered to have greater face validity in the study of substance use and abuse than other assays, and thus, allows for valuable insight into the neurobiological basis of addiction, and the development of substance abuse disorders. The technique typically involves surgically inserting a catheter into the jugular vein, which enables the infusion of drug solution after the performance of a desired operant behavior.
View Article and Find Full Text PDFFront Behav Neurosci
March 2022
The discovery of efficacious treatment options for neuropsychiatric conditions is a process that remains in jeopardy. Contributing to the failure of clinical trials, a strong positive bias exists in the reported results of preclinical studies, including in the field of neuroscience. However, despite clear recognition of major factors that lead to bias, efforts to address them have not made much meaningful change, receiving inadequate attention from the scientific community.
View Article and Find Full Text PDFThe fragile X mental retardation protein (FMRP), an RNA-binding protein, regulates cocaine-induced neuronal plasticity and is critical for the normal development of drug-induced locomotor sensitization, as well as reward-related learning in the conditioned place preference assay. However, it is unknown whether FMRP impacts behaviors that are used to more closely model substance use disorders. Utilizing a cocaine intravenous self-administration (IVSA) assay in Fmr1 knockout (KO) and wild-type (WT) littermate mice, we find that, despite normal acquisition and extinction learning, Fmr1 KO mice fail to make a normal upward shift in responding during dose-response testing.
View Article and Find Full Text PDFThe fragile X mental retardation protein (FMRP), an RNA-binding protein that mediates the transport, stability, and translation of hundreds of brain RNAs, is critically involved in regulating synaptic function. Loss of FMRP, as in fragile X syndrome (FXS), is a leading monogenic cause of autism and results in altered structural and functional synaptic plasticity, widely described in the hippocampus and cortex. Though FXS is associated with hyperactivity, impaired social interaction, and the development of repetitive or stereotyped behaviors, all of which are influenced by striatal activity, few studies have investigated the function of FMRP here.
View Article and Find Full Text PDFThe activity-regulated cytoskeleton-associated protein (Arc, also known as Arg3.1), an immediate early gene and synaptic regulator, is upregulated following a single cocaine exposure. However, there is not much known regarding Arc/Arg3.
View Article and Find Full Text PDFThe activity-regulated cytoskeleton-associated protein (Arc, also known as Arg3.1) regulates glutamatergic synapse plasticity and has been linked to neuropsychiatric illness; however, its role in behaviors associated with mood and anxiety disorders remains unclear. We find that stress upregulates Arc expression in the adult mouse nucleus accumbens (NAc)-a brain region implicated in mood and anxiety behaviors.
View Article and Find Full Text PDFIndividuals suffering from substance-use disorders develop strong associations between the drug's rewarding effects and environmental cues, creating powerful, enduring triggers for relapse. We found that dephosphorylated, nuclear histone deacetylase 5 (HDAC5) in the nucleus accumbens (NAc) reduced cocaine reward-context associations and relapse-like behaviors in a cocaine self-administration model. We also discovered that HDAC5 associates with an activity-sensitive enhancer of the Npas4 gene and negatively regulates NPAS4 expression.
View Article and Find Full Text PDFIt is thought that rewarding experiences with drugs create strong contextual associations and encourage repeated intake. In turn, repeated exposures to drugs of abuse make lasting alterations in the brain function of vulnerable individuals, and these persistent alterations likely serve to maintain the maladaptive drug seeking and taking behaviors characteristic of addiction/dependence(2). In rodents, reward experience and contextual associations are frequently measured using the conditioned place preference assay, or CPP, wherein preference for a previously drug-paired context is measured.
View Article and Find Full Text PDFAdolescent cigarette use is associated with reduced quitting success and continued smoking in adulthood. Interestingly, polymorphisms of the dopamine D3 receptor (DRD3) gene have been associated with smoking behavior, and the receptor is expressed in an age- and brain region-dependent manner that suggests relevance to addiction. Here, we investigate the possible role of dopamine-related receptors, including DRD3 and an intriguing splice variant known as D3nf, in nicotine-induced sensitization.
