Nicotine receptors mediating sensorimotor gating and its enhancement by systemic nicotine

Abstract

Prepulse inhibition (PPI) of startle occurs when intensity stimuli precede stronger startle-inducing stimuli by 10–1000 ms. PPI deficits are found in individuals with schizophrenia and other psychiatric disorders, and they correlate with other cognitive impairments. Animal research and clinical studies have demonstrated that both PPI and cognitive function can be enhanced by nicotine. PPI has been shown to be mediated, at least in part, by mesopontine cholinergic neurons that project to pontine startle neurons and activate muscarinic and potentially nicotine receptors (nAChRs). The subtypes and anatomical location of nAChRs involved in mediating and modulating PPI remain unresolved. We tested the hypothesis that nAChRs that are expressed by pontine startle neurons contribute to PPI. We also explored whether or not these pontine receptors are responsible for the nicotine enhancement of PPI. While systemic administration of nAChR antagonists had limited effects on PPI, PnC microinfusions of the non-α7nAChR preferring antagonist TMPH, but not of the α7nAChR antagonist MLA, into the PnC significantly reduced PPI. Electrophysiological recordings from startle-mediating PnC neurons confirmed that nicotine affects excitability of PnC neurons, which could be antagonized by TMPH, but not by MLA, indicating the expression of non-α7nAChR. In contrast, systemic nicotine enhancement of PPI was only reversed by systemic MLA and not by TMPH or local microinfusions of MLA into the PnC. In summary, our data indicate that non-α7nAChRs in the PnC contribute to PPI at stimulus intervals of 100 ms or less, whereas activation of α7nAChRs in other brain areas is responsible for the systemic nicotine enhancement of PPI. This is important knowledge for the correct interpretation of behavioral, preclinical, and clinical data as well as for developing drugs for the amelioration of PPI deficits and the enhancement of cognitive function.

Reduced Prepulse Inhibition as a Biomarker of Schizophrenia

“…An additional potential factor that could have affected to the data from the schizophrenia patients is related to the elevated proportion of smokers in our sample (close to 80%). However, it has been demonstrated that nicotine increases PPI in healthy humans (e.g., Della Casa et al, 1998 ), in schizophrenia patients (e.g., Hong et al, 2008 ), and in rodents (e.g., Pinnock et al, 2015 ), but our data indicates that PPI was reduced for the Schizophrenia patient’s sample. Therefore, we can discard an effect of the smoking status on our results.…”

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

“…Swerdlow et al 2008). Of course, these various drug effects might reflect sites of action anywhere from the PFC (Swerdlow et al 2012a, b) to the pons (Pinnock et al 2015) that might be more or less relevant to the ability of a drug to enhance the therapeutic impact of a cognitive therapy.…”

The Acoustic Sensorimotor Gating Predicts the Efficiency of Hypoxic Preconditioning. Participation of the Cholinergic System in This Phenomenon

“…In addition, α7 nAChRs of the hippocampus and cortex also play important roles in cognitive function in norm and pathology [29,30,[36][37][38][39], and there is evidence of a relationship between PPI and cognitive disturbances in patients with schizophrenia [9,10,40]. There are also single direct data that α7 nAChRs selectively mediate the stimulating effect of nicotine and other selective agonists on PPI [41,42].…”