Abstinence from Cocaine Self-Administration Heightens Neural Encoding of Goal-Directed Behaviors in the Accumbens

Abstract

Cocaine addiction in humans is characterized by cycles of abstinence from drug-taking and relapse. Here, electrophysiological recording procedures were used to determine whether nucleus accumbens (Acb) neuronal firing properties are altered following interruption and resumption of cocaine self-administration. Rats (n ¼ 12) were trained to self-administer cocaine (2 h daily sessions) then divided into two groups. Acb activity was recorded for Group 1 (controls) during two additional self-administration sessions completed over the next 2 days (test sessions 1 and 2). Acb activity was recorded for Group 2 (1-month) during one self-administration session completed the next day (test 1), and during a second self-administration session 1 month later (test 2). As in prior reports, a subset of Acb neurons exhibited patterned discharges (short duration and/or long-term cyclic alterations, termed 'phasically active') relative to cocaine-reinforced responding during test session 1. Remarkably, the percentage of phasically active cells dramatically increased (nearly two-fold) following 1-month abstinence, in the core but not the shell of the Acb. Likewise, the strength of the neural correlates (determined via signal-tobaseline ratios) also increased as a function of abstinence. Extinction experiments in another set of rats (n ¼ 12) revealed an increased motivational state for the drug following abstinence. The results show that abstinence from cocaine self-administration causes a dramatic increase in the number and strength of Acb neurons that encode cocaine-related information, thus representing the first neurophysiological correlate of heightened activation of the 'brain reward system' following abstinence and resumption (relapse) of cocaine consumption.

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

“…However, in the study of Hollander and Carelli (2005), there was evidence of such an enhancement in phasic firing. It is possible that such differential within-neuron changes in firing depend on neuroadaptations that occurred in the previous study but not in the present study.…”

“…These firing patterns were identified in the present study according to previously established statistical criteria (Peoples and West, 1996;Uzwiak et al, 1997;Peoples et al, 1998bPeoples et al, , 2004, which are described below. As a frame of reference for comparisons to investigations that use percent change criteria (eg Hollander and Carelli, 2005;Chang et al, 1994), the statistical criteria used to test for task-related firing responses were moderately more stringent than a percent-change rule of 100%.…”

How fast and how often: The pharmacokinetics of drug use are decisive in addiction

“…Just as the expression of behavioural sensitization is observed more readily following a period of drug withdrawal, it is possible that following limited daily self-administration sessions, an increase in drug intake might be observed after a sufficiently long abstinence period. However, it has been shown that in animals with a history of self-administering cocaine during short daily sessions, drug intake remains stable even following one month of forced abstinence (Ahmed andKoob, 1998 andCarelli, 2005). Thus, escalation of drug intake is often not observed following short daily selfadministration sessions, even though the same conditions can evoke psychomotor and neurochemical sensitization.…”

A scale-free systems theory of motivation and addiction

“…food vs. drug) corresponds to the emergence of differential and potentially mutually exclusive firing pattern arrays across medium spiny neurons of the NAc (Deadwyler et al, 2004). After extensive self-administration of an addictive drug, in which drug-seeking is installed as a major motivation, NAc firing patterns associated with drug intake become more robustly expressed (Hollander and Carelli, 2005). In this way, motivational firing pattern representations emerging sequentially in the ventral cortical-striatal module provide alternative pathways of progression (links) between concrete behavioral programs (nodes), which are in turn composed of habitual motor sequences as encoded by the dorsal cortical-striatal module.…”