Lab Projects: Neurobehavior

The main focus of neurobehavioral research in this lab is to understand the mechanism of action underlying the phenomenon of behavioral tolerance and sensitization in the context of behavioral disorders (e.g., bipolar disorder, ADHD), and drug abuse (e.g., amphetamine, Ritalin). We also study the behavioral consequences of drug abuse such as addiction and withdrawal in concert with their electrophysiological mechanisms.

Behavioral Sensitization

Behavioral sensitization refers to the progressive augmentation of behavioral responses to psychomotor stimulants that develops during their repeated administration and persists for long periods. This repeated administration produces gradual and incremental neuroadaptions that render the animals hypersensitive to these agents. Behavioral sensitization is used as a model to study learning and memory, bipolar disorder, and drug abuse. A fundamental conceptualization employed in studying the mechanisms of neural sensitization is that this phenomenon exhibits two distinct temporal domains: 1) the induction/initiation, and 2) the expression of sensitization. The induction of behavioral sensitization is defined as the transient sequence of cellular and molecular events precipitated by the psychostimulant that lead to the enduring changes in neuronal function responsible for behavioral augmentation. Induction of behavioral sensitization to psychostimulants occurs in the ventral tegmental area (VTA). Expression is defined as the neuronal alteration arising from the initiating process that mediates the augmented behavioral response and that is mediated by nucleus accumbens (NAc). The neuronal network that contributes to the long-term expression of behavioral sensitization to psychostimulants is distributed among several interconnected mesolimbic nuclei, which are termed the ‘motive circuit’. It has been suggested that the dopamine system underlies behavioral sensitization and psychosis induced by psychostimulants, as well as underlying the mechanism of drug addiction and craving. Recent reviews have hypothesized about its potential importance as a model for the intensification of drug craving. Repeated drug use only sensitizes the neuronal system responsible for ‘wanting’, (i.e., the addictive behavior which is fundamentally a problem of sensitization), and is responsible for transforming ‘wanting’ into ‘craving’. In addition to studying the long-term effects of drugs, our lab also studies the acute effects of drug administration.

Attention Deficit Hyperactivity Disorder (ADHD)

Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric syndrome of children. ADHD accounts for more referrals for treatment than any other childhood disorder, and more children receive medication for ADHD than for any other emotional or behavioral disorder. ADHD is also a major risk factor for later delinquency, substance abuse and personality disorders. The psychostimulant methylphenidate (Ritalin) is the drug most often used for treatment of ADHD. Children with ADHD are typically treated for periods of several years, sometimes extending into adulthood. Some professionals believe that many children who have been diagnosed with ADHD and are being treated for it do not really have the disorder because the diagnosis was made with methods that are not absolutely valid and/or reliable. This raises the question of whether early psychostimulant exposure will lead to permanent changes in adulthood, especially because the long-term effects of methylphenidate are still unknown. This long-term treatment in childhood may exert transient or permanent CNS effects in adulthood on true ADHD subjects as well as on the misdiagnosed subjects. We study the behavioral and neurophysiological effects of acute and long-term use of methylphenidate on animal models of ADHD. Our overall objective is to investigate behavioral and neurophysiological aspects of behavioral sensitization as the fundamental mechanisms underlying the effect of long-term sequelae of methylphenidate administration. The neurophysiological studies will investigate six brain sites considered to be essential in the induction and expression of sensitization to psychostimulants. All experiments will use female and male juvenile and adult ADHD animal model (SHR strain) and normal (WKY and SD strain) rats, both before and after prolonged periods of methylphenidate treatment followed by amphetamine.

Drug Abuse

Methylphenidate (Ritalin) has pharmacological properties similar to amphetamine and cocaine . When given intravenously (i.v.), methylphenidate can induce a sensation of euphoria. Methylphenidate has been abused both i.v. and intranasally. Thus, it is possible that its prolonged use may generate dependency, withdrawal, tolerance, and/or sensitization and cross-sensitization to other psychostimulants. Furthermore, repeated usage of a stimulant has also been shown to elicit sensitivity and addiction to other substances, such as heroin, cocaine, LSD and cannabis. The potential for abuse of methylphenidate has recently received considerable attention because of the increase in substance abuse predicted among inadequately medicated children, and because there is an increased incidence of substance abuse among ADHD subjects. Methylphenidate abuse could become a major problem in the future with the increasing prescription of this drug, since patients are not going to acknowledge willingly that they are abusing methylphenidate. It has been shown that patients abusing methylphenidate had little difficulty obtaining it from doctors, hospitals, and specialized clinics for children. The long-term effects of methylphenidate administration on the physiology of the CNS are cause for concern.

We also study the behavioral and neurophysiological effects of morphine, cocaine, amphetamine, and ethanol abuse and withdrawal.