ReviewSensitization to the reinforcing effects of cocaine following binge-abstinent self-administration
Section snippets
Reinforcement versus addiction
The dynamic process of cocaine addiction generally starts with recreational use and deteriorates over time into a compulsive drug taking disorder [1]. Our goal is to understand this process from a neurobiological perspective, the premise being that if we understood what changes occurred in the brain, we might be better equipped to design appropriate therapies and develop suitable medications. A secondary benefit is that we might gain some insight into basic mechanisms of neural plasticity.
Modeling addiction
The past few years have seen significant shifts in the way cocaine addiction has been studied. Traditionally, research into the neurobiology of drugs of abuse has focused on the sites and mechanisms of action of specific drugs (i.e. receptor pharmacology) and has emphasized tolerance and physical dependence as major contributors to drug reinforcement.
In a seminal paper [1], Gawin wrote that “addiction to cocaine does not cause gross physiological withdrawal symptoms”, and at the same time
Role of sensitization—do the reinforcing effects of cocaine sensitize?
Most generally, sensitization (or reverse tolerance) refers to an augmentation (generally, progressively increasing and enduring) of a particular drug response as a consequence of repeated drug administration. A vast literature has examined sensitization of psychostimulant-induced locomotor or stereotyped activity, and the anatomical and pharmacological details of both amphetamine- and cocaine-induced sensitization have been widely described [19], [20], [21], [22], [23], [24]. Sensitization to
Repeated cycles of ‘binge’ self-administration and withdrawal
Initially we tested whether animals given access to cocaine on a FR1 schedule for a 24 h ‘binge’ would affect responding on a PR schedule. Break points determined 24 h after the binge (to allow the cocaine to clear from the body) were found to be significantly decreased (see Fig. 2), consistent with an interpretation of tolerance to the reinforcing effects of cocaine. We hypothesized that over repeated cycles of these access conditions, tolerance would begin to dissipate and breakpoints would
What do we know about the requirements for self-administration to produce changes in break point?
The data can be summarized as follows
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Round-the-clock access to cocaine on a DT4 schedule (1.5 mg/kg/inj) produced an increase in cocaine-reinforced break points after 7 days of drug deprivation. This effect is robust and has been replicated a number of times.
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The increase in break points is only seen after a 7 day drug free period. Testing 2–3 days after the DT4 exposure does not produce changes significantly different from baseline.
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Interestingly, daily testing on the PR prevents the increase in
Are the neural substrates of locomotor sensitization the same as those that underlie sensitization to the reinforcing effects?
It is unclear at this stage whether the neural adaptations that underlie locomotor sensitization are identical to those which mediate the increased reinforcing efficacy of cocaine. It should be noted that Phillips et al. [35] showed that cocaine self-administration produced sensitization to the locomotor effects. However, the schedule used in that study (limited access on an FR 1 schedule) would not be expected to produce a change in cocaine-reinforced break points on a PR schedule. These data
Concluding remarks
There are a number of unanswered questions regarding sensitization to various effects of cocaine, the neurobiological substrates involved, and the significance of these changes (both behavioral and neurobiological) to humans. It is still unclear how administering several non-contingent injections can produce such profound effects weeks later, whereas cocaine self-administration for relatively long periods of time (weeks to months) fails to appreciably alter subsequent self-administration. It is
Acknowledgements
This work was supported by NIH grants P50DA06643, RO1DA14030 to DCSR, and K01DA13957 to DM.
References (67)
- et al.
Principles of initial experimental drug abuse liability assessment in humans
Drug Alcohol Depend
(2003) - et al.
An analysis of drug-seeking behavior in animals
Neurosci Biobehav Rev
(1981) - et al.
On the role of ascending catecholamine systems in intravenous self-administration of cocaine
Pharmacol Biochem Behav
(1977) - et al.
Neuroadaptations involved in amphetamine and cocaine addiction
Drug Alcohol Depend
(1998) - et al.
Lesions of central serotonin systems affect responding on a progressive ratio schedule reinforced either by intravenous cocaine or by food
Pharmacol Biochem Behav
(1994) - et al.
A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement
Pharmacol Biochem Behav
(1997) - et al.
Continuous infusion of selective dopamine uptake inhibitors or cocaine produces time-dependent changes in rat locomotor activity
Behav Brain Res
(1999) - et al.
The neural basis of drug craving: an incentive-sensitization theory of addiction
Brain Res Brain Res Rev
(1993) - et al.
Preexposure sensitizes rats to the rewarding effects of cocaine
Pharmacol Biochem Behav
(1990) - et al.
Sensitization and tolerance in psychostimulant self-administration
Pharmacol Biochem Behav
(1997)