Kappa Opioid Receptor Activation Potentiates the Cocaine-Induced Increase in Evoked Dopamine Release Recorded In Vivo in the Mouse Nucleus Accumbens

Abstract

Behavioral stressors increase addiction risk in humans and increase the rewarding valence of drugs of abuse including cocaine, nicotine and ethanol in animal models. Prior studies have established that this potentiation of drug reward was mediated by stress-induced release of the endogenous dynorphin opioids and subsequent kappa opioid receptor (KOR) activation. In this study, we used in vivo fast scan cyclic voltammetry to test the hypothesis that KOR activation before cocaine administration might potentiate the evoked release of dopamine from ventral tegmental (VTA) synaptic inputs to the nucleus accumbens (NAc) and thereby increase the rewarding valence of cocaine. The KOR agonist U50488 inhibited dopamine release evoked by either medial forebrain bundle (MFB) or pedunculopontine tegmental nucleus (PPTg) activation of VTA inputs to the shell or core of the mouse NAc. Cocaine administration increased the dopamine response recorded in either the shell or core evoked by either MFB or PPTg stimulation. Administration of U50488 15 min before cocaine blocked the conditioned place preference (CPP) to cocaine, but only significantly reduced the effect of cocaine on the dopamine response evoked by PPTg stimulation to NAc core. In contrast, administration of U50488 60 min before cocaine significantly potentiated cocaine CPP and significantly increased the effects of cocaine on the dopamine response evoked by either MFB or PPTg stimulation, recorded in either NAc shell or core. Results of this study support the concept that stress-induced activation of KOR by endogenous dynorphin opioids may enhance the rewarding valence of drugs of abuse by potentiating the evoked dopamine response.

The Brain on Drugs: From Reward to Addiction

“…The endogenous opioid system also contributes to the effects of stress on drug consumption. Specifically, dynorphin, through its activation of kappa receptors (KOR), is implicated in the stress-induced potentiation of drug reward (reviewed in Ehrich et al, 2014). Activation of KOR on DA terminals inhibits DA release in the NAc, which is implicated in the dysphoria that follows drug withdrawal (Tejeda et al, 2012).…”

Relative Timing Between Kappa Opioid Receptor Activation and Cocaine Determines the Impact on Reward and Dopamine Release

“…KOR agonists can increase the behavioral and neurochemical effects of psychostimulants, depending on the timing and context of KOR agonist exposure Ehrich et al, 2014;Fuentealba et al, 2006;Heidbreder et al, 1998). Treatment of rhesus monkeys with the KOR agonist U-50,488 increases cocaine choice (Negus, 2004), suggesting a KOR-mediated increase in the relative reinforcing effects of cocaine.…”

“…Importantly, a recent study used FSCV to demonstrate that an early effect of the KOR agonist U50,488 is a potentiation of stimulated dopamine release in the nucleus accumbens (Ehrich et al, 2014). ICSS is an operant paradigm that measures increases or decreases in reward sensitivity in real time.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…CREB, unlike DFosB, reduces the sensitivity to the rewarding effects of cocaine (tolerance) and increases SA and relapse via negative reinforcement. For instance, the k-opioid peptide dynorphin, regulated by CREB, suppresses DA transmission to the NAc via the activation of k-opioid receptors, thus impairing rewarding behaviors (Carlezon et al, 1998;Larson et al, 2011;Muschamp et al, 2011;Ehrich et al, 2014). Furthermore, the induction of DFosB in the NAc is dependent on CREB and serum response factor .…”