Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for β-2 Adrenergic Receptors

Drug-seeking behavior is maintained by encounters with drug-associated cues. Preventing retrieval of drug-associated memories that these cues provoke would therefore limit relapse susceptibility; however, little is known regarding the mechanisms of retrieval. Here, we show that b-adrenergic receptor activation is necessary for the retrieval of a cocaine-associated memory. Using a conditioned place preference (CPP) procedure, rats were conditioned to associate one chamber, but not another, with cocaine. When administered before a CPP trial, propranolol, but not saline, prevented retrieval of a cocaine-associated CPP. In subsequent drug-free trials, rats previously treated with propranolol continued to show a retrieval deficit, as no CPP was evident. This retrieval deficit was long lasting and robust, as the CPP did not re-emerge during a test for spontaneous recovery 14 days later or reinstate following a priming injection of cocaine. Moreover, the peripheral b-adrenergic receptor antagonist sotalol did not affect retrieval. Thus, retrieval of cocaine-associated memories is mediated by norepinephrine acting at central b-adrenergic receptors. Our findings support the use of propranolol, a commonly prescribed b-blocker, as an adjunct to exposure therapy for the treatment of addiction by preventing retrieval of drugassociated memories during and long after treatment, and by providing protection against relapse.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Propranolol Protects Against Cocaine-induced Reinstatementmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of β-Adrenergic Receptors Induces a Persistent Deficit in Retrieval of a Cocaine-Associated Memory Providing Protection against Reinstatement

Otis

Mueller

2011

“…In fact, yohimbine has been used to produce reinstatement (Lee et al, 2004;Shepard et al, 2004) as well as potentiate the cueinduced reinstatement of cocaine seeking (Feltenstein and See, 2006). The ability of yohimbine or footshock, but not cocaine itself, to reinstate cocaine seeking can be attenuated by treatment with propranolol, a2-receptor agonists, or a1-receptor antagonists indicating reliance on noradrenergic activity (Shaham et al, 2000;Mantsch et al, 2010;Le et al, 2011). While we did not observe an increase in cocaine seeking following administration of atomoxetine, some concern remains over whether drug treatments that augment noradrenergic activity may pose a risk rather than a benefit in promoting abstinence in recovering addicts.…”

Section: Discussionmentioning

confidence: 99%

Compound Stimulus Presentation and the Norepinephrine Reuptake Inhibitor Atomoxetine Enhance Long-Term Extinction of Cocaine-Seeking Behavior

Janak

Bowers²,

Corbit

2011

Drug abstinence is frequently compromised when addicted individuals are re-exposed to environmental stimuli previously associated with drug use. Research with human addicts and in animal models has demonstrated that extinction learning (non-reinforced cue-exposure) can reduce the capacity of such stimuli to induce relapse, yet extinction therapies have limited long-term success under real-world conditions (Bouton, 2002;O'Brien, 2008). We hypothesized that enhancing extinction would reduce the later ability of drugpredictive cues to precipitate drug-seeking behavior. We, therefore, tested whether compound stimulus presentation and pharmacological treatments that augment noradrenergic activity (atomoxetine; norepinephrine reuptake inhibitor) during extinction training would facilitate the extinction of drug-seeking behaviors, thus reducing relapse. Rats were trained that the presentation of a discrete cue signaled that a lever press response would result in cocaine reinforcement. Rats were subsequently extinguished and spontaneous recovery of drug-seeking behavior following presentation of previously drug-predictive cues was tested 4 weeks later. We find that compound stimulus presentations or pharmacologically increasing noradrenergic activity during extinction training results in less future recovery of responding, whereas propranolol treatment reduced the benefit seen with compound stimulus presentation. These data may have important implications for understanding the biological basis of extinction learning, as well as for improving the outcome of extinction-based therapies.

“…We know that, in rodents, βAR antagonists infused into the amygdala block fear memory enhancement following stressful stimuli Mantsch et al, 2010;Quirarte et al, 1998;Schmidt and Weinshenker, 2014;Vranjkovic et al, 2014); is required for fear conditioning behavior (Cahill et al, 1994;Dębiec and Ledoux, 2004;Rogan et al, 1997); and systemic administration of the βAR antagonist propranolol reduces the spontaneous firing rate of neurons within the BLA (Buffalari and Grace, 2007;Ferry et al, 1997;Huang et al, 1996). Generally, β-adrenergic receptors have been linked to amygdala-dependent learning of negative affective memories, and a predominate focus of this receptor system has been examining its role in modulating fear-related behaviors (McGaugh, 1988(McGaugh, , 2004Strange and Dolan, 2004).…”

Section: Introductionmentioning

confidence: 99%

Chemogenetic and Optogenetic Activation of Gαs Signaling in the Basolateral Amygdala Induces Acute and Social Anxiety-Like States

Siuda

Al‐Hasani

McCall

et al. 2016

Anxiety disorders are debilitating psychiatric illnesses with detrimental effects on human health. These heightened states of arousal are often in the absence of obvious threatening cues and are difficult to treat owing to a lack of understanding of the neural circuitry and cellular machinery mediating these conditions. Activation of noradrenergic circuitry in the basolateral amygdala is thought to have a role in stress, fear, and anxiety, and the specific cell and receptor types responsible is an active area of investigation. Here we take advantage of two novel cellular approaches to dissect the contributions of G-protein signaling in acute and social anxiety-like states. We used a chemogenetic approach utilizing the Gαs DREADD (rM3Ds) receptor and show that selective activation of generic Gαs signaling is sufficient to induce acute and social anxiety-like behavioral states in mice. Second, we use a recently characterized chimeric receptor composed of rhodopsin and the β 2 -adrenergic receptor (Opto-β 2 AR) with in vivo optogenetic techniques to selectively activate Gαs β-adrenergic signaling exclusively within excitatory neurons of the basolateral amygdala. We found that optogenetic induction of β-adrenergic signaling in the basolateral amygdala is sufficient to induce acute and social anxiety-like behavior. These findings support the conclusion that activation of Gαs signaling in the basolateral amygdala has a role in anxiety. These data also suggest that acute and social anxiety-like states may be mediated through signaling pathways identical to β-adrenergic receptors, thus providing support that inhibition of this system may be an effective anxiolytic therapy.