Role of the Central Cholinergic System in the Therapeutics of Schizophrenia

The therapeutic agents currently used to treat schizophrenia effectively improve psychotic symptoms; however, they are limited by adverse effects and poor efficacy when negative symptoms of the illness and cognitive dysfunction are considered. While optimal pharmacotherapy would directly target the neuropathology of schizophrenia neither the underlying neurobiological substrates of the behavioral symptoms nor the cognitive deficits have been clearly established. Abnormalities in the neurotransmitters dopamine, serotonin, glutamate, and GABA are commonly implicated in schizophrenia; however, it is not uncommon for alterations in the brain cholinergic system (e.g., choline acetyltransferase, nicotinic and muscarinic acetylcholine receptors) to also be reported. Further, there is now considerable evidence in the animal literature to suggest that both first and second generation antipsychotics (when administered chronically) can alter the levels of several cholinergic markers in the brain as well as impair memory-related task performance. Given the well-established importance of central cholinergic neurons to information processing and cognition, it is important that cholinergic function in schizophrenia be further elucidated and that the mechanisms of the chronic effects of antipsychotic drugs on this important neurotransmitter system be identified. A better understanding of these mechanisms would be expected to facilitate optimal treatment strategies for schizophrenia as well as the identification of novel therapeutic targets. In this review, the following topics are discussed: 1) the central cholinergic system in schizophrenia 2) effects of antipsychotic drugs on central cholinergic neurons 3) important neurotrophins in schizophrenia, especially those that support central cholinergic neurons; 4) novel strategies to optimize the therapeutics of schizophrenia via the use of cholinergic compounds as primary (i.e., antipsychotic) treatments as well as adjunctive, pro-cognitive agents

Nicotinic acetylcholine receptors in neurological and psychiatric diseases

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are widely distributed both pre- and post-synaptically in the mammalian brain. By modulating cation flux across cell membranes, neuronal nAChRs regulate neuronal excitability and the release of a variety of neurotransmitters to influence multiple physiologic and behavioral processes including synaptic plasticity, motor function, attention, learning and memory. Abnormalities of neuronal nAChRs have been implicated in the pathophysiology of neurologic disorders including Alzheimer’s disease, Parkinson’s disease, epilepsy, and Tourette´s syndrome, as well as psychiatric disorders including schizophrenia, depression, and anxiety. The potential role of nAChRs in a particular illness may be indicated by alterations in the expression of nAChRs in relevant brain regions, genetic variability in the genes encoding for nAChR subunit proteins, and/or clinical or preclinical observations where specific ligands showed a therapeutic effect. Over the past 25 years, extensive preclinical and some early clinical evidence suggested that ligands at nAChRs might have therapeutic potential for neurologic and psychiatric disorders. However, to date the only approved indications for nAChR ligands are smoking cessation and the treatment of dry eye disease. It has been argued that progress in nAChR drug discovery has been limited by translational gaps between the preclinical models and the human disease as well as unresolved questions regarding the pharmacological goal (i.e., agonism, antagonism or receptor desensitization) depending on the disease

Effects of cysteamine in chronic corticosterone-treated mice on proBDNF and mature BDNF (mBDNF) protein levels in the frontal cortex and hippocampus.

<p>CD-1 male mice were treated for 7 weeks with vehicle (0.45% hydroxypropyl-β-cyclodextrin) or corticosterone (CORT; 35 ug/ml) in the presence or absence of cysteamine (CYS; 150 mg/kg/day) during the last three weeks of corticosterone treatment. proBDNF and mBDNF protein levels were determined in the (A) frontal cortex and (B) hippocampus by Western blot analysis. The upper panels shows a representative autoradiogram of proBDNF and mBDNF and the lower panel represents the fold change in optical density values normalized to vehicle-treated controls. β-actin was used as a protein loading control. Values are mean ± SE (n = 6 mice per group). (C) BDNF protein levels as measured by ELISA in frontal cortex samples from mice treated with vehicle or cysteamine for 3 weeks as above. Data represent the fold change in BDNF protein levels (pg/mg protein) normalized to vehicle-treated controls. Values are mean ± SE (n = 5 mice per group).</p

Effects of cysteamine in chronic corticosterone-treated mice on anxiety-like behaviors as measured in the (A-B) Light/Dark test, (C) Elevated Plus Maze Maze test and (D) Tail Suspension Test.

