Activation of Kv7 channels normalizes hyperactivity of the VTA-NAcLat circuit and attenuates methamphetamine-induced conditioned place preference and sensitization in mice.

The brain circuit projecting from the ventral tegmental area (VTA) to the nucleus accumbens lateral shell (NAcLat) has a key role in methamphetamine (MA) addiction. As different dopamine (DA) neuron subpopulations in the VTA participate in different neuronal circuits, it is a challenge to isolate these DA neuron subtypes. Using retrograde tracing and Patch-seq, we isolated DA neurons in the VTA-NAcLat circuit in MA-treated mice and performed gene expression profiling. Among the differentially expressed genes, KCNQ genes were dramatically downregulated. KCNQ genes encode Kv7 channel proteins, which modulate neuronal excitability. Injection of both the Kv7.2/3 agonist ICA069673 and the Kv7.4 agonist fasudil into the VTA attenuated MA-induced conditioned place preference and locomotor sensitization and decreased neuronal excitability. Increasing Kv7.2/3 activity decreased neural oscillations, synaptic plasticity and DA release in the VTA-NacLat circuit in MA-treated mice. Furthermore, overexpression of only Kv7.3 channels in the VTA-NacLat circuit was sufficient to attenuate MA-induced reward behavior and decrease VTA neuron excitability. Activation of Kv7 channels in the VTA may become a novel treatment strategy for MA abuse.

Melatonin Regulates Neuronal Synaptic Plasticity in the Supramammillary Nucleus and Attenuates Methamphetamine-Induced Conditioned Place Preference and Sensitization in Mice.

Methamphetamine (METH) is an addictive drug that threatens human health. The supramammillary nucleus (SuM) and its neural circuits play key roles in the regulation of spatial memory retrieval, and hippocampal contextual or social memory. Melatonin (MLT), a pineal hormone, can regulate hypothalamic-neurohypophysial activity. Our previous study showed that MLT attenuates METH-induced locomotor sensitization. However, whether MLT regulates SuM function and participates in METH-induced contextual memory retrieval remains unclear. Using a mouse model of METH-conditioned place preference (CPP) and sensitization, we found that METH activated c-Fos expression and elevated calcium (Ca²âº) levels in SuM neurons. Chemogenetic inhibition of SuM attenuates CPP and sensitization. Pretreatment with MLT decreased c-Fos expression and Ca2+ levels in the SuM and reversed METH-induced addictive behavior, effects that were blocked with the selective MT2 receptors antagonist 4P-PDOT and the MT1 receptors antagonist S26131. Furthermore, MLT reduced SuM synaptic plasticity, glutamate (Glu) release, and neuronal oscillations caused by METH, which were blocked by 4P-PDOT. In conclusion, our data revealed that MLT regulates neuronal synaptic plasticity in the SuM, likely through the MLT receptors (MTs), and plays a role in modulating METH-addictive behavior.

Dopamine D1 receptor in orbitofrontal cortex to dorsal striatum pathway modulates methamphetamine addiction.

The orbitofrontal cortex (OFC)-dorsal striatum (DS) is an important neural circuit that contributes to addictive behavior, including compulsive reinforcement, yet the specific types of neurons that play a major role still need to be further elucidated. Here, we used a place conditioning paradigm to measure the conditioned responses to methamphetamine (MA). The results demonstrated that MA increases the expression of c-Fos, synaptic plasticity in OFC and DS. Patch-clamp recording showed that MA activated projection neurons from the OFC to the DS, and chemogenetic manipulation of neuronal activity in OFC-DS projection neurons affects conditioned place preference (CPP) scores. And the combined patch-electrochemical technique was used to detect the DA release in OFC, the data indicated that the DA release was increased in MA group. Additionally, SCH23390, a D1R antagonist, was used to verify the function of D1R projection neurons, showing that SCH23390 reversed MA addiction-like behavior. Collectively, these findings provide evidence for the D1R neuron is sufficient to regulate MA addiction in the OFC-DS pathway, and the study provides new insight into the underlying mechanism of pathological changes in MA addiction.

Inactivation of the Lateral Hypothalamus Attenuates Methamphetamine-Induced Conditioned Place Preference through Regulation of Kcnq3 Expression.

Repeated administration of methylamphetamine (MA) induces MA addiction, which is featured by awfully unpleasant physical and emotional experiences after drug use is terminated. Neurophysiological studies show that the lateral hypothalamus (LH) is involved in reward development and addictive behaviors. Here, we show that repeated administration of MA activates the expression of c-Fos in LH neurons responding to conditioned place preference (CPP). Chemogenetic inhibition of the LH can disrupt the addiction behavior, demonstrating that the LH plays an important role in MA-induced reward processing. Critically, MA remodels the neurons of LH synaptic plasticity, increases intracellular calcium level, and enhances spontaneous current and evoked potentials of neurons compared to the saline group. Furthermore, overexpression of the potassium voltage-gated channel subfamily Q member 3 (Kcnq3) expression can reverse the CPP score and alleviate the occurrence of addictive behaviors. Together, these results unravel a new neurobiological mechanism underlying the MA-induced addiction in the lateral hypothalamus, which could pave the way toward new and effective interventions for this addiction disease.

Astrocyte-derived lactate/NADH alters methamphetamine-induced memory consolidation and retrieval by regulating neuronal synaptic plasticity in the dorsal hippocampus.

Drug memory is associated with drug-taking experience and environmental cues, which mainly contribute to addiction. Recent studies report that glycogenolysis-derived lactate from astrocyte transport to neurons is necessary for long-term potentiation and memory formation instead of its function as an energy substrate. However, the role of astrocyte-neuron lactate transfer in neuronal plasticity and methamphetamine (METH)-induced addiction memory consolidation and retrieval, especially the underlying mechanisms, are not clear. C57BL/6 J mice trained for METH-induced conditioned place preference (CPP) were stereotaxically injected with the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) into the dorsal hippocampus (dHPC) 15 min before training. The CPP score was recorded, and neuronal synaptic plasticity was detected with Golgi staining. The neuronal Ca2+ levels were examined using AAV-GCaMP6 injection. Moreover, monocarboxylate transporters (MCT1, MCT2, MCT4) were inhibited with oligodeoxynucleotides in the dHPC to further prove the METH appetitive memory changes. The data showed that inhibiting lactate transport by microinjection with DAB or monocarboxylate transporter oligodeoxynucleotides in the dHPC completely destroyed METH-induced CPP, reduced Npas4 and other plasticity-associated gene expression and decreased neuronal Ca2+ levels and neuronal arborization and spine density, all of which were fully rescued by L-lactate coadministration except for MCT2-ODN administration. Furthermore, the downstream signaling molecule NADH could mimic lactate's effects and trigger METH CPP by influencing the redox state of neurons and regulating NMDA receptor activity. Collectively, these findings indicate that astrocyte-neuron lactate transfer is crucial for METH-induced memory consolidation and retrieval.