Selective bilateral lesion to caudate nucleus modulates the acute and chronic methylphenidate effects

Abstract

The psychostimulant methylphenidate (MPD) is currently the most prescribed drug therapy for attention deficit hyperactivity disorder (ADHD) and is used by students as a cognitive enhancer. The caudate nucleus (CN) is a structure within the motive circuit where MPD exerts its effects, it is known to contain high levels of dopaminergic cells and directly influence motor activity. The objective of this study was to understand the role of CN in response to acute and chronic administration of MPD using an open field assay. Specific and non-specific bilateral ablations were created in the CN using electrolytic lesion and injection of the neurotoxin 6-Hydoxydopamine (6-OHDA). Four groups of rats were used: intact control (n=4), sham operated (n=4), CN electrolytic lesion group (n=8) and CN 6-OHDA injected group (n=8). On experimental day one (ED1) all rats received a saline injection and baseline locomotive activity was recorded. On ED2 and ED3 CN sham, electrolytic lesion and/or 6-OHDA injected groups were made followed by four to five days recovery (ED3–7), followed by six daily 2.5 mg/kg MPD injections (ED9–14), three days of washout (ED15–17) and an MPD re-challenge of drug proceeding the washout days (ED18). Locomotor activity was obtained at ED1, 8, 9, 18 using an open field assay. The results show that the CN electrical lesion group responded to the acute and chronic MPD administration similar to the intact control and sham operated group, while the CN 6-OHDA injected lesion group that selectively depleted the CN dopaminergic neurophil prevented the acute and chronic effect of MPD administration. One possible interpretation why nonspecific electrical lesioning of the CN failed to prevent acute and chronic effects of MPD administration is due to destruction of both direct and the indirect CN pathways which act as an inhibitory/excitatory balance, making the net outcome no change for the electrical lesion group. The selective dopaminergic lesioning prevented the acute and the chronic effects of MPD administration suggesting dopaminergic pathways in CN play a significant role in the acute and chronic effect of MPD.

Behavioral and neuronal recording of the nucleus accumbens in adolescent rats following acute and repetitive exposure to methylphenidate

“…Surgery was performed as detailed in previous studies Claussen and Dafny 2012;Clauseen et al 2014). Rats were anesthetized on the day of surgery using 30 mg/kg ip pentobarbital, and the Sherwood and Timiras (1970) rat brain atlas was used as a guide to drill one hole above the frontal sinus and bilateral 0.6-mm diameter holes above the NAc (1.7 mm anterior to the bregma and 1.2 mm lateral from the midline).…”

“…One twisted electrode (consisting of 2 electrodes twisted together) was introduced into each NAc bilaterally by first inserting the twisted electrode to a depth of 6.8 mm, with concurrent monitoring of activity using a Grass emitter Hi Z Probe connected to a Grass P511 amplifier. Electrodes were fixed to the skull only when spike activity exhibited a noise ratio of at least 3:1 in both electrodes, and if this was not achieved, the electrode was inserted further in increments of ϳ10 m until the 3:1 ratio was attained Claussen and Dafny 2012). The rats were allowed to recover for 4 -7 days, and every day for 2 h the rats (with their home cages) were placed in the experimental behavioral apparatus and connected to the wireless (telemetric) head stage transmitter (ϳ4 gm in weight; Triangle BioSystems, Durham, NC) to allow for acclimation to the recording systems.…”

“…Spike sorting from the recording was conducted using Spike 2.7 software (CED) at sampling rates of up to 200 kHz and processed using low-and high-pass filters (0.3-3 kHz), with two window discriminatory levels accounting for both positiveand negative-going spikes. Spikes were processed as described in previous publications Claussen and Dafny 2012;Claussen et al 2014;Salek et al 2012). The parameters for spike sorting used on data recorded on day 1 from each particular electrode and animal were stored and reused identically on day 10, thus assuring that the spike patterns captured on these days were the same for each particular animal and electrode (see Figs.…”

“…These firing rates were subsequently found not to hold normality assumptions, and thus differences in mean firing rates were assessed using the critical ratio (CR) test, wherein CR ϭ ͑E Ϫ C͒ ⁄ ͙ ͓EϩC͔ ϭ Ϯ 1.96 ϭ P Ͻ 0.05 (C ϭ activity following saline [control] injection; E ϭ activity following MPD injection). CR values greater than ϩ1.96 indicate that the treatment elicited a significant increase in neuronal activity, while CR values less than Ϫ1.96 indicate that the treatment elicited a significant decrease in neuronal activity Claussen and Dafny 2012;Salek et al 2012). Three comparisons were made, similar to the behavioral comparisons in Analysis of Behavioral Data: first, the acute effect of MPD was evaluated by comparing day 1 baseline activity with day 1 activity following MPD administration.…”

Behavioral daily rhythmic activity pattern of adolescent female rat is modulated by acute and chronic cocaine

“…The neuroadaptation within the mesocorti-colimbic dopaminergic pathway, involving ventral teg-mental area, nucleus accumbens, and prefrontal cortex, is a major player in the development of behavioral sensitization (Chen et al 2009; Chong et al 2012; Claussen et al 2012; Claussen and Dafny 2012; Podet et al 2010; Salek et al 2012; Robinson and Becker 1986; Kalivas and Stewart 1991; Nestler 2002; Everitt and Robbins 2005; Kalivas and O’Brien 2008). Although not completely understood yet, there seems to be a relationship between behavioral sensitization and circadian clock genes in the brain, (Yuferov et al 2005; Abarca et al 2002; McClung et al 2005) because the degree of sensitization to psychostimulant is time dependent (Abarca et al 2002).…”