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Material addiction has now become a global problem. A variety of neurotransmitters are involved in the formation, withdrawal, and relapse of substance addiction. The research hotspots in the past 20 years have mainly focused on the dopamine (DA) transmitter in the limbic system of the midbrain, namely the "DA reward pathway" hypothesis [1]. At present, further studies have found that GABA and its receptors in the ventral dorsal cover area (VTA) and nucleus accumbens (NAc) of the midbrain play a key role in the process of substance dependence [2]. Neurotransmitters such as DA, glutamate, and serotonin (5-HT) regulate substance addiction through interaction with GABA neurons. We reviewed the mechanism of action of this neurotransmitter in addictive behaviors, and summarize it here.
1. The role of different GABA receptor subtypes in addictive behavior GABA includes two different receptor subtypes. GABA-A receptors dominated by ion channels and GABA-B receptor subtypes dominated by second messengers. Previous studies have focused on the relationship between GABA-A receptors and substance addiction. Studies have found that selective activation of GABA-A receptors can increase alcohol intake, while antagonists can inhibit alcohol intake. Further genetic studies have found that 31 single nucleotide polymorphic sites (SNPs) of the GABA-A2 receptor gene have a significant correlation with alcohol dependence [2]. In recent years, more research has focused on the relationship between GABA-B receptors and heroin addiction. Electrochemical records show that the content of DA transmitters in VTA of experimental rats is significantly increased after injection of heroin, while intravenous injection of GABA-B receptor agonist 2-OH-saclofen can block or reverse this effect. Similarly, activation of the GABA-B receptor on the ventral thalamus can also block heroin's self-administration behavior and drug-induced conditioned position preference [3]. To further evaluate the potential value of GABA-B receptor agonists for the treatment of addictive behaviors. Administration of GABA-B agonist baclofen and heroin to test rats simultaneously can reduce the DA release caused by heroin, while the self-administration behavior of rats after GABA-A receptor agonist administration did not change significantly. It is suggested that GABA-A agonists do not play an important role in the treatment of addictive behaviors. Systemic administration of rats or direct injection of GABA-A agonists in VTA can increase the release of DA in NAc by activating type A receptors, and this effect can also be suppressed by activating GABA-B receptors in VTA. However, some researchers have drawn different conclusions [4]: ​​GABA-A receptor antagonist administration can form a self-administration model through the DA neurotransmitter. The reason for this inconsistent conclusion may be due to the different sites of the activated receptor subtypes and the different behavioral sensitization capabilities. Further research is needed to confirm the regulatory role of GABA-A receptors in addictive behaviors. In short, different GABA receptor subtypes play a role in different stages of heroin addiction and withdrawal.
2. GABA-mediated DA deinhibitors regulate addictive behavior. GABA is the main inhibitory neurotransmitter in the central nervous system and plays an important role in regulating central nervous system activity. Since the activation of opioid receptors has an inhibitory effect on most neurons, the release of opioid-induced DA neurotransmitters was initially speculated to be mediated by some de-suppression function [5], that is, opioid inhibition In VTA, GABAergic neurons reduce GABA release, which increases the release of DA neuron release inhibition. This hypothesis has also been confirmed through a series of animal experiments. In animal experiments, it was found that systemic administration or direct administration in VTA mimics heroin addiction, the release of DA increased significantly, and the release of inhibitory neurotransmitter GA-BA decreased [6]. Anatomical evidence [3] also shows that most of the opioid receptors in VTA are located in GABAergic intermediate neurons, and direct intravenous injection of drugs can inhibit the release of GABA. In order to further understand the relationship between GABA and DA neurotransmitters and self-administration behavior, injecting GABA transaminase inhibitor (GVG) directly into the rat NAc, VTA, Pallidum (VP) increased the concentration of extracellular GABA, resulting in heroin-induced Self-administration behavior was obviously inhibited, and the electrochemical signal recorded by DA was significantly reduced [4]. This in turn provides a certain basis for GABA to participate in the regulation of DA, thereby participating in the formation of substance addiction.
