Biochemical Adaptations in the Mesolimbic Dopamine System in Response to Repeated Stress

Abstract

We have demonstrated previously that chronic administration of morphine, cocaine, or ethanol produces some common biochemical adaptations in the ventral tegmental area (VTA) and nucleus accumbens (NAc), components of the mesolimbic dopamine system implicated in the reinforcing and locomotor activating properties of these drugs of abuse. Because this neural pathway is also regulated by stress, and because stress has been shown to influence an animal's behavioral responses to drugs of abuse, it was of interest to determine whether repeated exposure to stress results in similar biochemical adaptations. By use of immunoblot analysis, we show here that a course of chronic "unpredictable" stress, like chronic drug exposure, increased levels of immunoreactivity of tyrosine hydroxylase and glial fibrillary acidic protein and decreased levels of immunoreactivity of neurofilament proteins in the VTA. Chronic unpredictable stress also increased levels of cyclic AMP-dependent protein kinase activity and decreased levels of immunoreactivity of the G protein subunit, Gi alpha, in the NAc. These effects required long-term exposure to stress and were in most cases not seen in the substantia nigra and caudate-putamen, components of the nigrostriatal dopamine system studied for comparison. The biochemical effects of chronic stress in the VTA and NAc differed among three strains of rat studied. Fischer 344 rats were the most responsive in that they exhibited all of the aforementioned adaptations, whereas Lewis rats were the least responsive in that they exhibited none of these adaptations; Sprague-Dawley rats exhibited an intermediate number of responses. Taken together, the results of the present study demonstrate that chronic exposure to stress results in biochemical adaptations in the mesolimbic dopamine system that resemble the chronic actions of several drugs of abuse. These adaptations could contribute to the convergent behavioral effects induced by treatments that are mediated via the VTA-NAc pathway.

Central Nervous System Monoamine Correlates of Social Dominance in Cynomolgus Monkeys (Macaca fascicularis)

“…26, NO. 4 eas of the mesocorticolimbic dopamine system in rodents (e.g., Ortiz et al 1996). Stress may also alter dopaminergic activity in human subjects, as indicated by changes in plasma and urine HVA concentrations in response to a variety of psychosocial challenges (e.g., Gruen and Baron 1984;Breier 1989;Sumiyoshi et al 1998;Posener et al 1999).…”

“…The former seems less likely because stress alone increases dopaminergic activity and subordinate animals are typically thought to experience more stress. For example, acute exposure to stress can increase dopamine metabolism and release in terminal ar- eas of the mesocorticolimbic dopamine system in rodents (e.g., Ortiz et al 1996). Stress may also alter dopaminergic activity in human subjects, as indicated by changes in plasma and urine HVA concentrations in response to a variety of psychosocial challenges (e.g., Gruen and Baron 1984;Breier 1989;Sumiyoshi et al 1998;Posener et al 1999).…”

Chronic Cold Stress Reduces the Spontaneous Activity of Ventral Tegmental Dopamine Neurons

“…These two effects may not be independent of each other, since increased burst-firing in LC neurons prolongs the inhibition of DA neurons following LC stimulation (Grenoff et al 1993). This, as well as differential changes in TH activity and gene expression in the LC and midbrain (Ortiz et al 1996;Richard et al 1988;Zigmond et al 1974) may contribute to the apparent persistence and sensitization of the activation of forebrain NE transmission versus the apparent adaptation of the mesolimbic/mesocortical DA systems. It is important to note, however, that changes in DA release cannot be easily predicted from changes in neuronal firing rate.…”

“…Moreover, examined across studies, DA efflux evoked by a novel stressor appears to be similar in cold-stressed and control rats (Finlay et al 1995;Gresch et al 1994). Thus, it appears that in contrast to their responses to acute stress, the mesocortical and mesolimbic DA systems may show adaptation in response to chronic stress (see also Ortiz et al 1996). The DAergic response contrasts with the sensitization of the sympathetic innervation to the adrenals and heightened response of the NE-containing neurons of the locus coeruleus in cold-stressed rats (Finlay et al 1995;Fluharty et al 1985;Gresch et al 1994;Jedema et al 1999Jedema et al , 2001Mana and Grace 1997).…”

Expression of Transcripts for Myelin Related Genes in Postmortem Brain from Cocaine Abusers

“…The brain areas critically involved in cocaine-induced modulation of neurotransmission and behavioral sensitization include the striatum, and in particular the mesolimbic dopamine system, consisting of the ventral tegmental area (VTA), nucleus accumbens (NAc) and their afferent and efferent connections [3]. Chronic administration of cocaine to animals causes structural and functional adaptations to dopaminergic and glutamatergic neurotransmission in both the VTA and NAc, as well as in cortical areas with projections to these areas [4][5][6][7]. Interestingly, the changes of mesolimbic neurocircuitry appear similar to those associated with experience-dependent plasticity.…”