The clinical literature has emphasized that the abuse potential of cocaine is related to its speed of onset and that each time a person experiences a rapid and intense cocaine rush there is an increased risk of further drug taking and an increased likelihood of addition. While it is well known that cocaine intake in rats shows a fast- rising loading phase, most rodent models of cocaine addiction instead have focused on the maintenance phase and have explored the effects of long access sessions. The general assumption is that more drug exposure and high intake produces an addicted phenotype. This grant challenges that premise. Our hypothesis is that brief episodes (eg. 5 min) of intense drug use are sufficient to cause a transition from recreational to binge-like patterns of intake. Our data show that self-administration procedures that engender spiking drug levels produce a more robust escalation of drug intake and a dramatic increase in the motivation to self- administer cocaine. Our hypothesis is that the number of 'spikes'(or loading phases) have a much greater impact on the addiction process than the maintenance phase or total drug intake. The experiments proposed in this grant are designed to confirm, extend and validate our initial findings.
Specific Aim 1 will test the hypothesis that the number of spikes, the change in spike height and the rise time of each spike is an important determinant of escalation of drug intake and the motivation to response (as measured by a progressive ratio schedule).
Specific Aim 1 will also test the hypothesis that cocaine self-administration is regulated by an endogenous circadian influence and that spiking cocaine levels can dysregulate this important physiological control mechanism. Our theoretical viewpoint draws heavily on modeling of cocaine concentrations in brain and it becomes important for us to examine and validate the assumptions underlying the model.
Specific Aim 2 will validate the kinetic model using self-administration procedures and will examine the effects of cocaine consumption on extracellular cocaine and dopamine parameters. A method for separating appetitive and consummatory responding will be developed in Specific Aim 3. A two lever procedure will allows us to study cocaine consumption on one lever and the motivation to gain access to cocaine on the other lever. By using a PR schedule and manipulating timeouts and time of day the procedure will enable us to test hypotheses regarding the relationship between brain levels cocaine, drug seeking and drug taking.

Public Health Relevance

The proposed work is expected to provide new insights into neural mechanisms involved in the addiction process. How people progress through various stages of the addiction process is determined, or at least predicted, by the pattern of drug use. These studies will use an animal model to a better understanding of how large doses and fast rising brain levels of cocaine affect specific neural targets and may potentially lead to new therapeutic strategies to dampen interest in drug taking.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-H (02))
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Wetherington, Cora Lee
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Wake Forest University Health Sciences
Schools of Medicine
United States
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Calipari, Erin S; Siciliano, Cody A; Zimmer, Benjamin A et al. (2015) Brief intermittent cocaine self-administration and abstinence sensitizes cocaine effects on the dopamine transporter and increases drug seeking. Neuropsychopharmacology 40:728-35
Calipari, Erin S; Ferris, Mark J; Siciliano, Cody A et al. (2014) Intermittent cocaine self-administration produces sensitization of stimulant effects at the dopamine transporter. J Pharmacol Exp Ther 349:192-8
Calipari, Erin S; Jones, Sara R (2014) Sensitized nucleus accumbens dopamine terminal responses to methylphenidate and dopamine transporter releasers after intermittent-access self-administration. Neuropharmacology 82:1-10
Zimmer, Benjamin A; Chiodo, Keri A; Roberts, David C S (2014) Reduction of the reinforcing effectiveness of cocaine by continuous D-amphetamine treatment in rats: importance of active self-administration during treatment period. Psychopharmacology (Berl) 231:949-54
Siciliano, Cody A; Calipari, Erin S; Jones, Sara R (2014) Amphetamine potency varies with dopamine uptake rate across striatal subregions. J Neurochem 131:348-55
Calipari, Erin S; Ferris, Mark J; Jones, Sara R (2014) Extended access of cocaine self-administration results in tolerance to the dopamine-elevating and locomotor-stimulating effects of cocaine. J Neurochem 128:224-32
Ferris, Mark J; Calipari, Erin S; Melchior, James R et al. (2013) Paradoxical tolerance to cocaine after initial supersensitivity in drug-use-prone animals. Eur J Neurosci 38:2628-36
Blume, Lawrence C; Bass, Caroline E; Childers, Steven R et al. (2013) Striatal CB1 and D2 receptors regulate expression of each other, CRIP1A and ? opioid systems. J Neurochem 124:808-20
Calipari, Erin S; Ferris, Mark J; Salahpour, Ali et al. (2013) Methylphenidate amplifies the potency and reinforcing effects of amphetamines by increasing dopamine transporter expression. Nat Commun 4:2720
Zimmer, Benjamin A; Dobrin, Carson V; Roberts, David C S (2013) Examination of behavioral strategies regulating cocaine intake in rats. Psychopharmacology (Berl) 225:935-44

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