Mouse model predicts effects of smoking and varenicline on event-related potentials in humans

Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
Nicotine & Tobacco Research (Impact Factor: 3.3). 06/2010; 12(6):589-97. DOI: 10.1093/ntr/ntq049
Source: PubMed


Nicotine alters auditory event-related potentials (ERPs) in rodents and humans and is an effective treatment for smoking cessation. Less is known about the effects of the partial nicotine agonist varenicline on ERPs.
We measured the effects of varenicline and nicotine on the mouse P20 and varenicline and smoking on the human P50 in a paired-click task. Eighteen mice were tested following nicotine, varenicline, and their combination. One hundred and fourteen current smokers enrolled in a placebo-controlled within-subject crossover study to test the effects of varenicline during smoking and abstinence. Thirty-two subjects participated in the ERP study, with half receiving placebo first and half varenicline first (VP).
Nicotine and varenicline enhanced mouse P20 amplitude, while nicotine improved P20 habituation by selectively increasing the first-click response. Similar to mice, abstinence reduced P50 habituation relative to smoking by reducing the first-click response. There was no effect of varenicline on P50 amplitude during abstinence across subjects. However, there was a significant effect of medication order on P50 amplitude during abstinence. Subjects in the PV group displayed reduced P50 during abstinence, which was blocked by varenicline. However, subjects in the VP group did not display abstinence-induced P50 reduction.
Data suggest that smoking improves sensory processing. Varenicline mimics amplitude changes associated with nicotine and smoking but fails to alter habituation. The effect of medication order suggests a possible carryover effect from the previous arm. This study supports the predictive validity of ERPs in mice as a marker of drug effects in human studies.

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Available from: Freda Patterson, Mar 25, 2014
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    • "Pharmacological and parametric manipulations have suggested a close correspondence between the rodent N40 and human N100 (Metzger et al. 2007; Amann et al. 2008; Swerdlow et al. 2012). For example, pharmacological manipulations using dopamine agonists and nicotinic cholinergic agonists in rodents produce alterations in N40 that closely overlap with the effects such drugs have on the human N100 (Siegel et al. 2005; Maxwell et al. 2006; Kanes et al. 2007; Metzger et al. 2007; Amann et al. 2010; Halene and Siegel 2008; Rudnick et al. 2009, 2010; Cao et al. 2012; Featherstone et al. 2012). As such, it is likely that the reduction in N40 amplitude observed here in BRAT rats is analogous to the N100 reductions observed in schizophrenia patients. "
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    ABSTRACT: Reductions in the levels of the neuropeptide vasopressin (VP) and its receptors have been associated with schizophrenia. VP is also critical for appropriate social behaviors in humans as well as rodents. One of the prominent symptoms of schizophrenia is asociality and these symptoms may develop prodromally. A reduction in event-related potential (ERP) peak amplitudes is an endophenotype of schizophrenia. In this study, we use the Brattleboro (BRAT) rat to assess the role of VP deficiency in vocal communication during early development and on auditory ERPs during adulthood. BRAT rats had similar vocal communication to wild-type littermate controls during postnatal days 2 and 5 but the time between vocalizations was increased and the power of the vocalizations was reduced beginning at postnatal day 9. During adulthood, BRAT rats had deficits in auditory ERPs including reduced N40 amplitude and reduced low and high gamma intertrial coherence. These results suggest that the role of VP on vocal communication is an age-dependent process. Additionally, the deficits in ERPs indicate an impairment of auditory information processing related to the reduction in VP. Therefore, manipulation of the VP system could provide a novel mechanism for treatment for negative symptoms of schizophrenia.
    10/2013; 1(5):e00100. DOI:10.1002/phy2.100
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    • "Previously, the effect of varenicline on auditory evoked responses of C57BL/6 mice was determined to produce an overall increase in P20 amplitude in response to both the first and second auditory stimuli (Rudnick et al., 2010). This study examined only the peak response, P20, and not the entire P20-N40 waveform. "
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    ABSTRACT: Varenicline, an FDA approved smoking cessation pharmacotherapy, is an α4β2* nicotinic acetylcholine receptor (nAChR) partial agonist and an α7* nAChR full agonist. Both subtypes of nAChR are involved in modulating auditory evoked responses in rodents. In DBA/2 mice, an inbred strain, auditory evoked responses to paired auditory stimuli fail to inhibit to the second stimulus. This mouse strain replicates the auditory evoked response inhibition deficit experienced by the majority of schizophrenia patients. In this current study, we examined the effects of five different doses of varenicline (0.06, 0.3, 0.6, 3 and 6mg/kg) on auditory evoked responses in anesthetized DBA/2 mice. We also administered α4β2* and α7* nAChR selective antagonists prior to varenicline administration to determine which nAChR subtypes mediate the effects of varenicline. Four of the five doses of varenicline produced improvements in auditory evoked response inhibition deficits. Selective blockade of either the α4β2* or α7* nAChR in competition with 0.6mg/kg varenicline prevented varenicline induced improvements. In competition with a higher dose of varenicline (3mg/kg) only blockade of the α4β2* nAChR prevented varenicline induced improvement in auditory evoked response inhibition. These data indicate the importance of α4β2* nAChRs and the potential involvement of the α7* subtype in varenicline's effects on auditory evoked responses in DBA/2 mice.
    Pharmacology Biochemistry and Behavior 07/2011; 100(1):17-24. DOI:10.1016/j.pbb.2011.07.001 · 2.78 Impact Factor
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    • "reduced DA tone) would be associated with reduced S 1 -P50 and P50 gating, and that nicotine would increase S 1 -P50 and P50 gating in the presence of the 10R allele. As evidence of nicotine-altered P50/gating in tobacco abstinent smokers may be interpreted as a reversal of withdrawal-induced alterations in sensory processing (Rudnick et al., 2010), and not an absolute affect of nicotine per se, these hypotheses were investigated in nonsmokers. "
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    ABSTRACT: Although schizophrenia has been considered primarily a disease of dopaminergic neurotransmission, the role of dopamine in auditory sensory gating deficits in this disorder and their amelioration by smoking/nicotine is unclear. Hypothesizing that individual differences in striatal dopamine levels may moderate auditory gating and its modulation by nicotine, this preliminary study used the mid-latency (P50) auditory event-related potential (ERP) to examine the single dose (6 mg) effects of nicotine (vs. placebo) gum on sensory gating in 24 healthy nonsmokers varying in the genetic expression of the dopamine transporter (DAT). Consistent with an inverted-U relationship between dopamine level and the drug effects, individuals carrying the 9R (lower gene expression) allele, which is related to greater striatal dopamine levels, tended to evidence increased baseline gating compared to 10R (higher gene expression) allele carriers and showed a reduction in gating with acute nicotine. The present results may help to understand the link between excessive smoking and sensory gating deficits in schizophrenia and to explain the potential functional implications of genetic disposition on nicotinic treatment in schizophrenia.
    Neuroscience 02/2011; 180:148-56. DOI:10.1016/j.neuroscience.2011.02.008 · 3.36 Impact Factor
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