Accumbal Neurons that are Activated during Cocaine Self-Administration are Spared from Inhibitory Effects of Repeated Cocaine Self-Administration

Abstract

Hypoactivity of the accumbens is induced by repeated cocaine exposure and is hypothesized to play a role in cocaine addiction. However, it is difficult to understand how a general hypoactivity of the accumbens, which facilitates multiple types of motivated behaviors, could contribute to the selective increase in drug-directed behavior that defines addiction. Electrophysiological recordings, made during sessions in which rats self-administer cocaine, show that most accumbal neurons that encode events related to drugdirected behavior achieve and maintain higher firing rates during the period of cocaine exposure (Task-Activated neurons) than do other accumbal neurons (Task-Non-Activated neurons). We have hypothesized that this difference in activity makes the neurons that facilitate drug-directed behavior less susceptible than other neurons to the chronic inhibitory effects of cocaine. A sparing of neurons that facilitate drug-directed behavior from chronic hypoactivity might lead to a relative increase in the transmission of neuronal signals that facilitate drug-directed behavior through accumbal circuits and thereby contribute to changes in behavior that characterize addiction (ie differential inhibition hypothesis). A prediction of the hypothesis is that neurons that are activated in relation to task events during cocaine self-administration sessions will show less of a decrease in firing across repeated self-administration sessions than will other neurons. To test this prediction, rats were exposed to 30 daily (6 h/day) cocaine self-administration sessions. Chronic extracellular recordings of single accumbal neurons were made during the second to third session and the 30th session. Between-session comparisons showed that decreases in firing were exhibited by Task-Non-Activated, but not by Task-Activated, neurons. During the day 30 session, the magnitude of the difference in firing rate between the two groups of neurons was positively related to the propensity of animals to seek and take cocaine. The findings of the present study are consistent with a basic prediction of the differential inhibition hypothesis and may be relevant to understanding cocaine addiction.

Brain-Cocaine Concentrations Determine the Dose Self-Administered by Rats on a Novel Behaviorally Dependent Dosing Schedule

“…The equations have been extensively used in behavioral self-administration (Ahmed and Koob, 2005;Samaha et al, 2002;Zernig et al, 2007), electrophysiological (Nicola and Deadwyler, 2000;Peoples and Cavanaugh, 2003;Peoples et al, 2004Peoples et al, , 2007, microdialysis (Wise et al, 1995), and voltammetric studies (Hermans et al, 2008;Stuber et al, 2005a, b), and a remarkable temporal relationship between modeled braincocaine concentration, NAc dopamine levels (Hermans et al, 2008;Shou et al, 2006;Wise et al, 1995), and cocaine-induced locomotor behavior (Shou et al, 2006) have been demonstrated. It is acknowledged that the relationship demonstrated here used modeled and not actual brain levels; nonetheless, the conclusions are based on relative changes in brain-cocaine concentrations and not the absolute magnitude.…”

Intermittent Cocaine Self-Administration Produces Sensitization of Stimulant Effects at the Dopamine Transporter

“…Brain-cocaine concentrations were estimated using equations used by Pan et al (1991) ). This equation has been widely used to correlate estimated brain-cocaine levels with behavioral (Ahmed and Koob, 2005), electrophysiological (Peoples et al, 2004(Peoples et al, , 2007, microdialysis (Wise et al, 1995), and voltammetric measures (Stuber et al, 2005a,b;Hermans et al, 2008). Estimates in brain-cocaine levels in the literature are highly variable, spanning from the nanomolar to the micromolar range.…”

The Motivation to Self-Administer is Increased After a History of Spiking Brain Levels of Cocaine

“…Fortunately, use of this model has been widespread. Many self-administration studies have applied the equation to estimate brain concentrations of cocaine in live animals (Ahmed and Koob, 2005;Samaha et al, 2002;Zernig et al, 2007;Zimmer et al, 2011), and the equations have also been applied in studies using electrophysiology (Nicola and Deadwyler, 2000;Peoples and Cavanaugh, 2003;Peoples et al, 2004Peoples et al, , 2007, microdialysis (Wise et al, 1995) and voltammetry (Hermans et al, 2008;Stuber et al, 2005a, b). These studies have demonstrated that the modeled brain-cocaine concentrations are highly correlated with NAc dopamine levels (Hermans et al, 2008;Shou et al, 2006;Wise et al, 1995) as well as cocaine-induced locomotor behavior (Shou et al, 2006).…”