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 a 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 five 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 three 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.

Nucleus accumbens neuronal activity correlates to the animal's behavioral response to acute and chronic methylphenidate

“…The NAc mediates reward behavior through dense dopaminergic projections from the ventral tegmental area (VTA) [6]. The VTA interacts with the pre-frontal cortex (PFC) glutamatergic transmission facilitating the rewarding actions of psychostimulants [7,8]. The NAc also receives excitatory glutamatergic inputs from the thalamus, hippocampus, and amygdala [9].…”

Acute and chronic dose–response effect of methylphenidate on ventral tegmental area neurons correlated with animal behavior

“…Both DA and GABA neurons in the VTA get input mediated by GABA and glutamate; those afferents containing glutamate come from the PFC, while those of GABA originate in the NAc (Beckstead et al, 1979; Johnson and North, 1992; Kalivas and Duffy, 1995). The dopaminergic neurons in the VTA co-express GABA-ergic or glutamatergic markers and it is thought that these DA neurons are activated by the glutamatergic inputs originating in the PFC and are involved with the induction of behavioral sensitization following repetitive exposure of psychostimulants (Scheggi et al, 2002; Tang et al, 2009; Wanchoo et al, 2010). In a morphological study, it has been shown that about two-thirds of the neurons in the VTA are dopaminergic, while the remaining neurons are mostly GABA (Nair-Roberts et al, 2008).…”

Improvement of Learning and Increase in Dopamine Level in the Frontal Cortex by Methylphenidate in Mice Lacking Dopamine Transporter

“…This may give rise to striatum dysfunction, leading to hyperactivity and learning deficits. Consistent with this possibility, MPH loses its locomotor-stimulating effects when selective dopaminergic lesions are made using 6-hydroxydopamine in the striatum [42] but not in the PFC [43]. A combined double lesion in the nucleus accumbens and striatum resulted in a severe deficit in the conditioned avoidance responding test [44].…”