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1.
Psychopharmacology (Berl) ; 234(9-10): 1573-1586, 2017 05.
Article in English | MEDLINE | ID: mdl-28243714

ABSTRACT

RATIONALE: Smoking is the leading cause of preventable death in the USA, but quit attempts result in withdrawal-induced cognitive dysfunction and predicts relapse. Greater understanding of the neural mechanism(s) underlying these cognitive deficits is required to develop targeted treatments to aid quit attempts. OBJECTIVES: We examined nicotine withdrawal-induced inattention in mice lacking the α7 nicotinic acetylcholine receptor (nAChR) using the five-choice continuous performance test (5C-CPT). METHODS: Mice were trained in the 5C-CPT prior to osmotic minipump implantation containing saline or nicotine. Experiment 1 used 40 mg kg-1 day-1 nicotine treatment and tested C57BL/6 mice 4, 28, and 52 h after pump removal. Experiment 2 used 14 and 40 mg kg-1 day-1 nicotine treatment in α7 nAChR knockout (KO) and wildtype (WT) littermates tested 4 h after pump removal. Subsets of WT mice were killed before and after pump removal to assess changes in receptor expression associated with nicotine administration and withdrawal. RESULTS: Nicotine withdrawal impaired attention in the 5C-CPT, driven by response inhibition and target detection deficits. The overall attentional deficit was absent in α7 nAChR KO mice despite response disinhibition in these mice. Synaptosomal glutamate mGluR5 and dopamine D4 receptor expression were reduced during chronic nicotine but increased during withdrawal, potentially contributing to cognitive deficits. CONCLUSIONS: The α7 nAChR may underlie nicotine withdrawal-induced deficits in target detection but is not required for response disinhibition deficits. Alterations to the glutamatergic and dopaminergic pathways may also contribute to withdrawal-induced attentional deficits, providing novel targets to alleviate the cognitive symptoms of withdrawal during quit attempts.


Subject(s)
Attention/physiology , Nicotine/administration & dosage , Nicotine/adverse effects , Psychomotor Performance/physiology , Substance Withdrawal Syndrome/metabolism , alpha7 Nicotinic Acetylcholine Receptor/deficiency , Animals , Attention/drug effects , Choice Behavior/drug effects , Choice Behavior/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Psychomotor Performance/drug effects , Substance Withdrawal Syndrome/psychology , Synaptosomes/drug effects , Synaptosomes/metabolism , alpha7 Nicotinic Acetylcholine Receptor/agonists
2.
Transl Psychiatry ; 4: e400, 2014 Jun 17.
Article in English | MEDLINE | ID: mdl-24937094

ABSTRACT

Autism spectrum disorders (ASDs) now affect 1-2% of the children born in the United States. Hundreds of genetic, metabolic and environmental factors are known to increase the risk of ASD. Similar factors are known to influence the risk of schizophrenia and bipolar disorder; however, a unifying mechanistic explanation has remained elusive. Here we used the maternal immune activation (MIA) mouse model of neurodevelopmental and neuropsychiatric disorders to study the effects of a single dose of the antipurinergic drug suramin on the behavior and metabolism of adult animals. We found that disturbances in social behavior, novelty preference and metabolism are not permanent but are treatable with antipurinergic therapy (APT) in this model of ASD and schizophrenia. A single dose of suramin (20 mg kg(-1) intraperitoneally (i.p.)) given to 6-month-old adults restored normal social behavior, novelty preference and metabolism. Comprehensive metabolomic analysis identified purine metabolism as the key regulatory pathway. Correction of purine metabolism normalized 17 of 18 metabolic pathways that were disturbed in the MIA model. Two days after treatment, the suramin concentration in the plasma and brainstem was 7.64 µM pmol µl(-1) (±0.50) and 5.15 pmol mg(-1) (±0.49), respectively. These data show good uptake of suramin into the central nervous system at the level of the brainstem. Most of the improvements associated with APT were lost after 5 weeks of drug washout, consistent with the 1-week plasma half-life of suramin in mice. Our results show that purine metabolism is a master regulator of behavior and metabolism in the MIA model, and that single-dose APT with suramin acutely reverses these abnormalities, even in adults.


Subject(s)
Behavior, Animal/drug effects , Child Development Disorders, Pervasive/drug therapy , Metabolic Networks and Pathways/drug effects , Purinergic Antagonists/pharmacology , Purines/metabolism , Social Behavior , Suramin/pharmacokinetics , Animals , Brain/drug effects , Brain/metabolism , Brain Stem/drug effects , Brain Stem/metabolism , Child Development Disorders, Pervasive/chemically induced , Disease Models, Animal , Male , Metabolomics , Mice , Mice, Inbred C57BL , Purinergic Antagonists/administration & dosage , Purinergic Antagonists/pharmacokinetics , Random Allocation , Suramin/administration & dosage , Suramin/pharmacology
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