Upregulation of the cAMP Pathway in the Locus Coeruleus

The LC, located on the floor of the fourth ventricle in the anterior pons, is the major noradrenergic nucleus in brain. The LC is a densely packed homogeneous nucleus that regulates attention, arousal, and autonomic tone. The LC's noradrenergic neurons have extremely widespread projections and innervate virtually all regions of the brain and spinal cord. Activation of the LC, which occurs upon precipitation of opiate withdrawal, increases noradrenergic transmission throughout the central nervous system and mediates some of the physical symptoms of withdrawal. Indeed, excitation of LC neurons is both necessary and sufficient to elicit certain behavioral signs of opiate withdrawal. Although physical dependence is not thought to be an important contributor to addiction per se, studies of opiate action in the LC have provided important insight into the types of neuroadaptations that opiates elicit in responsive neurons.

Acutely, opiates inhibit the firing rate of LC neurons by binding to x opioid receptors that are coupled to the Gi/o family of G proteins (Fig. 1) (3,5) Gi/o proteins couple directly to an inward rectifier K+ channel to mediate an increase in outward K+ current. The coupling to Gi/o also causes inhibition of adenylyl cyclase to decrease cAMP levels and reduce activity of cAMP-dependent protein kinase (PKA). This leads to a decrease in the conductance of a nonspecific cation channel, which has not yet been isolated at the molecular level (6). These two opiate actions, activation of an inward-rectifying K+ channel and inhibition of a nonspecific cation channel, diminish LC neuronal excitability.

Fig. 1. Scheme illustrating opiate actions in the locus coeruleus. Opiates acutely inhibit LC neurons by increasing the conductance of an inwardly rectifying K+ channel via coupling with subtypes of Gi/o, and by decreasing a Na+-dependent inward current via coupling with Gi/o and the consequent inhibition of adenylyl cyclase. Reduced levels of cAMP decrease protein kinase A (PKA) activity and the phosphorylation of the responsible channel or pump. Inhibition of the cAMP pathway also decreases phosphorylation of numerous other proteins and thereby affects many additional processes in the neuron. For example, it reduces the phosphorylation state of CREB, which may initiate some of the longer-term changes in locus coeruleus function. Upward bold arrows summarize effects of chronic morphine in the locus coeruleus. Chronic morphine increases levels of types I (ACI) and VIII (ACVIII) adenylyl cyclase, PKA catalytic (C) and regulatory type II (RII) subunits, and several phosphoproteins, including CREB and tyrosine hydroxylase (TH), the rate-limiting enzyme in norepinephrine biosynthesis. These changes contribute to the altered phenotype of the drug-addicted state. For example, the intrinsic excitability of LC neurons is increased via enhanced activity of the cAMP pathway and Na+-dependent inward current, which contributes to the tolerance, dependence, and withdrawal exhibited by these neurons. Upregulation of ACVIII and TH is mediated via CREB, whereas upregulation of ACI and of the PKA subunits appears to occur via a CREB-independent mechanism not yet identified (5).

In contrast, chronic opiate exposure increases the intrinsic excitability of LC neurons via upregulation of the cAMP pathway (5). In particular, chronic opiate exposure increases levels of expression of type I and type VIII adenylyl cyclase and of the cata lytic and type II regulatory subunits of PKA (7) This upregulation has been shown to increase the excitability of LC neurons partly via activation of the nonspecific cation channel. Upregulation of the cAMP pathway can be viewed as a homeostatic response of LC neurons to opiate inhibition and, therefore, as a mechanism of opiate tolerance and dependence in these neurons. The continued presence of morphine and the up-regulated cAMP pathway results in LC neurons firing at near-normal levels. When opiates are removed, the up-regulated cAMP pathway is unopposed and leads to overactivation of these neurons, as seen during withdrawal. Interestingly, the time course for the recovery of the cAMP pathway to normal, over a course of hours to days, parallels that of the diminution of the withdrawal syndrome.

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