Research ReportStimulation of the α4β2 nicotinic receptor by 5-I A-85380 improves auditory gating in DBA/2 mice
Introduction
The inability to correctly process sensory information is a cardinal symptom of schizophrenia. In particular, the inability to filter incoming auditory stimuli results in schizophrenia patients becoming overwhelmed or “flooded” by extraneous stimuli (Venables, 1964). The phenomenon of filtering repetitive auditory stimuli in order to properly focus attention is known as auditory gating. Auditory gating is deficient in schizophrenia patients (Freedman et al., 2003, Leonard et al., 2002). It has been proposed that the inability of these patients to properly gate auditory stimuli is due to a dysfunction of inhibitory circuits involving the hippocampus (Adler et al., 1998). One method for measuring the response to auditory stimuli in humans is by electroencephalographic recordings of the P50 auditory evoked potential. This potential is a measure of the brain's electrical response in the form of evoked waves to two identical auditory stimuli separated by 500 milliseconds (ms). In control subjects the amplitude of the P50 waveform response to the second stimulus (test stimulus) is decreased compared to the response to the first stimulus (conditioning stimulus). In schizophrenia patients however, there is no decrease in the P50 waveform amplitude to the second auditory stimulus indicating a failure to activate an inhibitory circuit which results in sensory stimuli overload (Venables, 1992).
The P20-N40 waveform complex in rodents is analogous to the P50 auditory evoked potential recordings in humans (Bickford-Wimer et al., 1990, Bickford and Wear, 1995, Simpson and Knight, 1993, Stevens et al., 1998). This waveform complex is defined as a positive inflection occurring 20–40 ms following stimulus onset and continuing through to the following negativity. This complex has been shown to have less variability than either individual component (Hashimoto et al., 2005). Data from both human and rodent studies have implicated nicotinic acetylcholine receptors (nAChRs) in the auditory gating deficit experienced by schizophrenia patients. Specifically, the α7 nAChR subtype has a decreased density in the CA3 region of the hippocampus and the dentate gyrus of post-mortem brain tissue from schizophrenia patients as compared to controls (Breese et al., 1997, Freedman et al., 1995). Genetic linkage studies indicate that the P50 auditory evoked potential deficit of schizophrenia patients corresponds to chromosome 15q14 which is the locus of the α7 nAChR gene (Chini et al., 1994, Freedman et al., 1997, Orr-Urtreger et al., 1995).
Pharmacologically, nicotine, a non-selective nAChR agonist, has been shown to improve deficient auditory gating in schizophrenia patients (Adler et al., 1993). The improvement in this deficit is proposed to be mediated through the α7 nAChR subtype. Rodent studies have demonstrated that nicotinic agonists, which correct the auditory gating deficit, act by selectively decreasing the amplitude of the test response and/or increasing the amplitude of the conditioning response (Radek et al., 2006, Stevens et al., 1998, Stevens and Wear, 1997). An alteration in the size of response amplitudes is reflected in the TC ratio. The TC ratio is the amplitude of the evoked response to the test stimulus (TAMP) divided by the amplitude of the evoked response to the conditioning stimulus (CAMP). A low TC ratio (≤ 0.4) indicates normal gating while a greater TC ratio (> 0.4) reflects an auditory gating deficit (Stevens et al., 1998). The decrease in amplitude of the test response indicates an inhibition of firing of a subpopulation of pyramidal cells in the hippocampus in response to the test stimulus (Adler et al., 1998). A strain of inbred mice, the DBA/2, models the auditory gating deficit experienced by schizophrenia patients. Similar to the reduction in hippocampal α7 nAChRs observed in human post-mortem brain tissue from schizophrenia patients, the DBA/2 strain of mice has reduced numbers of α7 receptors in the hippocampus, as well as a lack of inhibition of the P20-N40 response to the test stimulus (Adams et al., 2001, Stevens et al., 1996). Further support for the role of the α7 receptor in the gating deficit in DBA/2 mice is the improvement observed after administration of DMXB-A, also known as GTS-21, which is a selective α7 partial agonist (de Fiebre et al., 1995, Kem, 1997, Simosky et al., 2001, Stevens et al., 1999). Recently, a Phase I clinical study was conducted to assess the efficacy of DMXB-A in non-smoking schizophrenia patients on cognitive functioning and P50 sensory inhibition. The results showed improvements in both P50 sensory inhibition and neurocognitive measures following administration of this compound (Olincy et al., 2006).
