Altered nocifensive behavior in animal models of autism spectrum disorder: The role of the nicotinic cholinergic system

Abstract

Caretakers and clinicians alike have long recognized that individuals with autism spectrum disorder (ASD) can have altered sensory processing, which can contribute to its core symptoms. However, the pathobiology of sensory alterations in ASD is poorly understood. Here we examined nocifensive behavior in ASD mouse models, the BTBR T+Itpr3tf/J (BTBR) and the fragile-X mental retardation-1 knockout (Fmr1-KO) mice. We also examined the effects of nicotine on nocifensive behavior given that nicotine, a nicotinic cholinergic receptor (nAChR) agonist that has antinociceptive effects and was shown to improve social deficits and decrease repetitive behaviors in BTBR mice. Compared to respective controls, both BTBR and Fmr1-KO had hyporesponsiveness to noxious thermal stimuli and electrical stimulation of C-sensory fibers, normal responsiveness to electrical stimulation of Aβ- and Aδ-fiber, and hyperresponsiveness to visceral pain after acetic acid intraperitoneal injection. In BTBR, nicotine at lower doses increased, whereas at higher doses, it decreased hotplate latency compared to vehicle. In a significantly different effect pattern, in control mice, nicotine had antinociceptive effects to noxious heat only at the high dose. Interestingly, these nocifensive behavior alterations and differential responses to nicotine antinociceptive effects in BTBR mice were associated with significant downregulation of α3, α4, α5, α7, β2, β3, and β4 nAChR subunits in several cerebral regions both, during embryonic development and adulthood. Taken together, these findings further implicate nAChRs in behaviors alterations in the BTBR model and lend support to the hypothesis that nAChRs may be a target for treatment of behavior deficits and sensory dysfunction in ASD.

The Role of Nicotinic Receptors in the Attenuation of Autism‐Related Behaviors in a Murine BTBR T + tf/J Autistic Model

“…Similarly, with recent study reported that chronic nicotine in drinking water did not affect overall locomotion in male mice [Calarco et al, 2017], but female C57BL/6J; however, at a similar dose of nicotine in another past study showed that both male and female C57BL/6J mice increased in LA and only males showed locomotor activation at a lower dose of nicotine (100 μg/mL), but female mice were less sensitive to locomotor activation even though nicotine intake was actually higher in females than males, but plasma levels of cotinine were equivalent for both sexes [Caldarone et al, 2008]. In contrast, Wang et al [2016] reported that chronic oral nicotine at 200 and 400 μg/mL, but not 100 μg/mL, decreased overall physical activity of BTBR mice in the open-field test. Previous experiments reported that female rats had more locomotor sensitivity in response to chronic nicotine [Booze et al, 1999;Faraday, O'Donoghue, & Grunberg, 2003;Harrod et al, 2004;Kanýt, Stolerman, Chandler, Saigusa, & Pö gün, 1999], indicating sex and strain differences in behavioral locomotor response to nicotine treatment.…”

“…The doses of nicotine used in our study (50, 100, and 400 mcg/mL) were selected based on our previous studies and others in the literature [AlSharari et al, 2013;Grabus et al, 2005;Mesa-Gresa, Perez-Martinez, & Redolat, 2013;Caruso et al, 2018;Kamens et al, 2015;Klein, Stine, Vandenbergh, Whetzel, & Kamens, 2004;Wang et al, 2015;Wang et al, 2016] that have shown to increase plasma concentrations of nicotine and cotinine and to increase nicotine binding to high-affinity nAChRs in the brains of C57BL/6J mice [Caldarone, King, & Picciotto, 2008;King, Caldarone, & Picciotto, 2004;Sparks & Pauly, 1999;Calarco, Lee, & Picciotto, 2017]. Earlier studies have shown that nicotine can be administered chronically for several weeks in the drinking water to mice in a way that plasma nicotine pharmacokinetics and cotinine concentration mimic or similar to and above those reported in smokers of human smokers [Nordberg et al, 1985;Pekonen, Karlsson, Laakso, & Ahtee, 1993;Pietila, Laakso, & Ahtee, 1995;Klein et al, 2004;Grabus et al, 2005;Caldarone et al, 2008;Salas and De Biasi, 2008;Wang et al, 2015;Wang et al, 2016]. Chronic nicotine exposure is known to cause an increase in the density of neuronal nicotinic receptor subtypes and upregulates some nAChRs within the CNS [Marks, Burch, & Collins, 1983;Schwartz & Kellar, 1983;Schwartz & Kellar, 1985;Ksir, Hakan, Hall, & Kellar, 1985;Wonnacott, 1990;Pauly, Marks, Gross, & Collins, 1991;Pauly, Marks, Robinson, van de Kamp, & Collins, 1996;Sanderson et al, 1993;Trauth, Seidler, McCook, & Slotkin, 1999;…”

“…Nicotinic ACh receptors are involved in early brain development, nicotine-mediated alterations of neuronal structure, and persistent changes in behavior [Lozada et al, 2012; Ballesteros-Yáñez, Benavides-Piccione, Bourgeois, Changeux, & DeFelipe, 2010]. Recent studies showed the positive behavioral effects of the cholinergic system in different autistic-like rodent models, including BTBR [Karvat & Kimchi, 2014;Wang et al, 2015], in the fragile-X mental retardation-1 knockout, Fmr1 KO mice [Wang et al, 2016], in epilepsy associated with autism in pentylenetetrazol-kindled mice [Takechi, Suemaru, Kiyoi, Tanaka, & Araki, 2016]. The α4β2 nicotinic ACh receptor modulates autism-like behavioral and motor abnormalities in pentylenetetrazolkindled mice [Takechi et al, 2016].…”

“…For instance, a lower dose of 4 weeks of nicotine administration orally in drinking water increases sociability, while a higher dose reduces repetitive behavior in BTBR mice [Wang et al, 2015]. -Previous studies described the importance of the nicotinic cholinergic system in the modulation of altered nociception and sociability deficits in BTBR mice [Wang et al, 2016;Wang et al, 2015]. Hence, the rationale of our study is based on previous studies of targeting nicotinic receptors in BTBR T + tf/J mice in multiple behavioral tests, which may reveal the critical therapeutic implications of using pharmacological selective nicotinic ligands to treat the behavioral symptoms of autistic patients.…”

Meynert’s Nucleus Complex White Matter Abnormalities in Autism Spectrum Disorders: An MRI Study

“…While the biological bases of ASD are only partially understood, a wide range of experimental and clinical observations suggest that cholinergic system alterations could be involved in these disorders [2][3][4][5][6][7]. That is why some authors have proposed that the nicotinic cholinergic system might be involved in the pathogenesis of ASD [8]. Pathologic studies have indeed highlighted that nicotinic acetylcholine receptor subtypes are altered in brain of autistic individuals.…”