Bilateral six-hydroxydopamine administration to PFC prevents the expression of behavioral sensitization to methylphenidate

Abstract

Psychostimulants like amphetamine and methylphenidate (MPD) are used to treat attention deficit hyperactivity disorder (ADHD), which is marked by developmentally inappropriate inattention, hyperactivity, and impulsivity. Neuropsychological analyses indicate that ADHD patients are impaired on tasks of behavioral inhibition, reward reversal, and working memory, which are functions of the prefrontal cortex (PFC) and are modulated by the mesocortical dopamine (DA) system. Non-specific electrical lesioning of PFC eliminated the expression of behavioral sensitization elicited by chronic MPD administration. Behavioral sensitization is the progressive augmentation of locomotor activity as a result of repetitive (chronic) exposure to the drug. It is believed that the sensitization to chronic drug treatment is caused due to an increase in DA in the mesocorticolimbic DA system, which includes the PFC. Therefore, this study investigated the role of PFC DA in mediating the behavioral sensitization to repeated administration of MPD in adult male Sprague-Dawley rats. On experimental day (ED) 1, the behavior was recorded post-saline injection. On ED 2, the rats were divided into three groups--control, sham and bilateral 6-OHDA treated group; and the sham and 6-OHDA treated groups underwent respective surgeries. After 5 days of rest following surgery, the post-surgery baseline was recorded on ED 8 following a saline injection. All three groups received 2.5 mg/kg MPD for 6 days (from ED 9 to ED 14), followed by a 3-day washout period (ED 15 to ED 18). On ED 19, a rechallenge injection of 2.5 mg/kg MPD was given and locomotor activity was recorded. It was found that the 6-OHDA lesion group failed to exhibit behavioral sensitization to MPD. The involvement of the dopaminergic afferents of PFC in behavioral sensitization to MPD is discussed.

Figure 1

compares the pre and post surgery baseline for the lesion as well as both the sham groups. It was observed that the surgeries did not alter the baseline of any group. # - denotes significance (p < 0.05).

Figure 2

contrasts the locomotor activity in all three groups recorded after the first injection of MPD (ED 9) with the post-surgery baseline (ED 8). The figures on the left indicate temporal graphs of the locomotor activity, while the histograms on the right indicate the sum of total horizontal activity in 2 hours post injection. MPD caused a significant increase in locomotor activity in all three groups. # - denotes significance (p < 0.05).

Figure 3

indicates that the increase in locomotion observed after the first injection of MPD (ED 9) was maintained following the sixth consecutive injection of MPD (ED 14) in all three groups.

Figure 4

analyzes the locomotor activity during the washout period as compared to the post-surgery baseline. In the temporal graphs on the left, ^ denotes activity on ED 15 was significantly different than activity at that time point on ED 8. * denotes activity on ED 18 was significantly different than activity at that time point on ED 8. The two hour histograms indicate that the control group exhibited significantly increased locomotion on both the first day of the washout, while the sham group exhibited significantly elevated activity on only the first and not the last day of washout. The lesion group exhibited baseline locomotor activity on both the first as well as last day of washout. # - denotes significance (p < 0.05).

Figure 5

examines the locomotor activity following the MPD rechallenge injection (ED 19) as compared to the locomotor activity following the first injection of MPD (ED 9). It was noted that while control and sham group showed a significantly elevated activity following the rechallenge injection (sensitization), while the lesion group did not have a sensitized response. # - denotes significance (p < 0.05). In the temporal graph for the control group, it was observed that average 10 minute activity of the rechallenge injection was significantly higher than that of the acute injection for the first 30 minutes. In the 6-OHDA lesion in PFC group, this trend was reversed and the average 10 minute activity of the rechallenge injection was significantly lower than that of the acute injection at two time points.

Figure 6

shows the site of the syringe tip location in the brain. The black dots indicate the location of the injection sites for the 6-OHDA administrations (sections 3.7, 3.2 and 2.7 mm anterior to bregma) in the PFC, whereas the grey shaded area indicates the spread of 6-OHDA in the PFC.