Dopamine Uptake Changes Associated with Cocaine Self-Administration

Abstract

The present study was designed to reveal the relationship between cocaine-induced dopamine uptake changes and patterns of cocaine self-administration observed under a fixed ratio schedule. Cocaine was intravenously infused into anesthetized rats, according to inter-infusion intervals obtained from self-administering animals, and dopamine uptake changes (apparent Km) were assessed in the nucleus accumbens using voltammetry. The data demonstrate that cocaine-induced dopamine transporter (DAT) inhibition accounts for the accumbal dopamine fluctuations, which are associated with the cyclic regularity of cocaine intake observed during self-administration. Specifically, the inter-infusion intervals that are maintained during cocaine self-administration correlate with the maintenance of a rapidly changing level of dopamine uptake inhibition, which appears to be tightly regulated. Furthermore, this maintained level of dopamine uptake inhibition was found to shift upward using intervals from animals that had shown an escalation in the rate of cocaine self-administration. Although no significant change in the apparent Km was revealed in animals that exhibited an escalation in the rate of cocaine intake, an increased dopamine uptake rate was found suggesting an up-regulation of DAT number in response to a history of high cocaine intake. This is the first demonstration of the tight correlation that exists between the level of dopamine uptake inhibition and rates of cocaine self-administration. Moreover, a new mathematical model was created that quantitatively describes the changes in cocaine-induced dopamine uptake and correctly predicts the level of dopamine uptake inhibition. This model permits a computational interpretation of cocaine-induced dopamine uptake changes during cocaine self-administration.

A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration

“…As a precautionary note, it should be pointed out that the effect of cocaine self-administration history on DAT expression remains equivocal with examples of increased, decreased, and no change in DAT expression in all species investigated (Narendran and Martinez, 2008). For example, our observation of decreased DAT expression and V max following cocaine self-administration, despite being replicated numerous times in our model, differs to some degree from the majority of human studies (Narendran and Martinez, 2008;Little et al, 1993;Malison et al, 1998), and even some rat (Oleson et al, 2009;Calipari et al, 2013a) and nonhuman primate work (Letchworth et al, 2001). These examples show either increases or no change in DAT expression following a history of cocaine self-administration.…”

Alterations in tryptophan and purine metabolism in cocaine addiction: a metabolomic study

“…The role of neurotransmitter systems in cocaine addiction, although recognized (Engblom et al 2008;Oleson et al 2009;Patkar et al 2008), has not been comprehensively evaluated with respect to mechanisms of toxicity and addiction (Kalivas and Volkow 2005). Investigations of neurobiological actions of cocaine usually center on receptor binding and enzyme inhibition, with limited attention to events such as aberrant metabolism, oxidative stress, signaling disturbances, or membrane dysfunction.…”

Parsing the addiction phenomenon: Self-administration procedures modeling enhanced motivation for drug and escalation of drug intake

“…It should be emphasized, however, that the two dependent measures are very different. Final ratios reflect some measure of the motivation to obtain drug, while rate of drug intake on an FR1 schedule of reinforcement reflects the blood or brain level at which an animal will titrate its intake [46,47,48,49] but see also [50]. These are very different concepts.…”

“…In their study, Zittell-Lazarini and colleagues [56] demonstrated that very high rates of responding can be maintained under an FR1 schedule of reinforcement by cocaine doses as low as 8 μg/inf. Due to the observations that the rate of cocaine intake maintained under an FR1 schedule of reinforcement is titrated around some blood or brain level [47,57,58] and maximal responding occurs at the threshold, these authors [56] first suggested that behavioral economics analyses could be applied to threshold data.…”

“…In their study, Zittell-Lazarini and colleagues [56] demonstrated that very high rates of responding can be maintained under an FR1 schedule of reinforcement by cocaine doses as low as 8 μg/inf. Due to the observations that the rate of cocaine intake maintained under an FR1 schedule of reinforcement is titrated around some blood or brain level [47,57,58] and maximal responding occurs at the threshold, these authors [56] first suggested that behavioral economics analyses could be applied to threshold data.As shown in figure 4B and C, a relatively stable level of cocaine consumption is maintained as the available dose is decreased until a threshold dose is reached. Due to the observation that maximal responding occurs at this threshold dose, it can be inferred that the maintenance of drug intake at threshold is influenced by the price (i.e., effort) an animal expends to 'defend' a relative level of drug intake.…”