Amphetamine and cocaine induce different patterns of c‐fos mRNA expression in the striatum and subthalamic nucleus depending on environmental context

Abstract

In the dorsal striatum, there are two major populations of medium spiny projection neurons. One population is positive for dynorphin mRNA (DYN+), and these cells project preferentially to the substantia nigra, forming the so-called 'direct pathway'. A second population is positive for enkephalin mRNA (ENK+), and these cells influence the substantia nigra indirectly, via the globus pallidus and subthalamic nucleus. Psychostimulant drugs, such as amphetamine and cocaine, are reported to induce immediate early genes (IEGs) in only one subpopulation of dorsal striatal projection neurons, DYN+ cells. However, this apparent selectivity appears to be a function of environmental context. We found that when given in the animal's home cage, amphetamine and cocaine increased expression of the IEG, c-fos, almost exclusively in DYN+ cells. However, when given in a novel environment, amphetamine and cocaine increased c-fos mRNA in both DYN+ and ENK+ cells. Furthermore, amphetamine and cocaine increased c-fos mRNA expression in the subthalamic nucleus when administered in the novel environment, but not when given at home. We conclude that the neural circuitry engaged by psychostimulant drugs, and their ability to induce specific patterns of gene expression, are determined by the environmental context in which they are experienced. This may be related to the ability of environmental novelty to facilitate psychostimulant drug-induced neuroplasticity.

Stimulation of Adenosine Receptors Selectively Activates Gene Expression in Striatal Enkephalinergic Neurons

“…Since this activation has consequences at the gene level, adenosine could selectively facilitate plastic changes in the synapses of the GABAergic enkephalinergic neurons, which can have implications for drug therapy in neuropsychiatric disorders and drug abuse. For instance, there is experimental evidence for the existence of selective gene expression in GABAergic enkephalinergic neurons during sensitization to the behavioral effects of psychostimulants (Uslaner et al, 2001). In fact, genetic inactivation of A 2A receptors has been reported to attenuate amphetamineinduced behavioral sensitization (Chen et al, 2003).…”

Morphine-Induced c-fos mRNA Expression in Striatofugal Circuits: Modulation by Dose, Environmental Context, and Drug History

“…We have previously shown that manipulating factors such as dose, the environmental context surrounding drug administration, and drug history can strongly influence which striatofugal circuits are engaged by psychostimulant drugs (Badiani et al, 1999;Uslaner et al, 2001Uslaner et al, , 2003a. For example, psychostimulant administration in a novel test environment produces a dose-dependent increase in c-fos expression in EnkÀ cells compared to novelty alone (Uslaner et al, 2003a, b), and this increase in c-fos expression is maintained following repeated treatment and extended withdrawal (Uslaner et al, 2003a).…”

“…By contrast, psychostimulants show a different profile of cfos activation in Enk þ cells. Although high doses of amphetamine (but not cocaine) given in a novel test environment have a similar inhibitory effect on c-fos expression as does morphine (Uslaner et al, 2003a, b), low to moderate doses of either amphetamine or cocaine increase c-fos expression in Enk þ cells (Uslaner et al, 2001(Uslaner et al, , 2003a, an effect that is maintained following repeated treatment and extended withdrawal (Uslaner et al, 2003a).…”

“…Acute psychostimulant treatment in a novel test environment results in marked psychomotor activation and c-fos expression in Enk þ cells (Badiani et al, 1999;Uslaner et al, 2001), whereas acute administration of morphine has the opposite effect on locomotor activity and c-fos expression in Enk þ cells. It is tempting to speculate, therefore, that c-fos expression in these studies is secondary to changes in locomotor activity.…”

“…When given in the home cage, psychostimulants induce IEGs predominately in cells that coexpress mRNA for dopamine D1Rs, preprodynorphin, and preprotachykinin, and are part of the striatonigral pathway (Berretta et al, 1992;Cenci et al, 1992;Johansson et al, 1994;Ruskin and Marshall, 1994). When given in a novel test environment, however, psychostimulants also induce IEGs in cells that co-express mRNA for dopamine D2Rs and preproenkephalin and are part of the striatopallidal pathway (Jaber et al, 1995;Badiani et al, 1999;Uslaner et al, 2001).…”