Methylphenidate alleviates cognitive dysfunction from early Mn exposure: Role of catecholaminergic receptors

Abstract

Environmental manganese (Mn) exposure is associated with impaired attention and psychomotor functioning, as well as impulsivity/hyperactivity in children and adolescents. We have shown previously that developmental Mn exposure can cause these same dysfunctions in a rat model. Methylphenidate (MPH) lessens impairments in attention, impulse control, and sensorimotor function in children, but it is unknown whether MPH ameliorates these dysfunctions when induced by developmental Mn exposure. Here, we sought to (1) determine whether oral MPH treatment ameliorates the lasting attention and sensorimotor impairments caused by developmental Mn exposure, and (2) elucidate the mechanism(s) of Mn neurotoxicity and MPH effectiveness. Rats were given 50 mg Mn/kg/d orally over PND 1-21 and assessed as adults in a series of attention, impulse control and sensorimotor tasks during oral MPH treatment (0, 0.5, 1.5, or 3.0 mg/kg/d). Subsequently, selective catecholaminergic receptor antagonists were administered to gain insight into the mechanism(s) of action of Mn and MPH. Developmental Mn exposure caused persistent attention and sensorimotor impairments. MPH treatment at 0.5 mg/kg/d completely ameliorated the Mn attentional dysfunction, whereas the sensorimotor deficits were ameliorated by the 3.0 mg/kg/d MPH dose. Notably, the MPH benefit on attention was only apparent after prolonged treatment, while MPH efficacy for the sensorimotor deficits emerged early in treatment. Selectively antagonizing D1, D2, or α2_A receptors had no effect on the Mn-induced attentional dysfunction or MPH efficacy in this domain. However, antagonism of D2R attenuated the Mn sensorimotor deficits, whereas the efficacy of MPH to ameliorate those deficits was diminished by D1R antagonism. These findings demonstrate that MPH is effective in alleviating the lasting attention and sensorimotor dysfunction caused by developmental Mn exposure, and they clarify the mechanisms underlying developmental Mn neurotoxicity and MPH efficacy. Given that the cause of attention and psychomotor deficits in children is often unknown, these findings have implications for the treatment of environmentally-induced attentional and psychomotor dysfunction in children more broadly.

Keywords: ADHD; Attention; Manganese; Mechanisms; Methylphenidate; Sensorimotor.

Figure 1

A-D. Developmental postnatal Mn exposure produces deficits in attention and learning in the focused attention tasks with variable pre-cue delays. Accurate responses (%) for the control and the Mn groups, as a function of (A) test session block in the first focused attention task, and (B) increasing pre-cue delay in seconds (s) in the second focused attention task. Test session blocks are three successive daily test sessions per block. Premature responses (%) for the control and the Mn groups, as a function of test session block in (C) the first, and (D) second focused attention tasks. Data are lsmeans ± SEM of the control and Mn groups (n = 61–63/group). *p≤ .05 versus controls.

Figure 2

A-D. Panels A, B. Prolonged 0.5 mg/kg/d methylphenidate (MPH) treatment alleviates Mn attention deficits in the third focused attention task and the selective attention tasks with distractors. (A) Accurate responses (%) for the control and Mn groups, as a function of test session block and MPH dose in the third focused attention task. (B) Accurate responses (%) for the control and the Mn groups, as a function of distractor and MPH dose in the selective attention task. Panels C, D. Chronic low dose methylphenidate treatment decreases impulsivity in the Mn-exposed rats in the third focused attention task but heightens impulsivity at the highest MPH dose in the selective attention task. (C) Premature responses (%) for the control and the Mn groups, as a function of test session block and MPH dose in the third focused attention task. (D) Premature responses (%) for the control and the Mn groups, as a function of distractor and MPH dose in the selective attention task. For panels A and C, each test session block contains three daily test sessions. Data are lsmeans ± SEM of the control and Mn groups (n = 14–15/group). *p≤0.05 versus controls and ^#p≤0.05 versus 0 mg MPH/kg/d dose.

Figure 3

A, B. The attention deficit induced by Mn and MPH efficacy to alleviate the Mn dysfunction at the lowest 0.5 mg/kg/d dose are sustained into the antagonist treatment phase in the selective attention task, but are not altered by specific D1R, D2R, or α2AR antagonists. (A) Accurate responses (%) for the control and the Mn groups, as a function of MPH dose and distraction condition. (B) Accurate responses (%) for the control and the Mn groups, as a function of antagonist treatment and MPH dose. Data are lsmeans ± SEM of the control and Mn groups (n = 14–15/group). *p≤0.05 versus controls, and ^#p≤0.05 versus the 0 mg/kg/d MPH dose. Data in A are lsmeans ± SEM of the Mn and control groups under the vehicle antagonist treatment.

Figure 4

A-C. D1R or D2R antagonist treatment decreases premature responses and increases correct response latency, depending on MPH dose and Mn exposure level. (A) Premature responses (%) for the control and the Mn groups, as a function of MPH dose and distraction condition. (B) Premature responses (%) for the control and the Mn groups, as a function of antagonist receptor treatment and MPH dose. (C) Correct response latency for the control and the Mn groups, as a function of antagonist treatment and distraction condition. Data are lsmeans ± SEM of the control and Mn groups (n = 14–15/group). *p≤0.05 versus controls, ^#p≤0.05 versus 0 mg/kg/d MPH dose, and ^¥p≤0.05 versus vehicle antagonist treatment within MPH condition. Data in A are lsmeans ± SEM of the control and Mn groups under the vehicle antagonist treatment, while data in C are lsmeans ± SEM of the control and Mn groups under the 3.0 mg/kg/d MPH dose.

Figure 5

A, B. Developmental postnatal Mn exposure causes lasting sensorimotor deficits in the staircase test, and methylphenidate treatment at the highest 3.0 mg/kg/d dose alleviates those deficits. (A) Pellets taken (#) and (B) pellets misplaced (#) for the control and the Mn groups, as a function of MPH dose and staircase step. Data are lsmeans ± SEM of the control and Mn groups (n = 14–15/group). *p≤0.05 versus controls, and ^#p≤0.05 versus 0 mg/kg/d MPH dose.

Figure 6

A-D. The Mn sensorimotor deficits and MPH efficacy to alleviate those deficits at the highest 3.0 mg/kg/d dose are sustained into the antagonist treatment phase in the staircase test, with D2R antagonism improving the Mn-induced grasping deficit in the absence of MPH, and D1R antagonism attenuating MPH efficacy to alleviate Mn grasping deficit at the 3.0 mg/kg/d dose. (A) Pellets taken (#) and (B) pellets misplaced (#) for the control and the Mn groups, as a function of MPH dose and staircase step. (C) Pellets taken (#) and pellets misplaced (D) for the control and the Mn groups, as a function of antagonist treatment and MPH dose. Data are lsmeans ± SEM of the control and Mn groups (n = 14–15/group). *p≤0.05 versus controls, ^#p≤0.05 versus 0 mg/kg/d MPH dose, and ^¥p≤0.05 versus vehicle antagonist treatment. Data in A and B are lsmeans ± SEM of the control and Mn-exposed groups under the vehicle antagonist treatment condition. The statistical model for C and D included, respectively, staircase step data 4–6 or 1–4 where there was an apparent effect of Mn exposure and/or MPH treatment.