Research reportLocomotor sensitization to cocaine is associated with increased Fos expression in the accumbens, but not in the caudate
Introduction
Repeated administrations of psychostimulant drugs, such as cocaine or amphetamine, produce a progressive and persistent increase or sensitization of their psychomotor activating effects (for review see [29]). The rewarding effects of these drugs also sensitize as indicated by the facilitation of drug self-administration and conditioned place preference [14], [28]. Therefore, sensitization-related alterations in neuronal function are thought to contribute to the transition from ‘casual’ drug taking to the compulsive drug seeking and drug taking behaviors that characterize addiction [30].
Research on the neurobiology of sensitization has focused on the caudate and accumbens because these brain regions play important roles in psychomotor activation and reward-related processes. Histochemical detection of c-fos mRNA or Fos-protein [8], [12], [31], [35], [41] has often been used because these methodologies have the advantage of detecting changes in neural activity in large populations of neurons at the single cell level. Although potentiation of drug-induced c-fos or Fos has been observed following repeated treatments with amphetamine or cocaine [6], [22], most researchers have either failed to find changes [9], [23], [37] or have reported marked tolerance [4], [7], [15], [20], [26], [31], [35]. This is surprising in light of the evidence for sensitization-related increases in both dopamine and glutamate neurotransmission in the striatum (for recent review see [40]) and the established role of these neurotransmitter systems in regulating c-fos expression [19].
There are a number of reasons why evidence for psychomotor stimulant induced sensitization of c-fos or Fos regulation is fragmented. First, in the majority of published reports [7], [15], [20], [26], [31], [35], rats were tested within 24 h following the final drug treatment (except [4], [9], [23]). In contrast, robust behavioral and neurochemical sensitization are typically seen only after an extended drug-free period [24]. Second, the effects of past drug experience may be dose-dependent and in all previous studies, the regulation of Fos was assessed only following a single challenge dose of the drug. Third, and more important, most studies have focused on the caudate nucleus (except [6], [9], [12], [33], [34]) even though a number of alterations have been reported to be restricted to the accumbens [3], [36]. Thus, in the present experiment, we examined the regulation of Fos induction in both the caudate and accumbens following a treatment regimen shown to produce robust and persistent sensitization.
Section snippets
Subjects
Male Sprague Dawley rats (Charles River, Raleigh, NC) weighing 200–225g at arrival were housed individually in standard plastic cages in a temperature and humidity controlled room. Rats were maintained on a 12:12 h light/dark cycle (lights on at 8:00 PM) and were allowed ad libitum access to food and water. Rats were acclimatized to these housing conditions for a minimum of 7 days prior to any experimental manipulation.
Behavioral testing procedures
During the pretreatment phase of the experiment, rats were removed each day
Results
Behavioral data were obtained from a total of 168 rats. Because of a freezer malfunction, the brain tissue from only approximately half of the rats were assayed for Fos immunohistochemistry (n=5–6 for each group). Thus, the group sizes for Fos-immunohistochemical analyses were less than that for behavioral analyses.
Discussion
The first injection of cocaine (i.e., saline pretreated rats receiving cocaine on the challenge test) produced marked dose-dependent increases in the number of Fos-positive nuclei in the caudate, but not in the accumbens. This result is consistent with previous reports showing that the ability of cocaine to induce Fos and c-fos mRNA is much weaker in the accumbens compared to that in the dorsal portion of the striatum [6], [35]. Repeated injections of cocaine (7 daily injections of 15mg/kg
Acknowledgements
This research was supported by funding from the National Institute on Drug Abuse (NIDA) Intramural Research Program to B.T.H.
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