Mecamylamine blocks nicotine-induced enhancement of the P20 auditory event-related potential and evoked gamma

Abstract

Cigarette smoking is significantly more prevalent in individuals with schizophrenia than in non-affected populations. Certain neurocognitive deficits and disruptions common in schizophrenia may be altered by smoking, leading to the hypothesis that schizophrenics engage in smoking behavior to alleviate specific neurocognitive symptoms of the disorder. Additionally, research suggests that individuals with schizophrenia have altered auditory event-related potentials (ERPs) and abnormalities in evoked gamma oscillations which are both indices of sensory information processing. This study was conducted to examine the effect of acute administration of nicotine and the non-specific nicotinic antagonist mecamylamine on the P20 and N40 components of the ERP and evoked gamma oscillations in mice. Acute nicotine (1 mg/kg) significantly increased P20 amplitude, an effect that was blocked by pretreatment with mecamylamine (2 mg/kg). Additionally, acute nicotine increased the normal burst of evoked gamma following an auditory stimulus. The increase in evoked gamma was also blocked by mecamylamine pretreatment. Although acute nicotine decreased amplitude of the N40 component, this decrease was not attenuated by mecamylamine. These results replicate findings that nicotine may enhance early sensory information processing through the nicotinic acetylcholinergic receptor system in an established model (ERPs) and extend these findings in an emerging, novel model (evoked gamma oscillations) of sensory information processing. The results also support the hypothesis that nicotine may be beneficial to individuals with deficits in neurocognitive functions, such as those suffering from schizophrenia.

Figure 1

Grand average event related potential tracings and average ERPs for each drug condition. (A) Grand average ERP tracing. (B) ERP tracing from a single, saline-treated mouse. (C) Average ERP trace for mice following administration of saline. (D) Average ERP trace for mice following administration of 2 mg/kg mecamylamine. (E) Average ERP trace for mice following administration of 1 mg/kg nicotine. (F) Average ERP trace for mice following administration of 2 mg/kg mecamylamine followed by 1 mg/kg nicotine. ERP amplitude in microvolts is shown on the ordinate and time in milliseconds in displayed on the abscissa.

Figure 2

Grand average gamma oscillation tracings and gamma tracings from a single saline treated mouse. An 85 dB white noise stimulus was presented at 0 ms. (A) Grand average gamma filtered data; data were digitally band pass filtered between 31–61 Hz with 3dB cutoff points of 26.6 and 65.8 Hz and artifact rejected for movement. Inset depicts raw EEG data from a single mouse. (B) Grand average rectified gamma data; gamma data were rectified by squaring to produce a positive value for gamma activity at each point and enable measurement of the area under the curve (AUC). (C) Gamma filtered data from an individual mouse in the saline condition; data were digitally band pass filtered between 31–61 Hz with 3dB cutoff points of 26.6 and 65.8 Hz and artifact rejected for movement. (D) Rectified gamma data from a single mouse in the saline condition; gamma data were rectified by squaring to produce a positive value for gamma activity at each point and enable measurement of the area under the curve (AUC). The evoked window (0 – 70 ms) contains the normal, time-delimited burst of evoked gamma following a stimulus.

Figure 3

Mean amplitude of the P20 in C57BL/6J mice in each drug condition. Nicotine causes an amplification of the P20 ERP that is reversed by the non-specific nicotinic antagonist mecamylamine. Error bars represent standard error of the mean. Asterisk indicates a significant difference between the drug condition and the saline condition (p<0.05).

Figure 4

Mean amplitude of the N40 in C57BL/6J mice in each drug condition. Both nicotine and mecamylamine result in a reduction in the N40 ERP. Error bars represent standard error of the mean. Asterisk indicates a significant difference between the drug condition and the saline condition (p<0.05).

Figure 5

Mean area under the curve for rectified evoked gamma oscillations in C57BL/6J mice in each drug condition. Nicotine causes an increase in evoked gamma oscillations that is reversed by the non-specific nicotinic antagonist mecamylamine. Error bars represent standard error of the mean. Asterisk indicates a significant difference between the drug condition and the saline condition (p<0.05).

Figure 6

Pearson’s r correlations were performed for P20 and N40 amplitudes and AUC for evoked gamma across all four drug conditions. (A) P20 amplitude was significantly positively correlated (r = 0.84, p ≤ 0.001) with AUC for evoked gamma. (B) N40 amplitude was significantly positively correlated (r = 0.62, p ≤ 0.001) with AUC for evoked gamma.