A study led by researchers at the Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, has shown that amygdala kappa-opioid receptor (KOR)-dependent upregulation of glutamate transporter 1 (GLT1) mediates depressive-like behaviors in mouse models of opiate abstinence.

"This is the first study to elucidate the molecular mechanisms and the neural circuitry by which KORs modulate the depression associated with opiate withdrawal," said study leader Jing-Gen Liu, a professor in the Key Laboratory of Receptor Research at SIMM in Shanghai.

This finding has important treatment implications, as it identifies a promising new therapeutic target for preventing relapse in humans undergoing opiate withdrawal, in whom depression is a major cause of failure, the authors reported in the November 2, 2021, edition of Cell Reports.

Despite this, antidepressant treatments are not normally prescribed in recovering addicts and the biological bases of depression following opiate withdrawal remains poorly understood.

"Antidepressants are not regularly prescribed anti-addiction medications, although if recovering patients show depressive symptoms or anxiety, physicians in China may prescribe serotonin reuptake inhibitors (SSRIs) to reduce mood problems," said Liu.

Interestingly, "mirtazapine, a unique FDA-approved tricyclic antidepressant, has been shown to reduce methamphetamine withdrawal symptoms, including agitation, anxiety, irritability, anhedonia, suicide ideations, etc," he told BioWorld Science.

Regarding the biological basis of aversive depressive symptoms in opiate abstinence, KORs are widely expressed in the brain's reward circuitry, where they play a key role in regulating aversive emotions.

For example, one well-documented neuronal adaptation following chronic opiate or psychostimulant use concerns increased signaling by dynorphin, "the endogenous opioid peptide that activates KORs within the brain's reward circuit," noted Liu.

KORs also participate in opiate-abstinence-induced depression, with KOR antagonism or gene knockout having been shown to reduce emotional upset in heroin withdrawal studies.

However, the molecular mechanisms and neuronal circuitry via which KORs modulate aversive emotions in opiate abstinence remain unclear.

Nevertheless, emotional disorders and drug addiction are both thought to involve dysfunction in the brain's reward circuitry. The nucleus accumbens (NAc) has been shown to play a central role in depression pathophysiology.

Attenuation of NAc dopaminergic transmission may be critical for depression and there is evidence that opiate withdrawal-induced depressive-like behaviors are linked to decreased NAc dopamine (DA) release, which is modulated by KORs and inputs from other brain regions.

Attenuating excitatory drive onto the NAc can lead to depression, while dysregulated amygdala circuitry has been implicated in emotional regulatory disorders, including depression.

Amygdala KORs may also influence DA release in the NAc by regulating glutamatergic amygdala NAc inputs, contributing to morphine-abstinence-induced depressive-like behaviors.

In their new Cell Reports study, Liu and his team investigated whether presynaptic suppression of glutamatergic amygdala afferents from the amygdala to the NAc by KORs may be involved in such depressive behaviors.

In addition, they explored the molecular mechanisms whereby amygdalar KORs inhibited glutamatergic amygdala afferents to the NAc.

They discovered that morphine abstinence activated KORs by increasing expression of the KOR ligand dynorphin in the amygdala. This facilitated GLT1 expression via p38 mitogen-activated protein kinase (MAPK) activation.

"Morphine abstinence was shown to activate KORs by increasing endogenous KOR ligand dynorphin expression in the amygdala, which in turn increased GLT1 expression," said Liu.

Moreover, upregulation of GLT1 expression was shown to contribute to opiate-abstinence-elicited depressive-like behaviors through modulating amygdalar glutamatergic inputs to the NAc.

"Substantial evidence indicates that enhancement of excitatory synaptic transmission from the basolateral amygdala to the NAc facilitates the rewarding effect of opiates, whereas inhibition of the glutamatergic projections from amygdala to the NAc encodes aversive emotion of opiate abstinence," said Liu.

"This is a significant finding, as it reveals that increased GLT1 expression is responsible for the shift of amygdala-NAc projections from reinforcement of reward to facilitation of aversive emotions by attenuating amygdalar glutamatergic inputs to NAc.

Importantly, intra-amygdala injection of the experimental selective GLT1 inhibitor, dihydrokainic acid (DHK), or genetic knockdown of GLT1 expression in the amygdala, significantly suppressed morphine-abstinence-induced depressive-like behaviors.

"We found that both intra-amygdala injection of DHK and genetic knockdown of GLT1 using short hairpin RNA (shRNA) abolished morphine-abstinence-induced depressive-like behaviors," said Liu.

"To determine the function of GLT1, both depression-related anhedonia and behavioral despair mouse models were used," he said.

In addition, pharmacological and pharmacogenetic activation of amygdala-NAc projections was shown to prevent morphine-abstinence-induced behaviors.

"These data indicate that amydala-NAc projections play a crucial role in regulating the aversive emotions associated with morphine abstinence," noted Liu.

"We demonstrate that attenuation of the activity of amygdala-NAc projections contributes to morphine abstinence-induced depressive-like behaviors, while the attenuation of amygdala-NAc projections is attributed to upregulation of GLT1 expression in the amygdala in a KOR-dependent manner." /p>

Collectively, these study findings provide key molecular and circuit insights into the mechanisms of depression associated with opiate abstinence and have implications for antidepressant drug development.

Drug development

In this respect, "it will be important to verify the role of KORs and amygdala-NAc circuit in the depressive-like behaviors associated with other drugs, such as cocaine and methamphetamine," said Liu.

"KORs antagonists are currently being considered for treating major depressive disorder, for which it would be interesting to further examine the role of the amygdala-NAc circuit."

Moreover, previous studies have shown that the dynorphin/KORs system is involved in stress-induced reinstatement of drug seeking behavior, Liu noted.