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Typical monoamine-based antidepressants have significant limitations, including a time lag for therapeutic response and low efficacy (more than one-third of depressed patients fail to respond to multiple antidepressant medications and are considered treatment-resistant). Conversely, ketamine, an N-methyl-D-aspartate receptor antagonist, exhibits rapid and sustained antidepressant actions in patients with treatment-resistant depression. However, clinical use of ketamine is limited due to its serious side effects. Thus, there is a significant need to develop novel ketamine-like antidepressants with fewer side effects. We previously demonstrated that intracerebroventricular infusion of resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), specialized pro-resolving lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, produce antidepressant-like effects in mouse models of depression. Among resolvins, RvE1 produces the most potent antidepressant-like effects likely via ChemR23 in several mouse models of depression. Local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) also produces antidepressant-like effects, suggesting that these brain regions are sites of action of RvE1. Additionally, intranasal (i.n.) administration of RvE1 produces antidepressant-like effects through mechanisms similar to ketamine: activity-dependent release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and subsequent mechanistic target of rapamycin complex 1 (mTORC1) activation in the mPFC play a crucial role in the rapid and sustained antidepressant-like actions of i.n. RvE1. Moreover, the antidepressant-like effects of i.n. RvE1 require BDNF and VEGF release, but not mTORC1 activation, in the dorsal DG. These findings suggest that RvE1 can be a promising lead for a novel rapid-acting antidepressant.

Stress potentiates craving for addictive drugs including cocaine. To elucidate neural mechanisms underlying this effect of stress, we developed an experimental paradigm combining cocaine-induced conditioned place preference (CPP) with a restraint stress. Acute restraint stress exposure immediately before posttest significantly increased cocaine CPP scores. It has been suggested that the extracellular noradrenaline (NA) level is increased by stress in the laterodorsal tegmental nucleus (LDT), which sends cholinergic projections to dopamine (DA) neurons in the ventral tegmental area (VTA), and medial prefrontal cortex (mPFC), which receives DA input from the VTA. Thus, we investigated the roles of NA in these brain regions. Intra-LDT injection of an α2 or a β adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. In vitro whole-cell recordings revealed that α2 adrenoceptor stimulation reduced GABAergic inputs to LDT cholinergic neurons that were obtained from cocaine-, but not saline-, treated rats. On the other hand, α1, but not α2 or β, adrenoceptor stimulation excited mPFC pyramidal neurons. Intra-mPFC injection of an α1 adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. Additionally, chemogenetic silencing of mPFC excitatory neurons also reduced the stress-induced enhancement of cocaine CPP. These findings suggest that stress-induced increases in neuronal activity of the LDT and mPFC may contribute to the enhancement of cocaine craving.

The development and persistence of drug addiction are associated with the activation and adaptation of the brain reward circuitry, which consists of dopaminergic projection from the ventral tegmental area to the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC). In cocaine addiction, cocaine-induced activation and neuroplasticity in the brain reward circuitry may contribute to the acquisition and expression of rewarding memory of cocaine, which is critical for the reinstatement of cocaine seeking. However, it remains unclear which neuronal types causally contribute to the retrieval of cocaine-associated rewarding memory. To address this issue, we used DREADD (Designer Receptors Exclusively Activated by Designer Drugs) technology. To selectively suppress mPFC excitatory neurons, we infused an adeno-associated virus (AAV5 or AAV-DJ) vector expressing hM4Di, an inhibitory DREADD, under the control of CaMKII promotor into the mPFC of wildtype mice. To selectively suppress GABAergic neurons, we infused a Cre-dependent AAV (AAV5 or AAV-DJ) vector expressing hM4Di into the mPFC of GAD67-Cre mice or the NAc of vGAT-Cre mice. We found that, in cocaine conditioned place preference paradigm, the activity of mPFC pyramidal and NAc GABAergic neurons is causally related to the retrieval of cocaine-associated memory. The findings suggest that the mPFC-NAc circuit can be a potential therapeutic target for the drug addiction.