<p>CD-1 male mice were treated for 7 weeks with vehicle (0.45% hydroxypropyl-β-cyclodextrin) or corticosterone (CORT; 35 ug/ml) in the presence or absence of cysteamine (CYS; 150 mg/kg/day) during the last three weeks of the corticosterone treatment. (A) % of the time spent in the dark area, (B) % of the time spent in the lit area; (B) % of the number of entries in the open arms, and (D) the immobility score (in seconds). Values are mean ± SE (n = 8–9 mice per group). Bonferroni's post hoc test. *p<0.05 versus vehicle and ^#p<0.05 versus CORT.</p

Effects of chronic corticosterone treatment on TrkB protein levels in the hippocampus.

<p>CD-1 male mice were treated with corticosterone (CORT; 35 ug/ml/day) or vehicle (0.45% hydroxypropyl-β-cyclodextrin) for (A) 3, (B) 5 or (C) 7 weeks. TrkB protein levels were determined by Western blot analysis. The upper panel shows a representative autoradiogram of TrkB and the lower panel represents fold change in optical density values normalized to vehicle-treated controls. β-actin was used as a protein loading control. Values are mean ± SE (n = 5–6 mice per group). *p<0.05 versus vehicle.</p

Effects of chronic corticosterone treatment on TrkB mRNA levels in the frontal cortex and hippocampus.

<p>CD-1 male mice were treated with corticosterone (CORT; 35 ug/ml/day) or vehicle (0.45% hydroxypropyl-β-cyclodextrin) for 7 weeks. TrkB mRNA levels were determined by qRT-PCR analysis. The level of TrkB mRNA was normalized to that of RPS3 RNA in the same sample. Values are expressed as fold change relative to vehicle-treated mice. Open and filled bars represent vehicle and corticosterone-treated groups, respectively. Error bars represent standard Error (SE) of n = 4 mice per group.</p

Effects of chronic corticosterone treatment on TrkB protein levels in the frontal cortex.

<p>CD-1 male mice were treated with corticosterone (CORT; 35 ug/ml/day) or vehicle (0.45% hydroxypropyl-β-cyclodextrin) for (A) 3, (B) 5 or (C) 7 weeks. TrkB protein levels were determined by Western blot analysis. The upper panel shows a representative autoradiogram of TrkB and the lower panel represents the fold change in optical density values normalized to vehicle-treated controls. β-actin was used as a protein loading control. Values are mean ± SE (n = 5–6 mice per group). *p<0.05 versus vehicle.</p

Effects of cysteamine in chronic corticosterone-treated mice in the Open Field test.

<p>CD-1 male mice were treated for 7 weeks with vehicle (0.45% hydroxypropyl-β-cyclodextrin) or corticosterone (CORT; 35 ug/ml) in the presence or absence of cysteamine (CYS; 150 mg/kg/day) during the last three weeks of the corticosterone treatment. (A) Mean total of the time-spent in the center for the entire session, (B) the ambulatory counts for each 5 min period, (C) the total ambulatory distance and (D) the ambulatory distance in the center over total. Values plotted are mean ± SEM (n = 8–10 per group). Bonferroni's post hoc test. *p<0.05 versus vehicle and ^#p<0.05 versus CORT.</p

Effects of cysteamine in TrkB knockout mice on anxiety-like behaviors as measured in the (A) Open Field test, (B-C) Light/Dark test, (D) Elevated Plus Maze Maze test and (E) Tail Suspension Test.

<p>TrkB knock out (KO) and wild type (WT) male mice were treated for 3 weeks with vehicle (water) or cysteamine (CYS; 150 mg/kg/day). (A) Mean total of the time spent in the center for the entire session, (B) % of the time-spent in the lit area, (C) % of the time-spent in the dark area, (D) % of the time in open arms, and (E) the immobility score (in seconds). Values are mean ± SE (n = 6 mice per group). Bonferroni's post hoc test. *p<0.05 versus vehicle.</p

Effects of cysteamine in chronic corticosterone-treated mice on TrkB protein levels in the frontal cortex and hippocampus.

<p>CD-1 male mice were treated for 7 weeks with vehicle (0.45% hydroxypropyl-β-cyclodextrin) or corticosterone (CORT; 35 ug/ml) in the presence or absence of cysteamine (CYS; 150 mg/kg/day) during the last three weeks of corticosterone treatment. TrkB protein levels were determined in the (A) frontal cortex and (B) hippocampus by Western blot analysis. The upper panel shows a representative autoradiogram of TrkB and the lower panel represents the fold change in optical density values normalized to vehicle-treated controls. β-Actin was used as a protein loading control. Values are mean ± SE (n = 5–6 mice per group). *p<0.05 versus vehicle and ^#p<0.05 versus CORT.</p