Neurocircuitry underlying the preferential sensitivity of prefrontal catecholamines to low-dose psychostimulants

Abstract

Low doses of psychostimulants, including methylphenidate (MPH), are highly effective in the treatment of attention-deficit/hyperactivity disorder (ADHD). At these doses, psychostimulants improve prefrontal cortex (PFC)-dependent function. Recent evidence indicates that low and clinically relevant doses of psychostimulants target norepinephrine (NE) and dopamine (DA) signaling preferentially in the PFC. To better understand the neural mechanisms responsible for the regional selectivity of low-dose psychostimulant action, it is important to first identify the underlying neurocircuitry. The current study used reverse microdialysis to test the hypothesis that the preferential targeting of PFC catecholamines by low-dose psychostimulants involves direct action within the PFC, reflecting an intrinsic property of this region. For these studies, the effects of varying concentrations of MPH (0.25, 1.0, and 4.0 μM) on NE and DA efflux were examined within the PFC and select subcortical fields in unanesthetized rats. Low concentrations of MPH elicited significantly larger increases in extracellular levels of NE and DA in the PFC than in subcortical regions linked to motor-activating and arousal-promoting actions of psychostimulants (nucleus accumbens and medial septal area, respectively). The differential action of MPH across regions disappeared at higher concentrations. The enhanced sensitivity of PFC catecholamines to low and clinically relevant doses of psychostimulants, at least in part, reflects a unique sensitivity of this region to NE/DA transporter blockade. Available evidence suggests that the increased sensitivity of PFC catecholamines likely involves DA clearance through the NE transporter within the PFC.

Figure 1

Photomicrographs of Nissl-stained tissue sections depicting placement of dialysis probes within prefrontal cortex (PFC; a), nucleus accumbens (NAc; b), and medial septal area (MSA; c). For PFC, probes spanned the majority of the dorsoventral extent of the medial PFC. For NAc, probes were generally placed within the central portion corresponding to the core subdivision. For MSA, probes were placed medially, largely within the medial septum and diagonal band of Broca. Arrows indicate probe track and point toward midline. ac, anterior commissure; CC, corpus callosum; LV, lateral ventricle.

Figure 2

Regional effects of local application of methylphenidate (MPH) on extracellular levels of norepinephrine (NE) and dopamine (DA). Mean (±SEM) NE and DA levels expressed as percentage of baseline following local application of MPH at varying concentrations via reverse dialysis within the prefrontal cortex (PFC), nucleus accumbens (NAc), and medial septal area (MSA) are shown. (a–c) The effects of 0.25, 1.0, and 4.0 μM MPH, respectively, on DA (left panels) in the PFC, NAc and MSA and NE (right panels) in the PFC and MSA (1.0 μM only) are depicted. Values represent the average of two 30-min samples collected 2 h before (negative numbers) and beginning 30-min after MPH application (positive numbers). The 1.0 μM concentration elicited significantly larger increases in DA and NE relative to the subcortical regions in the second and third 60-min collection epochs. *P<0.05, **P<0.01 compared with Sample -1; ⁺P<0.05, ⁺⁺P<0.01 compared with NAc DA within the same sample epoch; ^#P<0.05 compared with MSA NE within the same sample epoch.

Figure 3

Locally administered methylphenidate (MPH) increases dopamine (DA) and norepinephrine (NE) preferentially within the prefrontal cortex (PFC). The effects of local application of 1.0 μM MPH on extracellular levels of DA and NE within the PFC, nucleus accumbens (NAc), and medial septal area (MSA) are shown. Data are an average (±SEM) of three 30-min samples collected 90–180 min following MPH application and are expressed as percent above baseline. At this dose, MPH produced only modest increases in DA and NE levels (∼50–60%) in subcortical regions (NAc and MSA), while eliciting significantly larger increases in DA and NE levels (∼100–120%) within the PFC. A similar pattern of effects is seen with systemic administration of MPH (Berridge et al, 2006). *P<0.05 relative to NAc DA and ⁺P<0.05 relative to MSA NE.