View Article and Find Full Text PDFRepeated cocaine exposure causes persistent, maladaptive alterations in brain and behavior, and hope for effective therapeutics lies in understanding these processes. We describe here an essential role for fragile X mental retardation protein (FMRP), an RNA-binding protein and regulator of dendritic protein synthesis, in cocaine conditioned place preference, behavioral sensitization, and motor stereotypy. Cocaine reward deficits in FMRP-deficient mice stem from elevated mGluR5 (or GRM5) function, similar to a subset of fragile X symptoms, and do not extend to natural reward.
View Article and Find Full Text PDFAdolescents with Attention Deficit Hyperactivity Disorder (ADHD) have higher rates of smoking than adolescents without ADHD. Since methylphenidate is the primary drug used to treat ADHD, it is likely that many adolescents are exposed to both methylphenidate and nicotine. Recent studies have established that adolescent nicotine induces long-term changes in several neurobehavioral variables.
View Article and Find Full Text PDFChromatin remodeling by histone deacetylases (HDACs) is a key mechanism regulating behavioral adaptations to cocaine use. We report here that cocaine and cyclic adenosine monophosphate (cAMP) signaling induce the transient nuclear accumulation of HDAC5 in rodent striatum. We show that cAMP-stimulated nuclear import of HDAC5 requires a signaling mechanism that involves transient, protein phosphatase 2A (PP2A)-dependent dephosphorylation of a Cdk5 site (S279) found within the HDAC5 nuclear localization sequence.
View Article and Find Full Text PDFFragile X syndrome (FXS), the most common genetic form of mental retardation and autism, is caused by loss-of-function mutations in an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). Neurons from patients and the mouse Fmr1 knockout (KO) model are characterized by an excess of dendritic spines, suggesting a deficit in excitatory synapse elimination. In response to neuronal activity, myocyte enhancer factor 2 (MEF2) transcription factors induce robust synapse elimination.
View Article and Find Full Text PDFHumans often start smoking during adolescence. Recent results suggest that rodents may also be particularly vulnerable to nicotine dependence during adolescence. We examined the effect of chronic nicotine exposure on gene expression profiles during adolescence in female rats, who were dosed with nicotine (and control animals were dosed with saline) via subcutaneously implanted osmotic minipumps.
View Article and Find Full Text PDFSixty male and female Long-Evans hooded rats were administered 1, 2, or 5mg/kg methylphenidate (MPH) suspended in apple juice on postnatal day (P)15 or P40 using a novel, non-invasive oral administration technique. Plasma was collected 15 min after ingestion and analyzed by high performance liquid chromatography-mass spectrometry (HPLC-MS) to confirm appropriate concentrations. HPLC-MS plasma analysis showed levels comparable to previous gavage studies using MPH.
View Article and Find Full Text PDFAdolescent nicotine exposure is associated with long-term use, and it has been suggested that this vulnerability to addiction may relate to lasting anxiogenic effects of the drug. However, few studies have addressed long-term effects of adolescent nicotine, and fewer yet have compared adolescent to adult exposure. Male and female Long-Evans rats continuously received nicotine bitartrate or sodium tartrate via osmotic mini-pumps over 15 days either during adolescence (p28-42) or adulthood (p85-99).
View Article and Find Full Text PDFThe objective of the current study was to examine how periadolescent nicotine exposure affects dendritic morphology of medium spiny neurons from the nucleus accumbens shell. Male Long-Evans hooded rats were chronically administered nicotine or saline for a period extending from postnatal day 22 (p22) to p69. Nicotine and saline administration was via subcutaneously implanted osmotic pumps.
View Article and Find Full Text PDFObjective: Fewer than one third of American women take folic acid daily, although many women report that they would take folic acid if their physicians advised them to do so. This study determined the impact of a physician intervention during routine gynecologic visits on folic acid supplementation.
Study Design: Patients were assigned randomly to receive brief folic acid counseling, a reminder phone call, and 30 folic acid tablets (n = 162 women; intervention group) or to receive counseling about other preventive health behaviors and a folic acid informational pamphlet (n = 160 women; control group).
Objective: Many health professional groups recommend folic acid supplementation for all women able to become pregnant. In this study, we document folic acid supplement use among a sample of women receiving routine gynecologic care.
Methods: A short questionnaire was administered to 322 women aged 18-45 years who were seeking routine gynecologic care at participating clinics in Little Rock, Arkansas.