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

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.

Descending glutamatergic pathways of PFC are involved in acute and chronic action of methylphenidate.

Progressive augmentation of behavioral response following repeated psychostimulant administrations is known as behavioral sensitization, and is an indicator of a drug's liability for abuse. It is known that methylphenidate (MPD) (also known as Ritalin), a drug used to treat attention-deficit hyperactivity disorder (ADHD), induces sensitization in animals following repeated injections. It was recently reported that bilateral electric (non-specific) lesion of prefrontal cortex (PFC) prevented MPD elicited behavioral sensitization. Since PFC sends glutamatergic afferents to both ventral tegmental area (VTA) and nucleus accumbens (NAc), sites that are involved in induction and expression of behavioral sensitization respectively and glutamate from PFC is known to modulate dopamine cell activity in VTA and NAc, this study investigated the role of descending glutamate from PFC in MPD elicited behavioral sensitization. Locomotor activity of three groups of rats-control, sham operated and group with specific chemical lesion of glutamate neurons of PFC-was recorded using an open-field assay. On experimental day (ED) 1, the locomotor activity was recorded post a saline injection. The sham and lesion groups underwent respective surgeries on ED 2, and were allowed to recover for 5 days (from ED 3 to ED 7). The post-surgery baseline was recorded on ED 8 following a saline injection. On ED's 9 through 14, 2.5 mg/kg MPD was given, followed by a 4-day washout period (ED 15 -18). All three groups received a rechallenge injection of 2.5 mg/kg on ED 19 and their locomotor activity on various days was analyzed. It was found that ibotenic acid lesion modulated the acute and chronic effects of MPD and hence suggests that PFC glutamatergic afferents are involved in the acute effect of MPD as well as in its chronic effects such as behavioral sensitization to MPD.

Psychostimulant treatment for ADHD is modulated by prefrontal cortex manipulation.

The psychostimulant amphetamine (Amph) is widely used treatments for attention-deficit hyperactivity disorder (ADHD). Chronic intermittent exposure to psychostimulants induces behavioral sensitization. The objective of this study was to investigate the role of prefrontal cortex (PFC) in the acute and chronic effect of Amph using the open-field assay. Male Sprague-Dawley rats were assigned randomly to three groups, (1) an intact control group (2) a PFC sham-operated group, and (3) a PFC lesion group. All the three groups showed increases in locomotor activity after acute amphetamine injection (P<0.05), and activity levels were especially augmented in PFC lesion group. Following chronic amphetamine, the control group and sham-operated group exhibited behavioral sensitization (P<0.05). However, the PFC lesion group failed to exhibit behavioral sensitization and the pattern of locomotion was altered, which indicated that the nature of behavioral sensitization was changed. The results suggest that PFC lesion enhance the acute effects of amphetamine on locomotor activity and is required for development of behavior sensitization.