Research reportEnvironmental context modulates the ability of cocaine and amphetamine to induce c-fos mRNA expression in the neocortex, caudate nucleus, and nucleus accumbens
Introduction
Drugs of abuse produce a wide range of behavioral and subjective effects, and with repeated administration they induce a number of neuroadaptive processes, including tolerance, sensitization, dependence and addiction. However, the acute effects of these drugs and their ability to induce neurobehavioral plasticity, are powerfully modulated by the context in which they are experienced. For example, using a simple animal model we have found that the acute psychomotor activating effects of amphetamine [7] and the ability of amphetamine, cocaine, or morphine to induce behavioral sensitization [2], [5], [8], [9], are greatly enhanced when a drug is given in a distinct and relatively novel environment, relative to when it is given in a physically identical cage in which the animals live (i.e., at ‘home’).
In exploring the neurobiological mechanisms by which environmental context modulates the effects of amphetamine, we found that amphetamine-induced expression of the immediate early genes (IEGs) c-fos and arc is powerfully modulated by environmental context [6], [15]. Specifically, animals treated with amphetamine in a novel environment show greater c-fos and arc mRNA expression in the caudate putamen, nucleus accumbens core and shell, and several cortical regions, as compared to animals treated in their home cage. However, it is unknown whether environmental novelty has a similar effect on the ability of cocaine to induce IEG expression. Thus, one goal of this study was to compare the effect of environmental context on amphetamine- and cocaine-induced c-fos mRNA expression. Furthermore, in our previous studies [6], [11], [15], IEG expression was quantified in the intact hemisphere of rats that had a unilateral 6-hydroxydopamine (6-OHDA) lesion of the mesostriatal dopamine system. This is potentially problematic because of the possibility of altered neurotransmission in the intact hemisphere of rats with a unilateral 6-OHDA lesion [21]. Thus, our second goal was to determine the effect of environmental context (home vs. novel) on amphetamine- and cocaine-induced c-fos mRNA expression in neurologically-intact rats.
Section snippets
Animals
A total of 56 male Sprague Dawley rats (Harlan, Indianapolis, IN) weighing 200–250 g were initially housed individually in stainless steel hanging cages in a temperature- and humidity-controlled colony room. The rats were kept on a 14:10 h light:dark cycle (lights on at 7:00 am) and were given food and water ad libitum. The animals were kept in the colony room for 7 days before any experimental manipulation. All experimental procedures were approved by the University of Michigan Committee on
Locomotor behavior
Fig. 1 shows the effect of each treatment on locomotor (crossover) activity over the 50 min following treatment. For statistical analysis, locomotor activity was collapsed over time. Two animals receiving amphetamine in the novel environment were eliminated due to VCR failure. Relative to the undisturbed group, saline at home produced a very small increase in locomotor activity only in the first 5 min interval (3.6±1.0 vs. 1.0±0.6), and these groups did not differ at all over the remaining 45
Discussion
This experiment was designed to address two main questions. (1) Does environmental novelty modulate the ability of cocaine to induce c-fos mRNA expression, as we have shown for amphetamine-induced c-fos mRNA expression? (2) Does this occur in neurologically-intact rats (in our previous studies we used rats that had a unilateral 6-OHDA lesion)? Both questions were answered in the affirmative. Specifically, in the dorsal region of the caudate putamen, the nucleus accumbens core and shell, the
Acknowledgements
This research was supported by a NIDA grant to TER (DA04294) and a NIMH grant to HA and SJW (MH42251). TER was also supported by a Senior Research Scientist Award from NIDA (KO5 DA00473). We thank Michelle Ostrander for her assistance in conducting these experiments.
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AB is now at the Department of Human Physiology and Pharmacology ‘Vittorio Erspamer’, University of Rome ‘La Sapienza’, Rome, Italy, and HEWD at the Department of Psychology, University of Colorado, Boulder (USA).