Detrimental effects of acute nicotine on the response-withholding performance of spontaneously hypertensive and Wistar Kyoto rats

Abstract

Rationale Attention-Deficit Hyperactivity Disorder (ADHD) is associated with a higher prevalence of smoking, which may be related to potential therapeutic effects of nicotine on ADHD symptoms. Whereas nicotine offers robust improvements in sustained attention, the effects of nicotine on impulsivity are unclear. Objectives The present study examined the effects of nicotine on the response inhibition capacity of spontaneously hypertensive rats (SHR), an animal model of ADHD, compared to that of a normotensive control Wistar Kyoto (WKY) using the Fixed Minimum Interval (FMI) schedule of reinforcement. Methods Tests were conducted following acute injections of subcutaneous nicotine (0.1 – 0.6 mg/kg). On each FMI trial, the first lever press initiated an inter-response time (IRT); a head entry into a food receptacle terminated the IRT. IRTs longer than 6 s were intermittently reinforced with sucrose. Results A model that assumes that only a proportion of IRTs are sensitive to the timing contingencies of the FMI provided a close fit to the data, regardless of strain or treatment. No baseline difference in FMI performance was observed between SHR and WKY. Nicotine reduced the duration of timed IRTs and the duration of latencies to the IRT-initiating lever press similarly for both strains. Nicotine dose-dependently increased the proportion of timed IRTs; the dose-response curve was shifted leftwards in SHR relative to WKY. Conclusions These results suggest that nicotine (a) reduces response-inhibition capacity (b) enhances the reinforcement efficacy of sucrose, and (c) dose-dependently enhances attention-like sensitivity to contingencies of reinforcement, through mechanisms that are yet unknown.

Validation of a method to assess ADHD-related impulsivity in animal models

“…Consistent with prior findings (Mazur, Wood-Isenberg, Watterson, & Sanabria, 2014; Mechner & Guevrekian, 1962), Experiment 1 shows that FMI latencies, particularly post-N, are substantially more sensitive than IRTs to a change in reinforcer efficacy. Latencies and IRTs, however, are sensitive to changes in withholding requirement.…”

“…These findings suggest a reduced specificity of the 5-CSRTT and the DRL tasks to changes in RIC. In contrast, RIC indices drawn from the FCN and the FMI tasks appear to be robust against changes in motivation (Mechner & Guevrekian, 2007; Mazur et al, 2014). …”

Interval timing under a behavioral microscope: Dissociating motivational and timing processes in fixed-interval performance

“…Following previous research (Daniels, Fox, et al, 2015;Daniels, Watterson, et al, 2015;Mazur et al, 2014;Sanabria & Killeen, 2008), it is assumed that Z L is the sum of two random variables, one gamma distributed (the pacemaker model of timing yields an Erlang distribution of temporal judgments; 4 the gamma distribution results from generalizing this model to allow for fractional pulses; see Killeen, 1991) and the other exponentially distributed, with mixture weights q L and 1 -q L , respectively,…”

“…The presence of rapid responding at the beginning of a schedule of reinforcement is often referred to as burst responding (e.g., Richards, Sabol, & Seiden, 1993) and has been observed in other schedules of reinforcement, such as the differential reinforcement of low rates (Richards et al 1993;Sanabria & Killeen, 2008), fixed minimum interval (Mazur et al, 2014;Mika et al, 2012;, switch task (Daniels, Fox, et al, 2015;Daniels, Watterson, et al, 2015), and lever holding (Sanabria & Killeen, 2008). Similar to nontimed FI latencies, burstgenerated intervals appear to be exponentially distributed (e.g., Sanabria & Killeen, 2008) and, thus, likely not generated by a timing mechanism.…”

“…However, such conclusions are often drawn from theoretical frameworks that assume that, while in a timing task, subjects are always engaged in timing. Such an assumption is inconsistent with a substantial amount of data that suggest that responsiveness to the temporal regularities of periodic stimuli fluctuates between trials (Daniels, Fox, Kyonka, & Sanabria, 2015;Daniels, Watterson, et al, 2015;Freestone, Balcı, Simen, & Church 2015;Lejeune & Wearden, 1991;Mazur, Wood-Isenberg, Watterson, & Sanabria, 2014;Mika et al, 2012;Sanabria & Killeen, 2008). More specifically, these data suggest that, at the beginning of each trial, subjects enter either a timing state, emitting target responses generated by a timing mechanism, or they enter a nontiming state, emitting target responses randomly.…”