Low doses of psychostimulants, including methylphenidate (MPH/Ritalin), are widely used clinically due to their behavioral-calming and cognition-enhancing actions. Less well-recognized is the fact that these drugs exert similar actions in both normal human and animal subjects. Of particular relevance to the proposed studies are the well-documented facilitatory actions of low- doses of MPH and other psychostimulants on prefrontal cortex (PFC)-dependent cognition (i.e. working memory and sustained attention). Despite these cognition-enhancing actions, these drugs possess certain risks, including toxicity and abuse/addiction. For this reason, there is much concern about the widespread use of these drugs, particularly in children. Moreover, these risks preclude use of these drugs in other disorders/conditions associated with relatively modest impairment in PFC- dependent cognition (i.e. normal aging, sleep deprivation). To better develop non-stimulant drugs for the treatment of ADHD and other disorders and conditions associated with impaired PFC- dependent cognition, it is important to understand the neural mechanisms responsible for the cognition-enhancing actions of low-dose psychostimulants. Surprisingly, little is known about the neural substrates underlying the behavioral/cognitive actions of low-dose stimulants. We recently demonstrated that at low doses that improve both working memory and sustained attention in rats, PFC catecholamine efflux displays a greater sensitivity than catecholamine efflux in a number of cortical and subcortical regions outside the PFC. Additional studies indicate that cognition-enhancing doses of MPH increase PFC neuronal responsivity, an effect not observed in the somatosensory cortex. Combined, these observations suggest a prominent role of the PFC in the cognition-enhancing actions of low-dose MPH. The proposed studies are designed to further test this hypothesis and to provide insight into the neural mechanisms that underlie these actions. These studies will use a combination of microdialysis measures of catecholamine release, electrophysiological measurement of PFC neuronal activity, pharmacological manipulations and tests PFC-dependent cognition. These studies will provide novel insight into the neurobiological mechanisms through which low-dose psychostimulants improve cognitive function. Additionally, these studies will provide important information for the development of new pharmacological treatments for ADHD and other disorders/conditions associated with PFC dysfunction.

Public Health Relevance

These studies will provide novel insight into the neural mechanisms that underlie the cognition- enhancing actions of low-dose psychostimulants as well as the neurobiology of higher cognitive function. Importantly, these studies will provide information necessary for the development of new pharmacological treatments lacking the potential adverse actions of psychostimulants for a variety of cognitive/behavioral disorders associated with prefrontal cortical dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH081843-05
Application #
8414857
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Winsky, Lois M
Project Start
2009-05-02
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$430,094
Indirect Cost
$138,230
Name
University of Wisconsin Madison
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Hupalo, Sofiya; Berridge, Craig W (2016) Working Memory Impairing Actions of Corticotropin-Releasing Factor (CRF) Neurotransmission in the Prefrontal Cortex. Neuropsychopharmacology 41:2733-40
España, Rodrigo A; Schmeichel, Brooke E; Berridge, Craig W (2016) Norepinephrine at the nexus of arousal, motivation and relapse. Brain Res 1641:207-16
Berridge, Craig W; Spencer, Robert C (2016) Differential cognitive actions of norepinephrine a2 and a1 receptor signaling in the prefrontal cortex. Brain Res 1641:189-96
Spencer, Robert C; Devilbiss, David M; Berridge, Craig W (2015) The cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex. Biol Psychiatry 77:940-50
Andrzejewski, Matthew E; Spencer, Robert C; Harris, Rachel L et al. (2014) The effects of clinically relevant doses of amphetamine and methylphenidate on signal detection and DRL in rats. Neuropharmacology 79:634-41
Schmeichel, Brooke E; Berridge, Craig W (2013) Neurocircuitry underlying the preferential sensitivity of prefrontal catecholamines to low-dose psychostimulants. Neuropsychopharmacology 38:1078-84
Schmeichel, Brooke E; Zemlan, Frank P; Berridge, Craig W (2013) A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: potential relevance to attention deficit hyperactivity disorder. Neuropharmacology 64:321-8
Devilbiss, David M; Jenison, Rick L; Berridge, Craig W (2012) Stress-induced impairment of a working memory task: role of spiking rate and spiking history predicted discharge. PLoS Comput Biol 8:e1002681
Spencer, Robert C; Klein, Raymond M; Berridge, Craig W (2012) Psychostimulants act within the prefrontal cortex to improve cognitive function. Biol Psychiatry 72:221-7
Berridge, Craig W; Shumsky, Jed S; Andrzejewski, Matt E et al. (2012) Differential sensitivity to psychostimulants across prefrontal cognitive tasks: differential involvement of noradrenergic α₁ - and α₂-receptors. Biol Psychiatry 71:467-73

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