Morphine withdrawal‐induced abnormalities in the VTA: confocal laser scanning microscopy

Abstract

Morphine withdrawal is characterized by functional alterations at the level of the ventrotegmental area. We investigated the effects of chronic morphine administration and withdrawal on the morphological properties of immuno-labelled tyrosine hydroxylase-positive neurons of the rat ventrotegmental area with a confocal laser scanning microscope. Morphological evaluation revealed a reduction in the area and perimeter of tyrosine hydroxylase-positive somata in morphine-withdrawn rats. Conversely, the number of cells per field was found to have increased in the naloxone group. Collectively, the present results indicate that withdrawal from a chronic morphine treatment, and not chronic morphine per se, modifies cellular morphology of tyrosine hydroxylase-positive, presumably dopamine-containing, neurons of the rat VTA. This is consistent with the idea that withdrawal from morphine alters functioning of the mesolimbic dopamine system and provides a direct morphological correlate for the functional abnormalities typical of morphine withdrawal.

Opiate-Induced Molecular and Cellular Plasticity of Ventral Tegmental Area and Locus Coeruleus Catecholamine Neurons

“…This increased rate then normalizes, or even decreases below baseline, in animals withdrawn from the opiate. Because there is evidence from our own work (Russo et al 2007), and others (Spiga et al 2003), that the soma size is also decreased at these later time-points, when firing rate has decreased, it may be the initial sustained increase in firing rate that is vital for induction or maintenance of the morphological change. In contrast, LC neuronal activity is acutely decreased by morphine administration, returns toward baseline levels in vivo with chronic administration, and only increases above normal levels on opiate withdrawal.…”

“…Additionally, this change could be blocked by systemic naltrexone, suggesting that MOR signaling was required, and local brain-derived neurotrophic factor (BDNF) infusion in VTA also prevented the decrease, suggesting that decreased neurotrophic signaling may underlie the morphological change. Importantly, this reduction in VTA DA neuron soma size is observed with chronic administration of heroin as well as morphine (Russo et al 2007), in passive and self-administration protocols (Spiga et al 2003;Chu et al 2007;Russo et al 2007), and across species, as we have recently characterized this effect in mouse and in postmortem tissue from human heroin abusers (Mazei-Robison et al 2011). Follow-up studies found no evidence of VTA DA neuronal death or injury (Sklair-Tavron et al 1996;Russo et al 2007) and that the decrease in cell size persists for 14 days after chronic morphine administration, but returns to baseline by 30 days.…”

The role of glutamate and its receptors in mesocorticolimbic dopaminergic regions in opioid addiction

“…When the VTA, NAc and central or lateral nucleus of amygdala were lesioned with a DC current, morphine-induced conditioned place preference (CPP) can be inhibited . Morphological study showed that the both volume and number of neurons in the VTA and NAc in morphine withdrawal rats decreased (Spiga et al, 2003). There are also evidence that indicates drug-seeking in morphine-dependent rats and heroin-induced self-administration are related to the electrical activities of DA neurons in the VTA and NAc (Chang et al, 1997;Kiyatkin and Rebee, 2001).…”

Endogenous Opioid-Induced Neuroplasticity of Dopaminergic Neurons in the Ventral Tegmental Area Influences Natural and Opiate Reward

“…Natural reward behaviors are mediated by the mesocorticolimbic system (Meisel and Mullins, 2006;Hoebel et al, 2009;Pitchers et al, 2010a;Young et al, 2011;Blum et al, 2012). Drugs of abuse cause neural alterations in this system, which in-turn contribute to development and expression of substance abuse (Hyman et al, 2006;.…”

“…Drugs of abuse cause neural alterations in this system, which in-turn contribute to development and expression of substance abuse (Hyman et al, 2006;. We previously determined that experience with natural reward behavior, i.e., sexual experience in male rats, also causes neural plasticity in the nucleus accumbens (NAc), including increased dendritic spines and deltaFosB (Pitchers et al, 2013). Inturn, this sex-induced plasticity is critical for the effects of sex experience on subsequent mating, manifested as the facilitation of initiation and performance of sexual behavior (Pitchers et al, , 2013.…”