Dissociable Rate-Dependent Effects of Oral Methylphenidate on Impulsivity and D_2/3Receptor Availability in the Striatum

Abstract

We have previously shown that impulsivity in rats is linked to decreased dopamine D 2/3 receptor availability in the ventral striatum. In the present study, we investigated, using longitudinal positron emission tomography (PET), the effects of orally administered methylphenidate (MPH), a first-line treatment for attention deficit hyperactivity disorder, on D 2/3 receptor availability in the dorsal and ventral striatum and related these changes to impulsivity. Rats were screened for impulsive behavior on a five-choice serial reaction time task. After a baseline PET scan with the D 2/3 ligand [ 18 F]fallypride, rats received 6 mg/kg MPH, orally, twice each day for 28 d. Rats were then reassessed for impulsivity and underwent a second [18 F]fallypride PET scan. Before MPH treatment, we found that D 2/3 receptor availability was significantly decreased in the left but not the right ventral striatum of high-impulse (HI) rats compared with low-impulse (LI) rats. MPH treatment increased impulsivity in LI rats, and modulated impulsivity and D 2/3 receptor availability in the dorsal and ventral striatum of HI rats through inverse relationships with baseline levels of impulsivity and D 2/3 receptor availability, respectively. However, we found no relationship between the effects of MPH on impulsivity and D 2/3 receptor availability in any of the striatal subregions investigated. These findings indicate that trait-like impulsivity is associated with decreased D 2/3 receptor availability in the left ventral striatum, and that stimulant drugs modulate impulsivity and striatal D 2/3 receptor availability through independent mechanisms.

Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats

“…To our knowledge, a sex difference in visual discrimination learning in untreated rats has not been reported before. Sex differences in previous studies have been noted in the areas of increased addiction vulnerability in male rats (Crawford et al 2011), higher levels of anxiety (Iñiguez et al 2010), and higher levels of impulsivity in male vs. female rats (Caprioli et al 2015). Rodent females, like human females, mature earlier than males: on average the development of genitalia and activation of sexual organs occurs 4–8 d faster (Spear 2015).…”

“…Previous studies have reported that MPH increases impulsivity in rats prescreened to be ‘low-impulsive’ before exposure (Caprioli et al 2015). Accordingly, a subset of our adult rats pretreated with MPH in adolescence may have had difficulty attending to the task demands in reversal learning.…”

“…Some of the most commonly-prescribed are MPH for ADHD (Shanks et al 2015; Caprioli et al 2015; Crawford et al 2011; Gray et al 2007), and fluoxetine (FLX) for the treatment of Major Depression (Iñiguez et al 2010; Iñiguez et al 2014; Homberg et al 2011). MPH exhibits a similar pharmacological profile to amphetamines and cocaine, may modulate neurodevelopment (Grund et al 2007; Thanos et al 2007; Adriani et al 2006), and by extension, may impact learning and behavior mediated by corticostriatal circuitry.…”

Dissecting Impulsivity: Brain Mechanisms and Neuropsychiatric Implications

“…Early on, (Dalley et al 2007) it was noticed that cocaine self-administration appeared to blunt the high impulsivity expressed as increased premature responding; this was reminiscent of effects of agents such as methylphenidate (Ritalin ® ) in combating impulsive behavior in ADHD and presumably arises from the effects of these drugs to increase catecholamine (i.e., DA and noradrenaline [NA] levels) in the synaptic cleft, by virtue of their actions, for example, to block the DA and NA transporters and hence block the reuptake of these neurotransmitters. More recently, this has been explored in further detail both with intravenously self-administered cocaine ) and orally administered methylphenidate (Caprioli et al 2015). In both cases, the stimulant drug reduced premature responding significantly in high-impulsive rats while increasing it in rats with lower (i.e., normal) baseline levels of premature responding (Fig.…”

“…This deficit (left scans) is corrected by cocaine and methylphenidate (right scans) with a corresponding reduction in behavioral impulsivity in the 5CSRTT (b, d, respectively). From Caprioli et al (2015) and Caprioli et al (2013) with permission…”