Glutaminergic Signaling in the Nucleus Accumbens Modulates the Behavioral Response to Acute and Chronic Methylphenidate

Abstract

Methylphenidate (MPD) is a psychostimulant that is widely used to treat attention deficit hyperactivity disorder, and is being increasingly misused as a recreational drug and cognitive enhancer. MPD acts on the reward system of the CNS through specific signaling pathways to produce its effects on behavior, including tolerance, withdrawal, and sensitization. The nucleus accumbens (NAc) is one of the predominant components of this system, however the role of the NAc's glutaminergic system in the behavioral response to MPD has not been studied. The objective of this study was to assess the role of glutaminergic signaling and the response to acute and chronic MPD exposure as measured by three different locomotive behaviors following selective bilateral lesions. Three groups of n=8 rats were used: control, sham NAc lesions, and glutaminergic-specific (ibotenic acid toxin) NAc lesions. On experimental day (ED) 1, all groups received saline injections to establish a baseline. On ED 2, NAc surgeries took place, followed by a 5-day recovery period (ED 3-7). On ED 8 saline was given to obtain a post-surgical baseline. Groups then received six daily MPD 2.5 mg/kg injections (ED 9-14) to produce a chronic effect, behavioral sensitization in this study, then three days of washout with no injection (ED 15-17), followed by a re-challenge with the previous 2.5 mg/kg MPD dose on ED 18. Locomotive activity was recorded for 60 minutes after each injection by a computerized animal activity monitoring system. All groups showed an increase in behavioral activity following acute MPD exposure, and developed behavioral sensitization following chronic MPD exposure that was maintained after three days of MPD washout. Compared to controls and sham lesions, the horizontal activity response was significantly (P<0.05) attenuated both acutely and chronically following glutaminergic selective ibotenic acid lesions to the NAc however the other indices showed no change. This indicates that glutaminergic signaling in the NAc plays a role in modulating the response to acute and chronic MPD.

The Ventral Tegmental Area (VTA), the Nucleus Accumbens (NAc), the Caudate Nucleus (CN) and the Prefrontal Cortex (PFC) role in the Response to Acute and Chronic Methylphenidate

“…The methods used in this review were published in detail [4,7,11,[13][14][15]59,60,68,69]. In short, 160 male Sprague-Dawley rats weighing 170-180 g were obtained from Harlan Labs (Indianapolis, IN, USA).…”

“…For the chemical specific ablation of dopaminergic and glutamatergic neurons 8.0 ug 6OH DA (Sigma St. Louis, Mo, USA) dissolved in 2 uL of 0.9% Saline containing 0.2 mg/ml ascorbic acid and 4.0 uL of 1 ug/ mL isotonic acid (Sigma St. Louis, Mo, USA) solution in depth similar to the non-specific electrolytic lesion for dopaminergic and the glutamatergic specific neurons ablation respectively. For the shame operation groups similar procedure (electrodes, cannula and coordination) were used but no current or injection were given [4,7,[13][14][15]59,60,69]. The cannulas and the electrodes were then removed, and incision closed with wound staples.…”

“…The glutaminergic signaling of the NAc appears to also modulate the effect of MPD. Selective lesions to the glutaminergic NAc signaling system do not lead to a gross disturbance in the acute or chronic response to MPD (Figure 4) [60], however when broken down into different locomotor expression of movement (horizontal activity vs. total distance vs. stereotypic movements), a significant difference is seen between groups [60]. Specifically, more goal directed forward movement as measured by horizontal activity (HA) was attenuated while stereotypic activity as measured by the number of stereotypic movements (NOS) was augmented following glutaminergic ablation of the NAc; total distance (TD) traveling remained unchanged [60].…”

“…One of the methods used to study them is to ablate a specific brain area of an animal model's CNS structure or signaling pathway (non-specifically or specifically) and challenge the subject to the substance. This manuscript reviews the non-specific electrolytic, dopaminergic specific, and glutaminergic specific lesions to the VTA (Figure 3) [59], to the NAc (Figure 4) [13,15,60], to the CN [4,7] (Figure 5) and to the PFC (Figure 6) [11,14,15], in the setting of acute and chronic MPD exposure that have been conducted. Bilateral non-specific lesions were conducted with electrolytic ablation [13,15,60], bilateral chemical dopaminergic specific lesions were obtained with local microinjection of the neurotoxin 6-hydroxydopamine (6-OHDA) [7,13,[61][62][63], and bilateral glutaminergic specific ablation was obtained with local microinjection of the neurotoxin ibotenic acid [64][65][66][67] within the VTA, NAc, CN & PFC.…”

“…This manuscript reviews the non-specific electrolytic, dopaminergic specific, and glutaminergic specific lesions to the VTA (Figure 3) [59], to the NAc (Figure 4) [13,15,60], to the CN [4,7] (Figure 5) and to the PFC (Figure 6) [11,14,15], in the setting of acute and chronic MPD exposure that have been conducted. Bilateral non-specific lesions were conducted with electrolytic ablation [13,15,60], bilateral chemical dopaminergic specific lesions were obtained with local microinjection of the neurotoxin 6-hydroxydopamine (6-OHDA) [7,13,[61][62][63], and bilateral glutaminergic specific ablation was obtained with local microinjection of the neurotoxin ibotenic acid [64][65][66][67] within the VTA, NAc, CN & PFC. Animal response to MPD was monitored and recorded with a computerized animal tracker in a behavioral open field assay, a means to track animal locomotive activity.…”