The mechanism of action of aminobutyric acid in substance abuse

The mechanism of action of aminobutyric acid in substance abuse
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 of the past 20 years have focused on the dopamine (DA) transmitter of the midbrain limbic system, the “DA reward pathway” hypothesis [1]. Further studies have found that the ventral tegmental region (VTA) and nucleus accumbens (NAc)-aminobutyric acid (GABA) and their receptors play a key role in the material dependence process [2]. Neurotransmitters such as DA, glutamate, and serotonin (5-HT) regulate substance addictive behavior through interaction with GABA neurons. We reviewed the mechanism of action of this neurotransmitter in addictive behavior and summarized it here.
1. The role of different GABA receptor subtypes in addictive behavior GABA includes two different receptor subtypes. The ion channel-based GABA-A receptor and the second messenger-based GABA-B receptor subtype. Previous studies have focused on the relationship between GABA-A receptors and substance addiction. Studies have found that selective activation of GABA-A receptors increases alcohol intake, while antagonists inhibit alcohol intake. Further genetic studies found that the 31 single nucleotide polymorphisms (SNPs) of the GABA-A2 receptor gene were significantly associated with alcohol dependence [2]. Recent studies have focused on the relationship between GABA-B receptors and heroin addiction. Electrochemical recordings showed that the level of DA transmitter in VTA was significantly increased after injection of heroin in experimental rats, and the effect was blocked or reversed by intravenous injection of GABA-B receptor agonist 2-OH-saclofen. Similarly activation of the GABA-B receptor in the ventral side of the thalamus can also block the self-administration behavior of heroin and drug-induced conditional position preference [3]. To further evaluate the potential value of GABA-B receptor agonists for the treatment of addictive behavior. Simultaneous administration of the GABA-B agonist baclofen and heroin in the test rats reduced heroin-induced DA release, whereas there was no significant change in the self-administration behavior of the rats after administration of the GABA-A receptor agonist. It is suggested that GABA-A agonists do not play an important role in the treatment of addictive behavior. 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 inhibited by activating GABA-B receptors in VTA. However, some researchers have come to different conclusions [4]: ​​Administration of GABA-A receptor antagonists can form a model of self-administration through the mediation of DA neurotransmitters. The reason for this inconsistent conclusion may be due to the different sites of the agonist receptor subtype and the different behavioral sensitization abilities. Further research is needed to confirm the regulation of GABA-A receptors in addictive behavior. In conclusion, different receptor subtypes of GABA play a role in different stages of heroin addiction and withdrawal.

2, GABA-mediated DA de-inhibitor regulation of addictive behavior GABA is the main inhibitory neurotransmitter of the central nervous system, plays an important regulatory role in central nervous activity. Since the activation of opioid receptors inhibits most neurons, the release of opioid-induced DA neurotransmitters is initially presumed to be mediated through some de-suppressive function [5], ie opioid inhibition. GABAergic neurons in VTA reduce GABA release, resulting in increased release of DA inhibitory neurons. This hypothesis was also confirmed by a series of animal experiments. In animal experiments, it was found that systemic administration or direct administration of VTA mimicked heroin addiction, the release of DA was significantly increased, and the release of the inhibitory neurotransmitter GA-BA was reduced [6]. Anatomical evidence [3] also showed that most of the opioid receptors in VTA are located in the GABAergic interneurons, and direct intravenous injection can inhibit the release of GABA. To further understand the relationship between GABA and DA neurotransmitters and self-administration behavior, injection of GABA transaminase inhibitor (GVG) directly into rat NAc, VTA, and globus pallidus (VP) increased extracellular GABA concentration, resulting in heroin-induced The self-administration behavior was significantly inhibited, and the electrochemical signal of DA release was significantly reduced [4]. This in turn provides a basis for GABA to participate in the regulation of DA and thus participate in the formation of substance addiction.

3, GABA-mediated addictive behavior in NAc NAc is an important nuclei of the midbrain-edge DA system, belonging to the forebrain marginal nucleus, located in the ventral striatum, and the bottom is adjacent to the ventral globus pallidus (VP). In NAc, mainly DA and GABAergic neurons. Some researchers [4] speculate that opioid receptor-mediated inhibition of GABAergic neurons may be directly involved in the formation of opioid potentiation effects. DA receptor activation in NAc inhibits GABA release in VTA and VP. This inhibition can be ameliorated by GABA transaminase inhibitors or GABA reuptake inhibitors to increase GABA concentration in VP and VTA, thereby inhibiting heroin-induced self-administration behavior [12]. In summary, GABAergic projection neurons located in NAc may be the final site of action for DA, non-DA neurotransmitters or other neuromodulations [4]. Because there is a positive feedback pathway to promote the release of DA in NAc, that is, the inhibition of GABAergic neurons by opioids and DA transmitters reduces the release of GABA in VTA. Eventually, DA release of DA neurons in VTA increased the release of DA. The above hypothesis suggests that opioid receptors induce opioid addiction behavior by acting on GABAergic interneurons. However, some studies do not seem to fully support this view [7], suggesting that some opioid receptors directly acting on DA neurons in VTA may directly inhibit DA neurotransmitter release. Neuroelectrophysiology showed that the electrochemical signal of DA in heroin self-administration behavior also decreased [11]. Both the increase and decrease in DA can be prevented by the opioid receptor blocker naloxone. These studies suggest that DA neurons in VTA may be simultaneously regulated by both opioid receptor-mediated direct inhibition and GABAergic neuron-mediated indirect de-suppression. The final release of DA depends on the combined effect of these two different mechanisms of action.

