Interaction of corticosterone and nicotine in regulation of prepulse inhibition in mice
Introduction
The involvement of stress in psychiatric illness, especially schizophrenia and bipolar disorder, is well accepted. For example, there appears to be a clear correlation between stressful life events and relapse frequency in schizophrenic patients (Birley and Brown, 1970) and relatively minor stressors may be predictive of relapse susceptibility (Norman and Malla, 1994). Additionally, there is some evidence for the involvement of stress in the onset of psychosis (Gruen and Baron, 1984) and stress reduction, through intervention, social skill training and education has also been found to be of benefit in the treatment of schizophrenia (Falloon, 1992, Liberman et al., 1986).
Despite this well-established connection, the mechanism by which stress affects schizophrenia is unknown. Schizophrenic patients display abnormalities in the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis, suggesting these patients may have an altered susceptibility and response to stress. Disruptions observed in the ANS of schizophrenic patients, such as increased basal heart rate (Gruzelier and Venables, 1975), high skin conductance (Kim et al., 1993) and high systolic blood pressure (Gruzelier and Venables, 1975), suggest that patients may be in a high state of arousal. Abnormalities reported in the HPA of schizophrenic patients are less clear, with studies reporting both normal (Van Cauter et al., 1991) and increased (Whalley et al., 1989) basal cortisol levels and correlating cortisol levels with both negative (Tandon et al., 1991) and positive symptoms (Keshavan et al., 1989).
There is also a strong link between schizophrenia and nicotine. This link was first suggested with the observation of very high rates of smoking among the mentally ill. The incidence of smoking in this group is approximately 60% compared to 25% in the general population. This rate is highest in schizophrenia, where smoking prevalence has been estimated at up to 90% (de Leon et al., 1995). A number of possible reasons for the high incidence of continued smoking among schizophrenics have been proposed. Clinical studies have shown smoking improves processing of auditory stimuli (sensory gating) in patients with schizophrenia, and is known to lessen negative symptoms by increasing dopamine release in the frontal cortex (Lyon, 1999). As cessation of smoking causes a worsening of schizophrenic symptoms, it has been suggested that smoking is a form of self-medication (Dalack et al., 1999). Nicotinic acetylcholine receptors (nAChRs) are pentameric receptors consisting of a combination of α and β subunits. In mammalian brain two of the most common nAChR subtypes are the heteropentameric α4β2 and homopentameric α7 subtypes (Leonard and Bertrand, 2001). A role for nAChRs in schizophrenia is suggested by aberrations in receptor regulation and number observed in schizophrenic brains. Post-mortem studies have shown a reduction in the expression of the α7 subtype in hippocampus (Freedman et al., 1995), frontal cortex (Guan et al., 1999) and thalamus (Court et al., 1999) of patients with schizophrenia. Similarly, α4β2 binding has been found to be reduced in the hippocampus, caudate and cortex of schizophrenic patients (Breese et al., 2000).
Deficits in gating of sensory stimuli displayed by patients with schizophrenia (Braff et al., 1999, Kumari et al., 2002) and bipolar disorder (Franks et al., 1983) can be measured with prepulse inhibition (PPI), which measures the ability of a weak prepulse to inhibit the reflexive startle response to a powerful sensory stimulus (Braff et al., 1999, Geyer et al., 2001). Deficiencies in sensory gating may lead to the sensory flooding and disturbed thought processes characteristic of schizophrenia. Because PPI of acoustic startle can be measured similarly in humans and experimental animals, it provides a unique opportunity to investigate central neurotransmitter mechanisms involved in sensory gating. There is substantial biochemical, pharmacological and genetic evidence for a nicotinic component of disrupted sensory gating, likely involving the α7-typenAChR. Injection of α7 antisense oligonucleotides into the lateral ventricles of rats caused a 40% decrease of α-bungarotoxin binding, indicative of α7 nAChR subtype expression, and abolished PPI responses (Leonard et al., 1996, Rollins et al., 1993). Sensory gating deficits have also been observed in rats following α-bungarotoxin and methyllycaconitine administration, both potent α7 nAChR antagonists (Luntz-Leybman et al., 1992, Rollins et al., 1993). A role for the α7 nAChR in schizophrenia is also supported by genetic evidence, as a sensory gating defect in schizophrenic patients and their first-degree relatives has been linked to a dinucleotide polymorphism at chromosome 15q13-14, the site of the α7 nAChR subunit (Freedman et al., 1997). Inbred mouse strains have also been shown to have differing degrees of PPI. Bullock and colleagues (Joels et al., 1997) examined PPI in six inbred mouse strains and found a significant correlation between levels of α-bungarotoxin binding in the hippocampus and degree of PPI.
Nicotine and stress may interact to affect PPI. It has been repeatedly shown that high dose corticosterone treatment leads to a decrease in α-bungarotoxin binding in a number of brain regions, an effect observed in both radioligand binding assays (Robinson et al., 1996, Stitzel et al., 1996a) and autoradiographical studies (Pauly and Collins, 1993). Reports of corticosterone effects on 3H-nicotine binding have been conflicting with both a small decrease (Pauly and Collins, 1993) and no effect (Robinson et al., 1996) reported. There is also evidence that corticosterone affects nAChR function, as chronic corticosterone treatment produced tolerance to nicotine (Robinson et al., 1996) and affected nAChR affinity (Ke and Lukas, 1996, von Euler et al., 1990). Stress has been shown to directly affect nAChR levels, with immobilization stress leading to decreases in 3H-cytisine binding (Takita and Muramatsu, 1995), indicative of α4-type nAChRs.
Given the evidence for a complex interaction between corticosterone, nicotine and PPI and the importance of these factors in schizophrenia, the aims of this study were to further investigate the effect of different levels of circulating corticosterone on the acute action of nicotine treatment on PPI and on the number and distribution of α7-type and α4β2-type nAChRs using receptor autoradiography.
Section snippets
Methods
We used male C57BL/6J mice obtained from Animal Resources Centre, Perth, Australia, and the breeding colony of the Department of Pathology, University of Melbourne. This latter breeding colony was sourced from the breeding colony of the Animal Resources Centre. After surgery, the animals were housed individually on Fibrecycle bedding and shredded paper in standard plastic mouse cages (l × w × h; 28 × 16 × 10 cm). They received Barastoc GR2 pellet food and tap water ad libitum. The animals were kept in an
Baseline parameters and startle responses
Final body weights of the mice showed significant differences between the groups (F(3.43) = 5.33, P = 0.003). Bonferroni-corrected t-test showed that body weights were significantly lower in ADX mice implanted with a 50 mg CORT pellet compared to sham-operated mice and to ADX mice implanted with a cholesterol pellet (Table 1). There were also significant group differences in spleen weights (F(3,43) = 25.9, P < 0.001) and spleen/body weight ratios (F(3,43) = 12.2, P < 0.001). Compared to sham-operated mice,
Discussion
The major finding of the present study is that chronic treatment with high dose corticosterone reduces prepulse inhibition in mice and that this disruption can be improved with acute high dose nicotine treatment. There was a significant difference between the ADX group chronically treated with cholesterol and the ADX group chronically treated with 50 mg of CORT, indicating there may be an interaction occurring between nicotine and the presence/absence of corticosterone. These data largely
Acknowledgements
Dr. van den Buuse was supported by the Griffith Fellowship of the University of Melbourne. Parts of the study were supported by the National Health and Medical Research Council of Australia.
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