Noradrenergic β-Receptor Antagonism within the Central Nucleus of the Amygdala or Bed Nucleus of the Stria Terminalis Attenuates the Negative/Anxiogenic Effects of Cocaine

Abstract

Cocaine has been shown to produce both initial rewarding and delayed anxiogenic effects. Although the neurobiology of cocaine's rewarding effects has been well studied, the mechanisms underlying its anxiogenic effects remain unclear. We used two behavioral assays to study these opposing actions of cocaine: a runway self-administration test and a modified place conditioning test. In the runway, the positive and negative effects of cocaine are reflected in the frequency of approach-avoidance conflict that animals develop about entering a goal box associated with cocaine delivery. In the place conditioning test, animals develop preferences for environments paired with the immediate/rewarding effects of cocaine, but avoid environments paired with the drug's delayed/anxiogenic actions. In the present study, these two behavioral assays were used to examine the role of norepinephrine (NE) transmission within the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), each of which has been implicated in drug-withdrawal-induced anxiety and stressinduced response reinstatement. Rats experienced 15 single daily cocaine-reinforced (1.0 mg/kg, i.v.) runway trials 10 min after intracranial injectionofthe␤1and␤2NEreceptorantagonistsbetaxololandICI118551orvehicleintotheCeAorBNST.NEantagonismofeitherregiondose dependently reduced approach-avoidance conflict behavior compared with that observed in vehicle-treated controls. In addition, NE antagonism selectively interfered with the expression of conditioned place aversions while leaving intact cocaine-induced place preferences. These data suggest a role for NE signaling within the BNST and the CeA in the anxiogenic actions of cocaine.

The Psychoactive Designer Drug and Bath Salt Constituent MDPV Causes Widespread Disruption of Brain Functional Connectivity

“…Noradrenergic inputs to the bed nucleus of stria terminalis and central nucleus of the amygdala, which are involved in the expression of anxiety-like behavior in rats (Fendt et al, 2005). Blockade of β-adrenergic receptors in these regions attenuates the delayed aversive (but not the immediate rewarding) effects of cocaine (Wenzel et al, 2014). Hence, it is possible that activation of adrenergic receptors may mediate (at least in part) the reported aversive effects of MDPV.…”

The Human BNST: Functional Role in Anxiety and Addiction

“…For example, the BNST is involved in the anxiogenic effects of cocaine intoxication (Wenzel et al, 2014). In addition, there is compelling evidence that the BNST mediates stressinduced reinstatement of drug-seeking behavior (Buffalari and See, 2011;Erb et al, 2001;Flavin and Winder, 2013;Jennings et al, 2013a), thus serving an important role in understanding relapse following a period of abstinence.…”

“…If alterations in BNST structure, function, or connectivity indeed underlie these disorders in humans, then the BNST becomes a novel, untapped treatment target. Supporting this potentially novel role is evidence from rodent studies that anxiety and addiction processes may be altered by drugs that target the BNST, including CRF antagonists (Walker et al, 2009), norepinephrine agonists (Park et al, 2013;Harris and Gewirtz, 2004) and antagonists (Wenzel et al, 2014), and endocannabinoid system targets (Glangetas et al, 2013).…”

“…Emerging evidence suggests that a tiny region in the ventral forebrain-the bed nucleus of the stria terminalis (BNST)-is a critical node in the stress response neurocircuitry and may play a significant role in both anxiety and addiction, two highly prevalent and debilitating stress-related disorders. Rodent studies of the BNST over the past two decades have led to exciting discoveries about its potential role in human psychopathology-seminal studies have shown a unique role for the BNST in contextual fear and sustained, anxiety-like responses in rodents (see, eg, Davis et al, 2010;Walker et al, 2003), and parallel work in drug addiction demonstrates the role of BNST in withdrawal related-anxiety and relapse (Buffalari and See, 2011;Silberman et al, 2013;Wenzel et al, 2014). Although anxiety and addiction are often considered to have distinct neurobiological bases-anxiety related to fear neurocircuitry and addiction related to reward circuitry-we now understand the two disorders also have many commonalities; for example, anxiety and addiction are both triggered by stress (Koob, 2009;McEwen, 2012), risk for both disorders is heightened in individuals with altered stress reactivity (Lovallo, 2006;Villada et al, 2014), and the two disorders are highly comorbid (Grant et al, 2004;Kessler et al, 2005b).…”

Adrenaline Rush: The Role of Adrenergic Receptors in Stimulant-Induced Behaviors

“…In this model, approach and retreat behaviors indicate the reinforcing and aversive effects, respectively, of cocaine. Combined administration of betaxolol and ICI-118,551 infused in the central amygdala or BNST decreased retreat behaviors (Wenzel et al, 2014). Therefore, it appears that the influence of NE on stimulant selfadministration depends on the sensitivity of the operant task to the NE-dependent, aversive effects of the drug.…”