Localizations and Projections of Brain Stress Systems?Norepinephrine

Norepinephrine binds to three distinct families of receptors?α₁, α₂, and β-adrenergic?each with three receptor subtypes (Rohrer and Kobilka, 1998). The α₁ receptor family comprises α_1a, α_1b, and α_1d. Each subtype activates phospholipase C and α₂ and are coupled to the inositol phosphate second messenger system via the G protein G_q. A centrally active α₁ receptor antagonist used in drug dependence research is prazosin. The α₂ family comprises α_2a, α_2b, and α_2c. Each subtype inhibits adenylate cyclase via coupling to the inhibitory G protein G_i. Two α₂ drugs commonly used in drug-dependence research are the α₂ agonist clonidine and the α₂ antagonist yohimbine. Because the α₂ receptor is hypothesized to be presynaptic, these drugs inhibit and facilitate noradrenergic function, respectively. The β-adrenergic receptor family comprises β₁, β₂, and β₃. Each subtype activates adenylate cyclase via coupling to the G protein G_s. Few β-adrenergic drugs have been explored in drug-dependence research, with the exception of the β-adrenergic antagonist propranolol, presumably because of poor brain bioavailability.

Precipitated morphine withdrawal increases norepinephrine release in the central nucleus of the amygdala and bed nucleus of the stria terminalis (Watanabe et al., 2003; Fuentealba et al., 2000). The noradrenergic α₂ agonist clonidine, a functional norepinephrine antagonist with presynaptic actions, blocked the suppression in responding for food during opioid withdrawal, a measure of the motivational component of opioid withdrawal (Sparber and Meyer, 1978) and the aversive stimulus effects (conditioned place aversions) of opioid withdrawal (Schulteis et al., 1998). Increased anxiety-like behavior was observed during cocaine and morphine withdrawal in rats and was blocked by the β-adrenergic antagonists propranolol and atenolol (Harris and Aston-Jones, 1993; Gold et al., 1980). Similar effects were observed with direct injections of a β-adrenergic antagonist directly into the central nucleus of the amygdala (Rudoy and van Bockstaele, 2007). Norepinephrine functional antagonists (β₁ antagonist and α₂ agonist) injected into the lateral bed nucleus of the stria terminalis blocked precipitated opiate withdrawal-induced place aversions (Delfs et al., 2000), and β-adrenergic antagonists produced similar effects when injected into the central nucleus of the amygdala (Watanabe et al., 2003). Studies that further localized the effects of norepinephrine in driving opioid withdrawal showed that ventral noradrenergic bundle lesions attenuated opioid withdrawal (Delfs et al., 2000), but virtually complete lesions of the dorsal noradrenergic bundle from the locus coeruleus with the neurotoxin 6-hydroxydopamine failed to block the place aversion produced by opioid withdrawal-induced place aversion (Caille et al., 1999). Consistent with the studies of the aversive effects of opioid withdrawal, the α₁ norepinephrine antagonist prazosin reduced heroin self-administration in dependent rats with extended access (Greenwell et al., 2008). Prazosin also selectively blocked the increased motivation to intravenously self-administer cocaine on a progressive-ratio schedule in rats with extended access to the drug (a procedure that is hypothesized to produce dependence) (Wee et al., 2008). The extended-access rats showed a decreased number of neurons with α₁ adrenergic-like immunoreactivity in the bed nucleus of the stria terminalis, suggesting that the α₁ noradrenergic system in the bed nucleus of the stria terminalis also may be involved in cocaine dependence (Wee et al., 2008).

Substantial evidence also has accumulated suggesting that, in animals and humans, central noradrenergic systems are activated during acute withdrawal from ethanol and may have motivational significance. Alcohol withdrawal in humans is associated with activation of noradrenergic function, and the signs and symptoms of alcohol withdrawal in humans are blocked by postsynaptic β-adrenergic blockade (Romach and Sellers, 1991). Alcohol withdrawal signs also are blocked in animals by administration of α₁ antagonists and β-adrenergic antagonists and selective blockade of norepinephrine synthesis (Trzaskowska and Kostowski, 1983). In dependent rats, the α₁ antagonist prazosin selectively blocked the increased drinking associated with acute withdrawal (Walker et al., 2008). Thus, converging data suggest that disruption of noradrenergic function blocks ethanol reinforcement, that noradrenergic neurotransmission is enhanced during ethanol withdrawal, and that noradrenergic functional antagonists can block aspects of ethanol withdrawal.

Chronic nicotine self-administration (23 hr access) increases norepinephrine release in the paraventricular nucleus of the hypothalamus and the amygdala, measured by in vivo microdialysis (Fu et al., 2001, 2003). However, during the late maintenance phase of 23 hr access to nicotine, norepinephrine release was no longer elevated in the amygdala, suggesting some desensitization/tolerance-like effect (Fu et al., 2003).

The role of norepinephrine in stress-induced reinstatement also follows a pattern of results similar to its role in the anxiety-like effects of acute withdrawal and dependence-induced increases in drug intake (for reviews, see Shaham et al., 2003; Lu et al., 2003). The α₂ adrenergic agonist clonidine decreased stress-induced reinstatement of cocaine, opiate, alcohol, and nicotine seeking (Le et al., 2005; Erb et al., 2000; Shaham et al., 2000; Zislis et al., 2007). The α₂ antagonist yohimbine reinstated drug seeking (Lee et al., 2004). Limited studies with intracerebral injections also have localized the effects of functional blockade of norepinephrine system on stress-induced reinstatement of morphine conditioned place preferences to the bed nucleus of the stria terminalis (Wang et al., 2001). β-adrenergic antagonists administered systemically also blocked stress-induced reinstatement of cocaine seeking (Leri et al., 2002).

Date: 2016-06-12; view: 302