Modafinil Administration to Preadolescent Rat Impairs Non-Selective Attention, Frontal Cortex D2 Expression and Mesolimbic GABA Levels

Abstract

The misuse of psychostimulants is an increasing behavior among young people, highlighting in some countries the abuse of modafinil (MOD) as a neuropotentiator. However, several clinical trials are investigating MOD as an alternative pharmacological treatment for attentional deficit and hyperactivity disorder (ADHD) in children and adolescents. On the other hand, the early use of psychostimulants and the misdiagnosis rates in ADHD make it crucial to investigate the brain effects of this type of drug in young healthy individuals. The aim of this work was to evaluate the effects of chronic MOD treatment on neurochemicals (γ-aminobutyric acid and glutamate), dopamine receptor 2 (D₂) expression and behavior (non-selective attention "NSA") in the mesocorticolimbic system of young healthy Sprague-Dawley rats. Preadolescent male rats were injected with MOD (75 mg/kg, i.p.) or a vehicle for 14 days (from postnatal day 22 to 35). At postnatal day 36, we measured the GLU and GABA contents and their extracellular levels in the nucleus accumbens (NAc). In addition, the GLU and GABA contents were measured in the ventral tegmental area (VTA) and D₂ protein levels in the prefrontal cortex (PFC). Chronic use of MOD during adolescence induces behavioral and neurochemical changes associated with the mesocorticolimbic system, such as a reduction in PFC D₂ expression, VTA GABA levels and NSA. These results contribute to the understanding of the neurological effects of chronic MOD use on a young healthy brain.

Keywords: ADHD; GABA; NSA; glutamate; modafinil; nucleus accumbens; prefrontal cortex; psychostimulants; ventral tegmental area.

Figure 1

NAc and VTA glutamate (GLU) and GABA tissue content after 14 days of vehicle or MOD treatment in young rats. (a) NAc GABA tissue content, (b) NAc GLU tissue content, (c) VTA GABA tissue content and (d) VTA GLU tissue content. Data are presented as the mean ± SEM for NAc measurements: vehicle n = 8 and modafinil n = 7. For VTA measurement: n = 7 per group. * p < 0.05.

Figure 2

Effect of chronic MOD treatment on extracellular and release of GABA levels in the nucleus accumbens (NAc) after 70 mM K⁺ stimulation by in vivo microdialysis. (a) Forty-five minutes after beginning the collection of samples, an aCSF containing 70 mM K⁺ was perfused through the dialysis probe for 15 min. GABA is expressed as a percentage of baseline. Basal GABA levels (pmol/µL) for the vehicle were 0.063 ± 0.006 and vehicle K⁺ 0.476 ± 0.115; MOD basal 0.898 ± 0.413 and MOD K⁺ 1.206 ± 0.498; vehicle (n = 7) and MOD (n = 5); ** p < 0.01; (b) GABA release levels in the NAc is expressed the mean of GABA levels ± SEM.

Figure 3

Non-selective attention (NSA) at day 1 and day 14 after vehicle (VEH) or modafinil (MOD) treatment in young male rats in 60 min test. Kruskal–Wallis test followed by Dunn post-hoc was used. Data are presented as the mean ± SEM; n = 5 or 6 per group. * p < 0.05.

Figure 4

Rearing frequency at days 1 and 14 in the vehicle (VEH) and modafinil (MOD) groups of young male rats. Kruskal–Wallis test followed by Dunn post-hoc was used. Data are presented as the mean ± SEM; n = 5 or 6 per group. *** p < 0.001.

Figure 5

Dopamine type 2 receptor (D₂) expression in the prefrontal cortex (PFC). (a) D₂ expression in PFC (b) Examples of blots for expression of D₂ in PFC after 14 days of treatment. Vehicle and MOD groups (n = 6), * p < 0.05; Data are expressed as mean ± SEM of arbitrary units of D₂ immunoreactivity normalized to GAPDH immunoreactivity.