Parsing the Addiction Phenomenon: Self-Administration Procedures Modeling Enhanced Motivation for Drug and Escalation of Drug Intake

Abstract

Investigators who study drug addiction are fortunate to have access to excellent animal models. Such models will be invaluable in the assessment of factors involved in the progression of drug addiction. The relevance of these findings, however, will depend on the general understanding of how each model is related to drug addiction. The present review focuses on several procedures that were designed to model the addiction process and questions whether these models are tapping into the same underlying process or whether each is addressing a unique feature. Furthermore, various factors (e.g., rate of drug onset, dose magnitude, early drug history, periods of abstinence) influencing the progression of these addiction-like changes in behavior are discussed.

Figure 1

Final ratios or drug intake can escalate over time during cocaine self-administration. A). (14) Two cumulative records show responding on the first experimental day (left) and the final experimental day (right) of PR training. Note the escalation of responses expended (vertical lines) to receive a final injection (diagonal ticks) increased across sessions. B). (17) Speed of injection effects the escalation of final ratios. Animals show increased final ratios during PR training when a high cocaine dose (1.5 mg/kg/inf IV) is delivered over 5-s (circles) but not 25-s (triangles) or 50-s (squares). C). (38) LgA training results in an escalation in cocaine intake. LgA rats (open circles) show an increased rate of cocaine intake across daily 6-hr sessions; whereas ShA rats (filled circles) show stable responding across daily 2-hr sessions.

Figure 2

PR training produces sensitization to the reinforcing effects of cocaine. (14) Two groups of rats were given access to 4 doses of cocaine under a PR schedule following different behavioral histories. One group of rats (filled squares) was tested after a self-administration history (see PR training) that results in an escalation of final ratios over 2 weeks. A second group of rats (open triangles) was tested after a history that produces stable final ratios. The augmentation of the reinforcing effects of cocaine following PR training was observed at all tested doses. Note the upward and leftward dose effect curve shift.

Figure 3

PR training does not produce behavioral and neurochemical sensitization. (37) A). PR training results in tolerance to the psychomotor activating effects of cocaine. PR trained rats (open squares) showed a tolerant psychomotor response to a cocaine challenge (15 mg/kg IP) in comparison to naïve rats (filled circles). B). PR trained animals show a tolerant cocaine-induced dopamine response in the nucleus accumbens shell. Administration of cocaine (15 mg/kg IP) resulted in decreased extracellular dopamine levels following both 1-day (open squares) and 14-days of withdrawal after PR training in comparison to naïve rats (filled circles).

Figure 4

PR and LgA training produce opposite effects in the threshold procedure. (64) Self-administration was assessed across a descending series of ten doses (237μg - 1 μg) under an FR1 schedule of reinforcement to measure consumption in the high dose range and thresholds in the low dose range. A) PR trained rats (filled circles) showed a higher response output (955 responses/hr ± 244 (SEM)) for remarkably low threshold doses (23.7−2.4 μg/inf) in comparison to control rats (open circles). B). PR trained rats (filled circles) did not consume more cocaine at high doses in comparison to control rats (open circles), but maintained consumption at lower thresholds. Note that considerable effort is expended to maintain consumption as these low doses. C). LgA trained rats (filled triangles) consumed more cocaine at high doses but reached threshold doses prior to ShA rats (open triangles).

Figure 5

Early exposure to high levels of cocaine intake attenuates the escalation of final ratios. (14) The left pane shows the initial pharmacological history of two groups of animals. One group was given access to cocaine under an FR1 reinforcement schedule for 1 day (filled circles) and another for 5 days (open circles). The next pane shows the final ratios for both groups over 14 days. Note that only the group with a limited initial pharmacological history showed an increase in final ratios. The next pane illustrates that both groups then received access to cocaine for 5 days under an FR1 reinforcement schedule. Note that both groups showed an escalation in the rate of responding. The final pane illustrates that the effects of high cocaine intake only transiently suppressed final ratios in the group that originally showed an escalation in final ratios (filled circles).

Figure 6

Periods of abstinence can increase final ratios, behavioral sensitization and cue-induced reinstatement. A). (70) Final ratios increase following abstinence periods. Seven days of abstinence following extended access (24-hr/day; 4 trials/hr; 10 days) conditions during cocaine self-administration results in rats that show increased final ratios (filled diamonds) in comparison to baseline final ratios (open circles). It should be noted that the abstinence period is necessary for the increase in final ratios. B). (72) Behavioral sensitization increases following abstinence periods. Cocaine-induced (15 mg/kg IP) psychomotor activation progressively increased over extended periods of abstinence following a sensitizing drug-treatment (30 mg/kg IP cocaine × 5 days). C). (73) Cue-reinforced responding increases, or incubates, over periods of abstinence. Following various periods of abstinence from cocaine self-administration animals were returned to operant chambers. Upon meeting extinction criteria (i.e., 15 responses/hr on a lever not paired with any cue), cue-induced reinstatement responding was assessed by reintroducing a conditioned tone-light cue in response to each lever press. The amount of tone-cue maintained responding increased following progressively longer periods of abstinence.