Neuropharmacology research in the Dafny / Swann Lab focuses on several areas. These include the treatment of psychiatric disorders, behavioral responses to drugs, analgesia, and modifiers of learning and memory.

Treatment of Behavioral Disorders

The recurrent nature of bipolar disorder may be associated with progressive changes in characteristics such as episode frequency, severity or sensitivity to external stressors. Treatment response might also change over time. A relatively large number of previous episodes of illness is associated with poor prophylactic response to lithium. Manic and depressive episodes could affect the course of illness by different mechanisms. The increased catecholamine output associated with manic or mixed episodes could alter illness course or treatment response by mechanisms related to behavioral sensitization. Repeated manic episodes could also be associated with repeated lithium discontinuation or with development of tolerance to treatments. Depressive episodes could alter the course of illness by resulting in increased exposure to antidepressive treatments. Alternatively, individuals with many episodes might be more refractory to certain antimanic treatments due to inherent characteristics associated with greater mood instability. There is little experimental information, however, about differential effects of depressive or manic episodes on subsequent anti-manic treatment response. We have investigated the effects of course of illness on antimanic response to different drugs as well as to placebo.

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 neurohysiological 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 strain) rats, both before and after prolonged periods of methylphenidate treatment followed by amphetamine.

Modifiers of Learning and Memory

MK-801 is a non-competitive antagonist of the N-methyl--aspartate receptor and is known to cause locomotor activity, stereotypy, and ataxia. It has been suggested that MK-801's effects are, at least in part, mediated by the dopaminergic system. Consistent with this proposed mechanism of action is the finding that MK-801 can modulate the acute locomotor effects of stimulant drugs such as amphetamine and cocaine. However, the dose-related interactions between MK-801 and the above stimulants appear to be somewhat complex with studies finding an augmented, reduced, or unchanged locomotor response with MK-801 and stimulant coadministration vs. stimulant alone. Another parameter that may affect the motor response to the MK-801 and stimulant coadministration is the nature of the stimulant. Cocaine and methylphenidate function primarily as dopamine reuptake-blockers and thus affect the vesicular pool of dopamine. Amphetamine, although also a reuptake-blocker, also enhances cytosolic dopamine release through diffusion exchange. Since their mechanisms of action differ, MK-801 may differentially modulate the acute locomotor response to each of these drugs. In addition, many studies have found that repeated treatment with MK-801 prior to stimulants such as amphetamine and cocaine resulted in the blocking of the expected sensitized response to stimulant challenge. These findings support the hypothesis that behavioral sensitization, which can be present even months later, involves some permanent neural and cellular changes which may resemble other forms of plasticity, such as long-term potentiation (LTP) or kindling, and that these changes, which can be blocked by MK-801, may be mediated by NMDA receptors. We use this drug and others to understand the underlying mechanisms of learning and memory/sensitization, drug abuse, and pain suppression.

Behavioral Response to Drugs

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. Repeated intermittent treatment with an addictive drug not only produces sensitization to that drug, but may also produce cross-sensitization to other drugs. Cross-sensitization between addictive drugs is another topic under investigation in this lab, since it is a model for the study of multi-drug abuse.

Analgesia

Since the discovery that profound analgesia can be produced by focal electrical stimulation of midbrain structures (e.g., periaqueductal gray, dorsal raphe), it has become increasingly apparent that analgesia is in part related to opioid agonists that interact with a variety of receptors. Pain modulation is a dynamic process which involves continuous interactions among complex ascending and descending pathways. Our pain research focuses on defining the sites responsible for the modulation of pain and how to modulate (suppress) pain. In addition, we also focus on strain and gender differences in analgesia and drug effects as well as study differences in mechanism of pain suppression between strains and genders.