Dopaminergic cellular and circuit contributions to kappa opioid receptor mediated aversion

Abstract

Neural circuits that enable an organism to protect itself by promoting escape from immediate threat and avoidance of future injury are conceptualized to carry an "aversive" signal. One of the key molecular elements of these circuits is the kappa opioid receptor (KOR) and its endogenous peptide agonist, dynorphin. In many cases, the aversive response to an experimental manipulation can be eliminated by selective blockade of KOR function, indicating its necessity in transmitting this signal. The dopamine system, through its contributions to reinforcement learning, is also involved in processing of aversive stimuli, and KOR control of dopamine in the context of aversive behavioral states has been intensely studied. In this review, we have discussed the multiple ways in which the KORs regulate dopamine dynamics with a central focus on dopamine neurons and projections from the ventral tegmental area. At the neuronal level, KOR agonists inhibit dopamine neurons both in the somatodendritic region as well as at terminal release sites, through various signaling pathways and ion channels, and these effects are specific to different synaptic sites. While the dominant hypotheses are that aversive states are driven by decreases in dopamine and increases in dynorphin, reported exceptions to these patterns indicate these ideas require refinement. This is critical given that KOR is being considered as a target for development of new therapeutics for anxiety, depression, pain, and other psychiatric disorders.

Figure 1:. Functional kappa opioid receptors are expressed on specific VTA circuit elements

In rat (top), dopamine cell bodies in the VTA that project to the medial prefrontal cortex (mPFC) and the amygdala (AMYG) are inhibited by kappa opioid receptor (KOR) activation, which open G protein coupled inwardly rectifying K⁺ channels. Dopamine neurons that project to the nucleus accumbens (NAc) do not show this response, however KOR activation inhibits release at dopamine terminals in the NAc. Excitatory glutamatergic inputs onto VTA neurons are also inhibited by KOR activation. These effects may also depend upon the source of the afferents and the projection target of the postsynaptic cell. In mouse (bottom), most NAc-projecting VTA dopamine cell bodies and some amygdala-projecting VTA dopamine neurons are directly inhibited by KOR activation. It is unknown if KOR activation also inhibits mPFC-projecting VTA dopamine neurons in mice. KORs also inhibit GABA release onto VTA neurons in mice.

Figure 2:. dopamine release in the nucleus accumbens.

Activation of kappa opioid receptors (KORs) on dopamine terminals results in inhibition of dopamine release. This occurs via coupling of KORs with Gi/o proteins activating one or more kinases (PKCβ, JNK, or ERK) and hyperpolarizing the cell via increasing K⁺ conductance or inhibition of Ca²⁺ channel function. Activation of KORs also increases p38 expression resulting in the activation of MAPK and further hyperpolarization of the cell. Activation of KORs has also been shown to increase DAT function, accelerating uptake. Dynorphin, in the NAc, is released from D1R containing medium spiny neurons and probably from afferents from the lateral hypothalamus. KOR, kappa opioid receptor; D1R, dopamine-1 receptor; DAT, dopamine transporter; Ca²⁺, calcium; K⁺, potassium; MAPK, mitogen activated protein kinases; JNK, c-Jun N-terminal kinases; pDYN, prodynorphin; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; BDNF, brain derived neurotrophic factor; AC, adenylyl cyclase; PKC, protein kinase.