Deficits in cognition and working memory accompany several neurological and neuropsychiatric disorders. Effective treatment of these symptoms is of paramount importance for full recovery and for improving medication compliance. Similar concerns have now been directed towards the treatment of substance abuse. Abused drugs from different classes have been associated with impairments in cognition and working memory. Cognition impairment is clearly an impediment to treatment and to the maintenance of abstinence. We have been studying a small library of analogs of choline that were originally characterized based on their cytoprotective actions. Two lead compounds have been characterized as excellent cognition-enhancing agents with the ability to improve working memory, attention, and sensory gating in primate and rodent models. These exciting new compounds evoke their pharmacological actions by a unique mechanism: desensitization of nicotinic cholinergic receptors without the antecedent activation. Many analogs are potent in their actions but have thus far exhibited no overt side effects or toxicity. In addition we have characterized reversible pharmacological models for impairments in working memory in monkeys utilizing ketamine (hallucinogen);nomifensine (cocaine/amphetamine-like activity);and amitriptyline (biogenic amine uptake inhibitor/anticholinergic). In rodents we use a cognitive task battery that also includes estimation of working memory, attention and sensory gating. Combining these models we expect to establish a characteristic pattern of choline analog-induced task improvements that suggest broad activity in the clinical setting of cognitive impairment, including substance abuse. Therefore we propose a drug discovery project with the central hypothesis that analogs of choline can improve aspects of working memory, attention, and sensory gating for use as adjuncts in the treatment of substance abuse. We plan to evaluate 40 analogs of choline belonging to 4 primary chemical classes in rodent models of working memory, attention, and sensory gating. Ten of these will progress to studies in rat models of chronic morphine, cocaine, and nicotine self-administration. Subjects have access on a 24 hr basis, and they can be tested for impairments in working memory after chronic self-administration and during acute withdrawal and protracted withdrawal. These same 10 compounds will be evaluated in macaque models of reversible pharmacological impairment in working memory as indicated above. These studies could lead to a ground-breaking advance towards a new pharmacological approach for the treatment of drug addicts, and for treating other types of addictive behaviors. In addition to cognitive improvement, choline analogs could also prevent the neural toxicity associated with the chronic abuse of several addictive substances.

Public Health Relevance

Abused drugs from different classes have been associated with impairments in cognition and working memory. Cognition impairment is clearly an impediment to treatment and to the maintenance of abstinence. We have been studying a small library of analogs of choline that were originally characterized based on their cytoprotective actions. These exciting new compounds evoke their pharmacological actions by a unique mechanism: desensitization of nicotinic cholinergic receptors without the antecedent activation. We propose a drug discovery project with the central hypothesis that analogs of choline can improve aspects of working memory, attention, and sensory gating for use as adjuncts in the treatment of substance abuse. We plan to evaluate 40 analogs of choline ten of which will progress to studies in rat models of chronic morphine, cocaine, and nicotine self-administration. They also will be evaluated in macaque models of reversible pharmacological impairment in working memory as indicated above. These studies could lead to a ground-breaking advance towards a new pharmacological approach for the treatment of drug addicts, and for treating other types of addictive behaviors. In addition to cognitive improvement, choline analogs could also prevent the neural toxicity associated with the chronic abuse of several addictive substances.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA029127-05
Application #
8616366
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (91))
Program Officer
Davis, Hirsch D
Project Start
2010-04-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$320,828
Indirect Cost
$102,578
Name
Georgia Regents University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Gao, Jie; Adam, Bao-Ling; Terry Jr, Alvin V (2014) Evaluation of nicotine and cotinine analogs as potential neuroprotective agents for Alzheimer's disease. Bioorg Med Chem Lett 24:1472-8
Terry Jr, Alvin V; Callahan, Patrick M; Schade, Rosann et al. (2014) Alpha 2A adrenergic receptor agonist, guanfacine, attenuates cocaine-related impairments of inhibitory response control and working memory in animal models. Pharmacol Biochem Behav 126:63-72
Wilson, Christina A; Terry Jr, Alvin V (2013) Variable maternal stress in rats alters locomotor activity, social behavior, and recognition memory in the adult offspring. Pharmacol Biochem Behav 104:47-61
Wilson, Christina A; Vazdarjanova, Almira; Terry Jr, Alvin V (2013) Exposure to variable prenatal stress in rats: effects on anxiety-related behaviors, innate and contextual fear, and fear extinction. Behav Brain Res 238:279-88
Terry Jr, A V (2012) Functional consequences of repeated organophosphate exposure: potential non-cholinergic mechanisms. Pharmacol Ther 134:355-65
Terry Jr, Alvin V; Decker, Michael W (2011) Neurobiology of nAChRs and cognition: a mini review of Dr. Jerry J. Buccafusco's contributions over a 25 year career. Biochem Pharmacol 82:883-90
Terry Jr, Alvin V; Callahan, Patrick M; Hall, Brandon et al. (2011) Alzheimer's disease and age-related memory decline (preclinical). Pharmacol Biochem Behav 99:190-210
Hall, Brandon J; Pearson, Laura S; Terry Jr, Alvin V et al. (2011) The use-dependent, nicotinic antagonist BTMPS reduces the adverse consequences of morphine self-administration in rats in an abstinence model of drug seeking. Neuropharmacology 61:798-806