Although the transcriptional modulator interferon-related developmental regulator 1 (Ifrd1) has been identified as a transcriptional coactivator/repressor in various cells, including bone-resorbing osteoclasts, no attention has been paid to its role in bone-forming osteoblasts. Therefore, in this study we show that Ifrd1 is a critical mediator of both osteoblastogenesis and osteoclastogenesis through its expression in osteoblasts. Ifrd1 deficiency enhanced both osteoblast differentiation and maturation, and increased the expression of Runt-related transcription factor 2 and Osterix. A coculture experiment revealed that Ifrd1 deficient osteoblasts have higher osteoprotegerin (OPG) expression and less ability to support osteoclastogenesis. These findings suggest that Ifrd1 plays a pivotal role in bone homeostasis through its expression in osteoblasts, and represents a therapeutic target for bone disease.

Cocaine-induced neuroplasticity in brain reward circuitry consisting of the ventral tegmental area (VTA), nucleus accumbens and medial pre- frontal cortex is critical for developing cocaine addiction. Recent studies have investigated the involvement of brain areas in addition to the mesocorticolimbic circuitry in cocaine addiction. One such area is the laterodorsal tegmental nucleus (LDT). Cholinergic neurons in the LDT project to the VTA and regulate the activity of dopaminergic neurons. Using the cocaine-induced conditioned place preference (CPP) paradigm in rats, we found that the activity of LDT cholinergic neurons and cholinergic transmission-from the LDT to VTA are critical for the acquisition and expression of cocaine CPP. Moreover, ex vivo electrophysiological analyses revealed that chronic cocaine administration induces plasticity in excitatory synaptic transmission and membrane excitability of LDT cholinergic neurons. Furthermore, noradrenaline, which is released from locus coeruleus axon terminals, attenuated inhibitory synaptic transmission in LDT cholinergic neurons which were obtained from rats that had received chronic cocaine but not saline administrations. This cocaine-induced plasticity in LDT cholinergic neurons may enhance the excitability of these neurons, resulting in changes in the reward circuit activity that might be associated with the development of addicted behaviors induced by cocaine.

A large body of literature indicates that neural adaptations induced by cocaine in the mesocorticolibic system cause addictive behaviors. Emerging evidence suggests that the laterdorsal tegmental nucleus (LDT), which contains cholinergic, glutamatergic and GABAergic neurons and innervates the ventral tegmental area (VTA), might also contribute to the development of cocaine addiction. In this review, we summarize our recent findings showing that neuroplasticity elicited by cocaine administration in LDT cholinergic neurons is involved in the expression of addictive behaviors. Ex vivo electrophysiological recordings obtained from repeatedly cocaine administered rats revealed and increased excitatory synaptic transmission to and enhanced intrinsic membrane excitability in LDT cholinergic neurons. The former depended on enhanced glutamate release probability form presynaptic terminals and the latter was mediated by increased persistent sodium conductance. Additionally, intra-LDT administration of AMPA/HMDA receptor antagonists or a persistent sodium channel blocker attenuated the expression of cocaine-induced conditioned place preference. These findings suggest that chronic cocaine exposure-induced neuroplasticity in LDT cholinergic neurons may activate LDT cholinergic neurons, which in turn may enhance the activity of dopamine neurons in the VTA, leading to the development of cocaine addiction.

Although the involvement and plasticity of the mesocorticolimbic dopamine (DA) system in cocaine-induced addiction have been studied extensively, the role of the brainstem cholinergic system in cocaine addiction remains largely unexplored. The laterodorsal tegmental nucleus (LDT) contains cholinergic neurons that innervate the ventral tegmental area (VTA) and is crucial for regulating the activity of VTA DA neurons, implying that LDT may also be associated with cocaine addiction. In this review, we summarize our recent findings showing that cholinergic transmission from the LDT to the VTA is involved in acquisition and expression of cocaine-induced conditioned place preference and that, after repeated cocaine exposures, these neurons exhibit synaptic plasticity, which is dependent on NMDA receptor activation, nitric oxide production, and the activity of medial prefrontal cortex. The findings strongly suggest that LDT cholinergic neurons may critically contribute to developing cocaine-induced addiction.