Role of Noradrenergic Signaling by the Nucleus Tractus Solitarius in Mediating Opiate Reward

The mechanisms underlying responses to drugs of abuse have been widely investigated; however, less is known about pathways normally protective against the development of drug reinforcement. These pathways are also important since they may regulate individual differences in vulnerability to addiction. The neuropeptide galanin and its binding sites are expressed in brain areas important for drug reward. Previous studies have shown that centrally infused galanin attenuates morphine place preference and peripheral injection of galnon, a galanin agonist, decreases opiate withdrawal signs. The current studies in galanin knockout (GKO) mice examined the hypothesis that galanin is an endogenous negative regulator of opiate reward and identified downstream signaling pathways regulated by galanin. We show that GKO mice demonstrate increased locomotor activation following morphine administration, which is inhibited by acute administration of galnon. GKO mice also show enhanced morphine place preference, supporting the idea that galanin normally antagonizes opiate reward. In addition, morphine-induced ERK1/2 phosphorylation was increased in the VTA of both wild-type and GKO mice, but only the GKO mice showed increases in ERK1/2 and CREB phosphorylation in the amygdala or nucleus accumbens. Furthermore, a single systemic injection of galnon in GKO mice was sufficient to reverse some of the biochemical changes brought about by morphine administration. These data suggest that galanin normally attenuates behavioral and neurochemical effects of opiates; thus, galanin agonists may represent a new class of therapeutic targets for opiate addiction.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Hawes

Brunzell

Narasimhaiah

et al. 2007

“…Because CPP is an associative learning paradigm, manipulations of NE could alter the development or expression of a psychostimulant CPP in the absence of any effect on the rewarding properties of the drugs. However, this is unlikely, as mice that completely lack NE still express a normal conditioned taste aversion to lithium chloride and ethanol and show a CPP to food (Weinshenker et al, 2000;Schank et al, 2006;Olson et al, 2006). Interestingly, NE depletion early in development either has no effect (neonatal 6-OHDA lesion; Spyraki et al, 1982a) or even enhances (DBH knockout mice; Schank et al, 2006) psychostimulant CPP, probably due to compensatory changes in the DA system during development (see below).…”

Section: Ne and Psychostimulant Cppmentioning

confidence: 99%

“…For example, morphine-induced locomotion is abolished in DBH knockout mice that lack NE, a deficit that is partially reversed by pharmacological restoration of NE or viralmediated reexpression of DBH in the DNB or VNB (Olson et al, 2006). In addition, both genetic deletion and pharmacological blockade of a1bARs prevent morphineinduced locomotion (Drouin et al, 2002) and the development of locomotor sensitization (Auclair et al, 2004).…”

Section: Ne and Opiate-induced Locomotion/sensitizationmentioning

confidence: 99%

There and Back Again: A Tale of Norepinephrine and Drug Addiction

Weinshenker

Schroeder

2006

Self Cite

323

277

Fueled by anatomical, electrophysiological, and pharmacological analyses of endogenous brain reward systems, norepinephrine (NE) was identified as a key mediator of both natural and drug-induced reward in the late 1960s and early 1970s. However, reward experiments from the mid-1970s that could distinguish between the noradrenergic and dopaminergic systems resulted in the prevailing view that dopamine (DA) was the primary 'reward transmitter' (a belief holding some sway still today), thereby pushing NE into the background. Most damaging to the NE hypothesis of reward were studies demonstrating that NE receptor antagonists and NE reuptake inhibitors failed to impact drug self-administration. In recent years new tools, such as genetically engineered mice, and new experimental paradigms, such as reinstatement of drug seeking following withdrawal, have propelled NE back into the awareness of addiction researchers. Of particular interest is disulfiram, an inhibitor of the NE biosynthetic enzyme dopamine b-hydroxylase, which has demonstrated promising efficacy in the treatment of cocaine dependence in preliminary clinical trials. The purpose of this review is to synthesize the new data linking NE to critical aspects of DA signaling and drug addiction, with a focus on psychostimulants (eg, cocaine), opiates (eg, morphine), and alcohol.

“…Despite the critical role of DA in the effects of drugs of abuse, some data indicate, however, that noradrenergic rather than dopaminergic transmission is necessary for morphine-induced reward (Drouin et al, 2002b;Hnasko et al, 2005;Ventura et al, 2005;Olson et al, 2006). Whatever the hypothesis, it has been shown that addictive drugs share the ability to induce long-lasting cellular adaptations in neural systems, such as alterations in gene expression (Hyman and Malenka, 2001;Nestler, 2001).…”

Section: Introductionmentioning

confidence: 99%

Drugs of Abuse Specifically Sensitize Noradrenergic and Serotonergic Neurons Via a Non-Dopaminergic Mechanism

Lanteri

Salomon

Torrens

et al. 2007

A challenge in drug dependence is to delineate long-term neurochemical modifications induced by drugs of abuse. Repeated damphetamine was recently shown to disrupt a mutual regulatory link between noradrenergic and serotonergic neurons, thus inducing long-term increased responses to d-amphetamine and para-chloroamphetamine, respectively. We show here that such a sensitization of noradrenergic and serotonergic neurons also occurs following repeated treatment with cocaine, morphine, or alcohol, three compounds belonging to main groups of addictive substances. In all cases, this sensitization is prevented by a1b-adrenergic and 5-HT 2A receptors blockade, indicating the critical role of these receptors on long-term effects of drugs of abuse. However, repeated treatments with two non-addictive antidepressants, venlafaxine, and clorimipramine, which nevertheless inhibit noradrenergic and serotonergic reuptake, do not induce noradrenergic and serotonergic neurons sensitization. Similarly, this sensitization does not occur following repeated treatments with a specific inhibitor of dopamine (DA) reuptake, GBR12783. Moreover, we show that the effects of SCH23390, a D1 receptor antagonist known to inhibit development of d-amphetamine behavioral sensitization, are due to its 5-HT 2C receptor agonist property. SCH23390 blocks amphetamine-induced release of norepinephrine and RS102221, a 5-HT 2C antagonist, can reverse this inhibition as well as inhibition of noradrenergic sensitization and development of behavioral sensitization induced by repeated damphetamine. We propose that noradrenergic/serotonergic uncoupling is a common neurochemical consequence of repeated consumption of drugs of abuse, unrelated with DA release. Our data also suggest that compounds able to restore the link between noradrenergic and serotonergic modulatory systems could represent important therapeutic targets for investigation.