Correction of the gating deficit in schizophrenia patients after administration of nicotine may be due in part to its activation of high-affinity neuronal nicotinic receptors. These high-affinity nAChRs consist of β2 subunits in conjunction with α4 subunits with or without other α-subunits (Flores et al., 1992, Gerzanich et al., 1998, Lindstrom et al., 1987). Assessment of the role of α4β2 receptors in the gating deficit has not been as well explored as that of the α7 receptor. It was first noted by Stevens and Wear (1997) that ABT-418, an α4β2 agonist, produced an increase in the conditioning amplitude of P20-N40 auditory evoked potentials in DBA/2 mice. However, ABT-418 is not selective for the α4β2 receptor (Briggs et al., 1995, Papke et al., 1997) and was found to also decrease test amplitude (TAMP) which was blocked by administration of the α7 antagonist α-bungarotoxin (α-BTX) (Stevens and Wear, 1997). Radioligand binding studies of hippocampal homogenates from schizophrenic smokers suggested a decrease in the binding of both 3H-nicotine and 3H-cytisine, a radioligand selective for α4β2, as compared to that of non-schizophrenic smokers, indicating a decrease in the high-affinity receptor levels in schizophrenic hippocampus (Breese et al., 2000, Freedman et al., 1995). In postmortem hippocampus and thalamus from non-schizophrenic smokers there is an increase in 3H-nicotine binding indicating an up-regulation of high-affinity nicotinic receptors (Breese et al., 1997), while schizophrenic smokers fail to show a similar up-regulation of these receptors with nicotine exposure. This suggests an abnormal response of these receptors to cigarette smoking in the schizophrenic population (Adams and Stevens, 2007, Breese et al., 2000). Data regarding the genes encoding the α4 and β2 subunits indicate that molecular variants in only one of the genes does not alone confer susceptibility to schizophrenia, but an interaction between variants in the α4 gene along with the β2 gene do produce a significant risk for schizophrenia (De Luca et al., 2006).
Recently, a study by Radek et al. (2006) specifically addressed the involvement of α4β2 nAChRs in the auditory gating deficit in unanesthetized DBA/2 mice. It was determined that nicotine improved auditory gating in DBA/2 mice, in part, by significantly increasing the conditioning amplitude. Co-administration of the α4β2 antagonist dihydro-β-erythroidine (DHβE) blocked the increase in CAMP observed with nicotine. Nicotine is a non-selective agonist (Papke et al., 2007) but the administration of DHβE and the resultant blockade of the increase in CAMP suggests a role for the high-affinity nicotine receptor in the auditory gating deficit of DBA/2 mice (Radek et al., 2006). Therefore, to further our understanding of α4β2 nAChR participation in the auditory gating deficit we studied the response of anesthetized DBA/2 mice to a relatively selective α4β2 agonist, 5-I A-85380 (Koren et al., 1998, Mukhin et al., 2000). The effects of 5-I A-85380 upon auditory gating were assessed with and without prior central administration of either DHβE or α-BTX.
Section snippets
Results
In concert with previous studies, anesthetized DBA/2 mice showed a deficit in auditory gating as evidenced by high TC ratios (test amplitude/conditioning amplitude ≥ 0.4) during baseline recordings, prior to drug administration (Fig. 1, Fig. 2). The α4β2 agonist 5-I A-85380 produced significant decreases in TC ratios following intraperitoneal (IP) administration of 0.1, 0.3 and 1 mg/kg doses as compared to averaged baseline recordings (Fig. 1, Fig. 2). Repeated measures analysis (MANOVA)
Discussion
The goal of the present study was to test an agonist with relative selectivity for the α4β2 receptor to confirm the findings of Radek et al. (2006) on the role of the α4β2 nAChRs in auditory gating. 5-I A-85380 is a halogenated analog of A-85380. This compound has been shown to have a very high affinity for nAChRs in rat brain (Ki = 11 pM for the α4β2 receptor) with binding that is saturable and reversible (Koren et al., 1998, Mukhin et al., 2000). The 125I- or 123I-radiolabeled forms of this
Animals
Male DBA/2 mice (20–25g) were obtained from Harlan SD (Indianapolis, IN) and housed five to a cage in the Center for Comparative Medicine at the University of Colorado Denver, School of Medicine (UCD-SOM). The mice were provided water and food (Harlan Teklad, Indianapolis, IN) ad libitum. Lighting was cycled at 12h intervals (lights on at 0600h). Rodent procedures were performed in accordance with the Principles of Laboratory Animal Care (Institute of Laboratory Animal Research, 1996) with
Acknowledgments
This study was supported by NIH R01 MH 73725-01 (K.E.S.), a T32 MH15442-28 training grant (K.M.W.), and research funds from the Developmental Psychobiology Endowment Fund at the UCD-SOM (K.M.W.).
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