Chronic morphine induces visible changes in the morphology of mesolimbic dopamine neurons.

Abstract

The mesolimbic dopamine system, which arises in the ventral tegmental area (VTA), is an important neural substrate for opiate reinforcement and addiction. Chronic exposure to opiates is known to produce biochemical adaptations in this brain region. We now show that these adaptations are associated with structural changes in VTA dopamine neurons. Individual VTA neurons in paraformaldehyde-fixed brain sections from control or morphine-treated rats were injected with the fluorescent dye Lucifer yellow. The identity of the injected cells as dopaminergic or nondopaminergic was determined by immunohistochemical labeling of the sections for tyrosine hydroxylase. Chronic morphine treatment resulted in a mean -25% reduction in the area and perimeter of VTA dopamine neurons. This reduction in cell size was prevented by concomitant treatment of rats with naltrexone, an opioid receptor antagonist, as well as by intra-VTA infusion of brain-derived neurotrophic factor. In contrast, chronic morphine treatment did not alter the size of nondopaminergic neurons in the VTA, nor did it affect the total number of dopaminergic neurons in this brain region. The results of these studies provide direct evidence for structural alterations in VTA dopamine neurons as a consequence of chronic opiate exposure, which could contribute to changes in mesolimbic dopamine function associated with addiction.

Cytoskeletal Genes Regulation by Chronic Morphine Treatment in Rat Striatum

“…We found significant regulation of several genes related to neuronal plasticity following chronic morphine treatment. Although we cannot exclude a contribution of mild withdrawal in the observed modifications, the differential expression of cytoskeletal genes supports and extends the previous studies showing morphological alteration of neurons (Sklair-Tavron et al, 1996) after chronic morphine treatment. Moreover, chronic opiate exposure decreases neurofilament proteins in rat and human brain (Beitner-Johnson et al, 1992;, which are not only implicated in axonal transport but are also responsible for maintaining the caliber of axons (review in Al-Chalabi and Miller, 2003).…”

“…This protein has a key role in receptor endocytosis and is able to interact with microtubules, actin cytoskeleton, and the mitogen-activated protein kinase signalling pathway (review in Sever, 2002). Among the remarkable changes observed following repetitive administration of morphine, a reduction in the size of dopaminergic neurons in the ventral tegmental area and a decrease in dendritic branching and spine density in the cerebral cortex and nucleus accumbens have been reported (Sklair-Tavron et al, 1996;Robinson and Kolb, 1999). Consistent with these morphological changes, the expression and function of neurofilament proteins are altered by chronic morphine treatment in the ventral tegmental area in rats (BeitnerJohnson et al, 1992;.…”

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

“…One possible involvement could be through opiate's interference with the neurotrophines (eg, BDNF) supporting neuronal survival (Weickert et al, 2003;Angelucci et al, 2005) with consequential damage of mesolimbic dopaminergic neurons (Sklair-Tavron et al, 1996). Furthermore, similarly to methadone-maintained patients (Willenbring et al, 1989;Zador et al, 1996), exaggerated opioidergic activity could enhance hedonic preference (ie, liking) for sweet and fatty foods (Doyle et al, 1993;Pecina and Berridge, 1995;.…”

Regulation of α-Synuclein Expression in Limbic and Motor Brain Regions of Morphine-Treated Mice

“…Opiates, when administered acutely, indirectly stimulate dopaminergic neurons located in the ventral mesencephalon, which innervate several forebrain regions, including the nucleus accumbens, dorsal striatum, amygdala, and prefrontal cortex (Di Chiara and North, 1992). Neuroadaptations in presynaptic and postsynaptic parts of these dopaminergic projections, some of which have been identified, may account for lasting behavioral effects of prolonged opiate use (Sklair-Tavron et al, 1996;Hyman and Malenka, 2001;Nestler, 2001Nestler, , 2004.…”