3. GABA-mediated addictive behavior in NAc NAc is an important nucleus of the midbrain-limb DA system, belonging to the forebrain marginal nucleus, located on the ventral side of the striatum, and the bottom is adjacent to the ventral pale ball (VP). NAc is mainly DA and GABAergic neurons. Some researchers [4] speculate that perhaps the opioid receptor-mediated inhibition of GABAergic neurons is directly involved in the formation of opioid strengthening effects. The activation of DA receptors in NAc can inhibit the release of GABA in VTA and VP. This inhibitory effect can be improved by increasing the GABA concentration in VP and VTA by GABA aminotransferase inhibitors or GABA reuptake inhibitors, thereby inhibiting heroin-induced self-administration behavior [12]. In short, the GABAergic neurons located in NAc may be the final action sites of DA, non-DA neurotransmitters or other neuromodulation [4]. Because there is a positive feedback pathway to promote the release of DA in NAc, that is, opioids and DA transmitters jointly inhibit GABAergic neurons and reduce the release of GABA in VTA. In the end, the DA release of DA neurons in VTA inhibits the increase of DA release. The above hypothesis believes that opioid receptors induce opioid addiction by acting on GABAergic intermediate neurons. However, some research conclusions do not seem to fully support this view [7], that some opioid receptors directly act on DA neurons in VTA, which may directly inhibit the release of DA neurotransmitters. Neuroelectrophysiology showed that the electrochemical signal of DA also decreased in heroin's self-administration behavior [11]. Both the increase and decrease of DA signal can be blocked by the opioid receptor blocker naloxone. These studies indicate that DA neurons in VTA may be simultaneously regulated by opioid receptor-mediated direct inhibition and GABAergic neurons-mediated indirect de-suppression. The final amount of DA released depends on the combined effect of these two different mechanisms of action.
4. The interaction of GABAergic neurons and glutamate. Glutamic acid is the main excitatory neurotransmitter in mammals. On the one hand, it participates in normal neurophysiological activities and plays an important role in neural plasticity. On the other hand Excitatory neurotoxicity caused by excessive activation of glutamate receptors can cause pathological changes in the nervous system. DA energy neurons in VTA are double regulated by GABA neurons and excitatory neurotransmitter glutamate. The latter's role is to change the release of DA from point-like release to cluster-like release [8]. Pharmacological experiments have found that activation of glutamate receptors in VTA can cause an increase in the release of DA transmitters in NAc, and animals exhibit spontaneous seeking behavior. Preventing the release of presynaptic glutamate can inhibit drug-induced conditioned positional preferences. In order to further clarify the role of glutamate in addictive behaviors, the administration of NMDA receptor antagonists not only inhibited the drug-induced conditioned place preference, but also attenuated the learned self-administration behavior. Clinical pharmacological tests have found that injecting NMDA receptor antagonist-methafin into VTA can relieve withdrawal symptoms and drug cravings of heroin addicts [9]. But NMDA plays a completely opposite role in NAc and VTA [9]. NMDA receptor antagonists in NAc cannot change the conditioned positional preferences learned in rats. The differential mechanism of glutamate in different parts has not been fully elucidated. According to anatomical speculation [4, 16]: it may be that most of the NMDA receptors in NAc are located at the synapses of GABA neurons, while the NMDA receptors in VTA are located at the synapses of DA neurons. The glutamatergic nerve fibers in the prefrontal lobe of the brain project onto the NAc to form excitatory synaptic connections. Therefore, activation of glutamate receptors excites GABA neurons, which increases the release of up-regulated functions and inhibits DA secretion. The glutamatergic neurons in VTA directly promote the release of DA by activating NMDA receptors and induce addictive behaviors. Exogenous opioids compete with glutamic acid for GABAergic neurons in NAc. If GABA neurons are suppressed to the greatest extent by exogenous opioids, the excitatory neurotransmitter glutamate loses its antagonistic effect on addictive behavior in NAc.
