The prefrontal cortex and the caudate nucleus respond conjointly to methylphenidate (Ritalin). Concomitant behavioral and neuronal recording study

Highlights

• MPD elicits sensitization in some animals and tolerance in others.

• Sensitization and tolerance are experimental biomarkers indicating a drug of abuse.

• PFC and CN neuronal firing rates increased in sensitized animals.

• PFC and CN neuronal firing rates decreased in tolerant animals.

• Dose-response differences between the PFC and CN were observed.

Abstract

Methylphenidate (MPD) is commonly used to treat attention-deficit hyperactivity disorder (ADHD). Recently, it is being abused for cognitive enhancement and recreation leading to concerns regarding its addictive potential. The prefrontal cortex (PFC) and caudate nucleus (CN) are two of the brain structures involved in the motive/reward circuit most affected by MPD and are also thought to be responsible for ADHD phenomena. This study is unique in that it investigated acute and chronic, dose-response MPD exposure on animals’ behavior activity concomitantly with PFC and CN neuronal circuitry in freely behaving adult animals without the interference of anesthesia. Further, it compared acute and chronic MPD action on over 1,000 subcortical and cortical neurons simultaneously, allowing for a more accurate interpretation of drug action on corticostriatal neuronal circuitry. For this experiment, four groups of animals were used: saline (control), 0.6, 2.5, and 10.0 mg/kg MPD following acute and repetitive exposure. The data shows that the same MPD dose elicits behavioral sensitization in some animals and tolerance in others and that the PFC and CN neuronal activity correlates with the animals' behavioral responses to MPD. The expression of sensitization and tolerance are experimental biomarkers indicating that a drug has addictive potential. In general, a greater percentage of CN units responded to both acute and chronic MPD exposure as compared to PFC units. Dose response differences between the PFC and the CN units were observed. The dichotomy that some PFC and CN units responded to the same MPD dose by excitation and other units by attenuation in neuronal firing rate is discussed. In conclusion, to understand the mechanism of action of the drug, it is essential to study, simultaneously, on more than one brain site, the electrophysiological and behavioral effects of acute and chronic drug exposure, as sensitization and tolerance are experimental biomarkers indicating that a drug has addictive potential. The behavioral and neuronal data obtained from this study indicates that chronic MPD exposure results in behavioral and biochemical changes consistent with a substance abuse disorder.

Introduction

Methylphenidate (MPD) is one of the most commonly prescribed psychostimulants used to treat attention deficit hyperactivity disorder (ADHD) (Busardò et al., 2016; Storebø et al., 2015; Zito et al., 2000). Though MPD effectively treats the disorder in patients who are diagnosed with ADHD, its recreational use is becoming more prevalent for its ability to improve cognitive enhancement (Arria and Wish, 2006; Arria et al., 2008). In fact, studies have shown that over 20 % of college students on some college campuses use MPD and other cognitive enhancing drugs without a prescription (Dietz et al., 2013) with some MPD abusers using the drug for daily cognitive enhancement (chronic effect), and others using the drug occasionally (acute effect). Further, the dose of MPD abused varies from individual to individual with some abusing low dose MPD (0.6 mg/kg and 2.5 mg/kg) and others abusing high dose MPD (10.0 mg/kg). This is of particular concern as MPD abuse is extremely dangerous with intravenous or intranasal MPD consumption having an even higher mortality rate than that of cocaine or amphetamines (Garland, 1998: Gatley et al., 1999; Llana and Crimson, 1999; Massello and Carpenter, 1999). Further, uncontrolled and unmonitored use of MPD can lead to undesirable behavioral changes in the brain that can lead to more severe outcomes such as depression or death as well as the potential for addiction and withdrawal symptoms (Morton and Stockton, 2000). The unintended consequences of MPD usage in those who do not have ADHD necessitate the study of MPD’s effects in normal subjects.

MPD and other drugs used in ADHD treatment, work by affecting the concentrations of neurotransmitters in the brain. Specifically, MPD works by increasing the release of catecholamines (CA) such as dopamine in regions of the brain involved in motivation and reward: prefrontal cortex (PFC), caudate nucleus (CN), ventral tegmental area, nucleus accumbens, etc. (Fleckenstein et al., 2007; Kuczenski and Segal, 2002; Svetlov et al., 2007). The PFC, in particular, is the part of the brain primarily involved in higher cortical processing, decision-making, impulse control, and other features that are inhibited in ADHD (Siddiqui et al., 2008). Additionally, it is one of many CNS sites that comprise the motive circuit, a group of neural structures that affect the brain’s reward system and underlie the effects of pychostimulant exposure on the brain (Berridge, 2006; Pierce and Kalivas, 1997). Further, the prefrontal cortex makes extensive connections with many other brains areas, and if damaged, could result in deficits in decision-making and working memory as well as personality changes (Bechara et al., 1994; Damasio et al., 1990; Kane and Engle, 2002). One of these connections that the PFC makes is with the CN. These frontostriatal connections play critical roles in procedural learning, inhibitory control of action, and personality (Tekin and Cummings, 2002). While the exact reasons behind why increased CA levels lead to improvement in ADHD symptoms are unclear, fMRI studies have found PFC hypoactivity and altered frontostriatal connections in ADHD individuals (Blum et al., 2008; Bush, 2010). Thus the goals of this study are to investigate and compare the roles of both acute and chronic, dose-dependent MPD exposure on the PFC and CN neuronal populations and behavioral activities in ordinary (as opposed to ADHD or hyperactive) freely behaving adult animals implanted previously with electrodes within the PFC and CN.