[Why do schizophrenic patients smoke?].
Psychiatrische Poliklinik, Inselspital, Bern, Schweiz.Der Nervenarzt (Impact Factor: 0.79). 04/2005; 76(3):287-94.
Patients suffering from schizophrenia are known to show an increased prevalence of nicotine addiction. The aim of this paper is to elucidate the relationship between schizophrenia and (chronic) use of nicotine. Nicotine seems to improve cognitive functions critically affected in schizophrenia, in particular sustained attention, focused attention, working memory, short-term memory, and recognition memory. Furthermore, several studies using evoked potentials (P50 paradigm) and prepulse inhibition of the acoustic startle reflex suggest that deficient preattentive information processing, a core feature of schizophrenia illness, is improved following treatment with nicotine. Smoking can also improve extrapyramidal secondary effects of antipsychotic medication and it induces cytochrome P4501A2, an enzyme system involved in the metabolism of several antipsychotics. There is substantial evidence that nicotine could be used by patients with schizophrenia as a "self-medication" to improve deficits in attention, cognition, and information processing and to reduce side effects of antipsychotic medication. Possible pharmacotherapeutic approaches for the regulation of abnormal neurotransmission at nicotinic acetylcholine receptors are discussed.
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ABSTRACT: This chapter presents the significant results from genome scans for six different mental disorders and observe shared chromosomal susceptibility regions among all of them. From this first analysis, it is observed that chromosome 15, particularly, shared common susceptibility regions for some disorders, including autism spectrum disorder (ASD), schizophrenia (SZ), BP, attention deficit hyperactivity disorder (ADHD), and alchohol disorder (ALC). The only significant linkage results for catatonia in a subgroup of SZ are also observed on chromosome 15. The chapter presents chromosomes with significant genome scan results for ASD putting an emphasis on chromosome 15 where chromosomal rearrangements and abnormalities, and candidate gene analyses are also presented in relation to ASD and catatonia susceptibility loci. Chromosome 15 contains three to four regions shared by five different mental disorders and some interesting candidate genes. As such, this chromosome is a prime target for direct investigations of common intermediate phenotypes in relevant cohorts. Catatonia seems to be a shared syndrome in ASD, SZ, and BP, and may be a useful intermediate phenotype. Findings suggest overlapping susceptibility regions on chromosome 15.
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ABSTRACT: Startle responses are attenuated by prepulse inhibition (PPI), which is considered to reflect a sensorimotor gating mechanism and is impaired in patients suffering from schizophrenia. A midbrain circuit that mediates PPI in rats has been proposed and behavioral experiments have indicated an important role of acetylcholine and GABA in inhibiting startle. We here test the hypothesis that activation of the midbrain neurons can inhibit startle signaling through a cholinergic mechanism. We have developed a brain slice that comprises startle mediating giant pontine neurons as well as midbrain mesopontine neurons required for PPI. Patch clamp recordings of startle mediating brainstem neurons combined with stimulation of sensory afferents within the startle pathway and activation of mesopontine neurons revealed a delayed inhibition of synaptic transmission 300 ms and 1 s after midbrain activation. The latter was reversed by the muscarinic antagonist scopolamine. Further, there was a shift in the paired pulse ratio 1 s but not 300 ms after midbrain stimulation. Our results show that there is a direct cholinergic projection from the proposed PPI midbrain circuit to startle mediating neurons in the brainstem and that this projection inhibits synaptic transmission in the startle pathway in a distinct time window through the activation of presynaptic muscarinic receptors. Moreover, there is indication for a different receptor that mediates inhibition through this projection in a shorter time window and is located postsynaptically. Our results contribute to the understanding of mechanisms underlying PPI, which is important for developing new targets in the treatment of disorders accompanied with pre-attentive cognitive deficits.
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ABSTRACT: Blockade of NMDA glutamate receptors with dizocilpine (MK-801) has been shown to cause substantial cognitive deficits and has been used to model symptoms of schizophrenia. Nicotine or nicotinic agonists, in contrast, may enhance cognitive or attentional functions and be of therapeutic potential in schizophrenia. Nicotinic-glutamatergic interactions, therefore, may have important implications in cognitive functions and antipsychotic treatments. Clozapine, a widely used antipsychotic drug, has been shown in some studies to be effective in ameliorating the cognitive deficits associated with schizophrenia. However, there is some evidence to suggest that clozapine similar to haloperidol may impair sustained attention in rats. In this study, we sought to determine whether chronic nicotine or dizocilpine may modify the effects of acute clozapine on attentional parameters and whether the behavioral effects would correlate with nicotinic or NMDA receptor densities in discrete brain regions. Adult female rats trained on an operant visual signal detection task were given 4 weeks of nicotine (5 mg/kg/day), dizocilpine (0.15 mg/kg/day), the same doses of both nicotine and dizocilpine as a mixture, or saline by osmotic minipump. While on chronic treatment, rats received acute injections of various doses of clozapine (0, 0.625, 1.25, 2.5 mg/kg, sc) 10 min prior to tests on attentional tasks. The pumps were removed on day 28 and 24 h later the animals were sacrificed for measurements of receptor densities in specific brain regions. The percent correct hit as a measure of sustained attention was significantly impaired by clozapine in a dose-related manner. Neither chronic nicotine nor dizocilpine affected this measure on their own or modified the effects of clozapine. Both nicotine and dizocilpine affected the receptor bindings in a region specific manner and their combination further modified the effects of each other in selective regions. Attentional performance was inversely correlated with alpha-bungarotoxin binding in the frontal cortex only. In conclusion, the data suggest attentional impairments with clozapine alone and no modification of this effect with nicotine or dizocilpine. Moreover, cortical low affinity nicotinic receptors may have a role in attentional functions.
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