The endogenous dynorphin-opioid receptor (KOR) system encodes the dysphoric component of the stress response and controls the risk of depression-like and addiction behaviors; however, the molecular and neural circuit mechanisms are not understood. In this study, we report that KOR activation of p38␣ MAPK in ventral tegmental (VTA) dopaminergic neurons was required for conditioned place aversion (CPA) in mice. Conditional genetic deletion of floxed KOR or floxed p38␣ MAPK by Cre recombinase expression in dopaminergic neurons blocked place aversion to the KOR agonist U50,488. Selective viral rescue by wild-type KOR expression in dopaminergic neurons of KOR Ϫ/Ϫ mice restored U50,488-CPA, whereas expression of a mutated form of KOR that could not initiate p38␣ MAPK activation did not. Surprisingly, while p38␣ MAPK inactivation blocked U50,488-CPA, p38␣ MAPK was not required for KOR inhibition of evoked dopamine release measured by fast scan cyclic voltammetry in the nucleus accumbens. In contrast, KOR activation acutely inhibited VTA dopaminergic neuron firing, and repeated exposure attenuated the opioid response. This adaptation to repeated exposure was blocked by conditional deletion of p38␣ MAPK, which also blocked KOR-induced tyrosine phosphorylation of the inwardly rectifying potassium channel (GIRK) subunit Kir3.1 in VTA dopaminergic neurons. Consistent with the reduced response, GIRK phosphorylation at this amino terminal tyrosine residue (Y12) enhances channel deactivation. Thus, contrary to prevailing expectations, these results suggest that opioid-induced aversion requires regulation of VTA dopaminergic neuron somatic excitability through a p38␣ MAPK effect on GIRK deactivation kinetics rather than by presynaptically inhibiting dopamine release.

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.

In their recent paper, "Poststress block of kappa opioid receptors rescues long-term potentiation of inhibitory synapses and prevents reinstatement of cocaine seeking," Polter and colleagues showed that cold-water swim stress exposure blocks LTP of GABAergic synaptic input recorded in ventral tegmental area (VTA) dopamine neurons of male Sprague-Dawley rats (1). The effects of stress exposure on LTP GABA were blocked by pretreatment with the glucocorticoid antagonist RU-486 or the kappa opioid receptor (KOR) antagonist norbinaltorphimine (norBNI). Importantly, norBNI given 4 days after stress exposure could reverse the effects of swim-stress on LTP GABA and block stress-induced reinstatement of cocaine self-administration. Because stress-exposure is such a wellrecognized risk factor for the development of compulsive drug abuse and relapse during intervals of abstinence, the demonstration that norBNI given after stress exposure could promote stress-resilience and reverse the adverse effects of prior stress exposure are important preclinical advances in the development of addiction therapeutics. The Polter study also increases our understanding of the complex effects of stress on the reward circuitry controlling addictive drug effects.Multiple synaptic inputs converge on the VTA dopaminergic neurons to regulate their excitability, and these neurons, in turn, project broadly to critical targets in the brain to coordinate the drug seeking behaviors initiated by addictive drugs (2) (Figure 1). Understanding this circuit and defining the effects of stress-mediators on the functioning of these neurons seems vital in the development of novel treatments for addiction, which has appropriately been described as a 'stress-surfeit' disorder by Koob and colleagues (3). The intimate relationship between stress vulnerability and addiction risk was summarized there and in other reviews on this topic, and the reciprocal concepts that stress exposure increases addiction risk and that addictive drug exposure increases stress vulnerability have now been supported by an extensive literature. Breaking this cycle by blocking the actions of the stress-mediators holds great promise, but understanding how these antagonists act on the reward circuit requires the kind of high-resolution circuit analysis described by Polter and colleagues (1).The authors report no financial conflicts of interest. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptStress exposure produces adaptive physiological responses vital for the individual's survival. As such, some mildly stressful experiences can be perceived as 'exciting' and positive when controlled by the individual, but persistent uncontrolled stressful experiences are aversive and can cause lasting changes in the reward circuitry (4). Corticotrophin releasing factor (CRF) orchestrates the classically recognized stress response by activating the hypothalamic-pituitary-adrenal glucocorticoid response, but CRF also acts intracerebrally to produce some of the cogn...

Exploration of an object by arm movement and somatosensation is a serial process that relies on memories and expectations. The present experiments tested the hypothesis that this process involves breaking the object into component shapes (primitives). This was tested by having human subjects explore shapes composed of semicircular arcs, as well as quarter circles or quarter ellipses. The subjects' perception was reported using a visual display. In the first experiment, in which a series of semicircular arcs was presented, with offsets that differed from trial to trial, performance was consistent with the perception of two (left and right) semicircles. In the second experiment, subjects often failed to detect the quarter circles or quarter ellipses and again behaved as if the object was composed of two (top and bottom) semicircles. The results suggest that the synthesis of haptically sensed shapes is biased toward simple geometric objects and that it can be strongly influenced by expectations.

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