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Review
. 2012 Jul;2(7):a012070.
doi: 10.1101/cshperspect.a012070.

Opiate-induced molecular and cellular plasticity of ventral tegmental area and locus coeruleus catecholamine neurons

Michelle S Mazei-Robison  1 , Eric J Nestler
Affiliations
Review

Opiate-induced molecular and cellular plasticity of ventral tegmental area and locus coeruleus catecholamine neurons

Michelle S Mazei-Robison et al. Cold Spring Harb Perspect Med. 2012 Jul.

Abstract

The study of neuronal adaptations induced by opiate drugs is particularly relevant today given their widespread prescription and nonprescription use. Although much is known about the acute actions of such drugs on the nervous system, a great deal of work remains to fully understand their chronic effects. Here, we focus on longer-lasting adaptations that occur in two catecholaminergic brain regions that mediate distinct behavioral actions of opiates: ventral tegmental area (VTA) dopaminergic neurons, important for drug reward, and locus coeruleus (LC) noradrenergic neurons, important for physical dependence and withdrawal. We focus on changes in cellular, synaptic, and structural plasticity in these brain regions that contribute to opiate dependence and addiction. Understanding the molecular determinants of this opiate-induced plasticity will be critical for the development of better treatments for opiate addiction and perhaps safer opiate drugs for medicinal use.

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Figures

Figure 1.
Figure 1.
Cartoon of a sagittal section of rodent brain illustrating the VTA and LC and their major afferent and efferent projections. DAergic (red) and GABAergic (blue) neurons in VTA project to limbic and cortical structures and receive glutamatergic (black-dash, PFC) and GABAergic input (blue-dash, NAc, VP). Noradrenergic neurons (green) in LC innervate multiple regions including HIPP and PFC and receive glutamatergic input from PGi. Abbreviations: AMY, amygdala; HIPP, hippocampus; LC, locus coeruleus; NAc, nucleus accumbens; PFC, prefrontal cortex; PGi, nucleus paragigantocellularis; VP, ventral pallidum; VTA, ventral tegmental area.
Figure 2.
Figure 2.
Cellular and projection complexity within VTA. The proportion of DA (red) to GABA (blue) neurons varies among VTA subnuclei with higher DA:GABA ratios observed in more rostral subregions such as rostral linear nucleus (RL) compared to more caudal subnuclei such as paranigral (PN) and parainterfascicular (PIF) regions. Additionally, DA neuronal projections differ throughout with VTA with more lateral regions such as parabrachial nucleus (PBP) projecting to NAc lateral shell (Lat Sh), whereas medial regions such as PN have diverse projections including amygdala (AMY), prefrontal cortex (PFC), NAc core, and NAc medial shell (Med Sh). Limited work has examined GABA neuronal projections; there is some evidence that GABA neurons in rostral PBP have a strong projection to PFC, whereas there are few rostral PBP DA neurons that project to PFC, but a large caudal DA PBP projection; this suggests that the PBP-PFC projection is not only defined regionally, but is also neuronal-subtype specific (Lammel et al. 2008). (Cell counts used are from Nair-Roberts et al. 2008 and projections are from retrograde labeling studies by Lammel et al. 2008.)
Figure 3.
Figure 3.
Chronic morphine decreases VTA DA soma size yet increases neuronal excitability, while DA transmission to NAc is decreased. The net effect of morphine is a less responsive reward pathway, i.e., reward tolerance. Down-regulation of IRS2-AKT signaling (blue) in VTA mediates the effects of chronic morphine on soma size and electrical excitability; the effect on excitability is mediated via decreased GABAA currents and suppression of K+ channel expression. Morphine-induced down-regulation of mTORC2 activity in VTA is crucial for these morphine-induced morphological and physiological adaptations as well as for reward tolerance. In contrast to mTORC2, chronic morphine increases mTORC1 activity (red), which does not appear to directly influence these morphine-induced adaptations. Chronic morphine also decreases DA output to NAc, as well as decreasing dendritic branching and the number of dendritic spines on medium spiny GABA neurons in NAc, further suppressing normal DA signaling in the mesolimbic circuit.
Figure 4.
Figure 4.
Up-regulation of the cAMP pathway in LC as a mechanism of opiate tolerance and dependence. Top panel, Opiates acutely inhibit the functional activity of the cAMP pathway (indicated by cellular levels of cAMP and cAMP-dependent protein phosphorylation). With continued opiate exposure, functional activity of the cAMP pathway gradually recovers, and increases far above control levels following removal of the opiate (e.g., by administration of the opioid receptor antagonist naloxone). These changes in the functional state of the cAMP pathway are mediated via induction of adenylyl cyclases (AC) and protein kinase A (PKA) in response to chronic administration of opiates. Induction of these enzymes accounts for the gradual recovery in the functional activity of the cAMP pathway that occurs during chronic opiate exposure (tolerance and dependence) and activation of the cAMP pathway observed on removal of opiate (withdrawal). Bottom panel, Opiates acutely inhibit LC neurons by increasing the conductance of an inwardly rectifying K+ channel via coupling with subtypes of Gi/o and, possibly, by decreasing a Na+-dependent inward current via coupling with Gi/o and the consequent inhibition of AC, reduced levels of PKA activity, and reduced phosphorylation of the channel or pump responsible. Inhibition of the cAMP pathway also decreases the phosphorylation of many other proteins and, thereby, affects numerous other neuronal processes. For example, it reduces the phosphorylation state of cAMP response element-binding protein (CREB), which initiates some of the longer-term changes in LC function. Chronic administration of morphine increases the levels of ACI, ACVIII, PKA catalytic (cat.) and regulatory subunits, and several phosphoproteins, including CREB and tyrosine hydroxylase (TH) (indicated by red arrows). These changes contribute to the altered phenotype of the drug-addicted state. For example, the intrinsic excitability of LC neurons is increased by enhanced activity of the cAMP pathway and Na+-dependent inward current, which contributes to the tolerance, dependence, and withdrawal showed by these neurons. Up-regulation of ACVIII and TH is mediated via CREB, whereas up-regulation of ACI and of the PKA subunits appears to occur via an unidentified, CREB-independent mechanism.
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