5. Interaction between GABAergic neurons and 5-HT Some studies have shown that 5-HT transmitters are also involved in the regulation of opioid addiction behaviors. Rapid administration of drugs can increase the concentration of 5-HT in the diencephalon and increase the release of 5-HT in the dorsal raphe nucleus and NAc [10]. Direct injection of drugs into the dorsal spinal nucleus can also increase the release of 5-HT in NAc, so it is speculated that the regulation of 5-HT on opioid addiction behavior also has a GABA neuron-mediated de-suppression effect. Animal experiments show that different receptor subtypes play different roles in addictive behaviors [4]. 5-HT1 receptor blockers can completely change the inhibitory effect of phenfluramine and restore self-administration. In contrast, 5-HT3 receptor blockers inhibit DA release and conditioned positional preference. The final effect on opioid addiction behavior depends on the results of 5-HT1 and 5-HT3 receptors co-regulating GABA neurons.
6. Prospects for the treatment of addictive behaviors by GABA There is a large amount of evidence in animal experiments and human trials that GABA-B agonists can reduce the craving for drugs [17]. A preliminary study on heroin addicts found that baclofen can significantly reduce the craving for addictive substances, and it also plays a role in clinically alcohol-dependent patients. Some studies have shown [18]: For rodents injecting cocaine in small doses, baclofen can reduce the craving for addictive substances. There is no obvious inhibition of craving. After continuous withdrawal of cocaine-administered mice, the basal secretion level of GABA in NAc increased significantly. This increase in basal secretion level may be due to the regulation of the desensitization mechanism of the GABA-B autoreceptor [19]. Different doses of GABA agonists have different inhibitory effects on addictive behaviors. Low-dose baclofen (0.5 mg / kg) was given for 5 consecutive days to treat addictive behaviors, and rats resumed self-administration two days after drug withdrawal Behavior, and the large dose of baclofen (1.0 mg / kg) did not resume its self-administration behavior after stopping the drug for 5 consecutive days [20]. This may be related to the activation of different conduction pathways by different doses of GABA-B agonists. In addition, other side effects caused by GABA-B antagonists are also specific issues affecting drug development.
7. Summary
It is currently believed that there are complex neurobiochemical circuits in the formation and regulation of addictive behaviors. DA and other neurotransmitters ultimately influence addictive behavior through the regulation of GABAergic neurons through different mechanisms of action [4]. Through the neurobiochemical circuit, we summarize the regulation mechanism of addictive behavior as follows.
â‘ Activation of receptors and receptors located in different parts of GABAergic neurons can lead to the rise and downregulation of DA neurotransmitters to produce reward and aversion effects, respectively.
â‘¡The activation of opioid receptors can inhibit the secretion of GABA neurons. After the release of GABA is reduced, the release of DA neurons can be inhibited and the activation of reward pathways can be increased [11-13].
â‘¢ DA and opioids can synergistically inhibit GABA interneurons and promote addictive behavior in NAc.
â‘£Glutamate neurons in VTA promote the occurrence of addictive behaviors by activating DA neurons, while glutamate neurons in NAc inhibit the occurrence of addictive behaviors by activating GABAergic neurons.
⑤ 5-HT neurotransmitters in NAc act on GABAergic neurons through different receptor subtypes to regulate addictive behavior [14-15].
In short, the mechanism of substance addiction is still very complicated, not only can these neurotransmitter systems be fully explained, but may also be related to some other neural mechanisms [19]. Existing research has only made some preliminary progress, and most of the theories are still in the hypothesis stage. Only by understanding the mechanism of substance addiction can we provide a theoretical basis for the treatment of addictive behaviors and drug development to truly solve the social problems caused by drug use.
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