4. Interaction between GABAergic neurons and glutamate Glutamate 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. Excitatory neurotoxicity caused by over-activation of glutamate receptors can lead to pathological changes in the nervous system. DA neurons in VTA undergo dual regulation of GABA neurons and the excitatory neurotransmitter glutamate. The latter effect is to release the release of DA from a point-like release to a 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 spontaneous behavior in animals. Preventing the release of presynaptic glutamate can inhibit drug-induced conditioned place preference. To further clarify the role of glutamate in addictive behavior, administration of NMDA receptor antagonists not only inhibits drug-induced conditioned place preference, but also attenuates the learned self-administration behavior. Clinical pharmacology trials have found that injection of NMDA receptor antagonist, methadone, in VTA can alleviate withdrawal symptoms and drug cravings in heroin dependent patients [9]. However, NMDA plays a completely opposite role in NAc and VTA [9]. NMDA receptor antagonists in NAc do not alter the conditional positional preferences acquired in rats. The mechanism of the difference in the mechanism of action of glutamate at different sites has not been fully elucidated. According to anatomy [4, 16]: Probably because the NMDA receptor in NAc is mostly located on the synapse of GABA neurons, while the NMDA receptor in VTA is located in the DA neuron synapse. The glutamatergic nerve fibers in the prefrontal cortex of the brain project into the NAc to form an excitatory synaptic connection, thus activating the glutamate receptor and exciting the GABA neurons, causing an increase in their functional up-regulation release, which in turn inhibits DA secretion. Glutamate neurons in VTA directly promote the release of DA by activating NMDA receptors, and induce addictive behavior. Exogenous opioids compete with glutamate for GABAergic neurons in NAc. If GABA neurons are maximally inhibited by exogenous opioids, the excitatory neurotransmitter, glutamate, loses its antagonistic effect on addictive behavior in NAc.

5. Interaction of GABAergic neurons with 5-HT Some studies have shown that 5-HT transmitters are also involved in the regulation of opioid addiction behavior. Rapid administration of the drug increases the concentration of 5-HT in the interbrain and increases the release of 5-HT in the dorsal raphe nucleus and NAc [10]. Injecting the drug directly into the dorsal nucleus can also increase the release of 5-HT in NAc. Therefore, it is speculated that 5-HT regulation of opioid addiction also has a de-inhibition effect mediated by GABA neurons. Animal experiments have shown that different receptor subtypes play different roles in addictive behavior [4]. 5-HT1 receptor blockers can completely alter the inhibition of flupiramine to restore self-administration behavior. The opposite 5-HT3 receptor blocker inhibits DA release and conditional positional preference. The final effect on opioid addiction behavior depends on the joint regulation of 5-HT1 and 5-HT3 receptors on GABA neurons.

6. Prospects for the treatment of addictive behavior in GABA There is ample evidence in animal and human trials that GABA-B agonists can reduce the craving for drugs [17]. A preliminary study of heroin addicts found that giving baclofen significantly reduced the craving for addictive substances and played a role in clinically alcohol-dependent patients. Some studies have shown that [18]: for small doses of cocaine in rodents, baclofen can reduce the craving for addictive substances, but in the case of high doses of cocaine (1.51 mg / kg), for addictive substances There is no obvious inhibition of craving. After rapid withdrawal from cocaine-administered mice, the basal secretion level of GABA in NAc was significantly increased. This increase in basal secretion may be due to the desensitization mechanism of GABA-B autoreceptors [19]. Different doses of GABA agonists have different inhibitory effects on addictive behavior. Low doses of baclofen (0.5 mg/kg) are given for 5 consecutive days to treat addictive behavior. Two days after withdrawal, the rats resume self-administration. Behavior, while high-dose baclofen (1.0 mg/kg) was discontinued for 5 consecutive days, and did not resume self-administration [20]. This may be related to different conduction pathways for different doses of GABA-B agonist activation. In addition, other side effects caused by GABA-B antagonists are also specific problems affecting drug development.

7, summary
At present, there is a complex neural biochemical loop in the formation and regulation of addictive behavior. DA and other neurotransmitters ultimately influence addictive behavior through different mechanisms of action through the regulation of GABAergic neurons [4]. Through the neural biochemical loop, we summarize the regulatory mechanisms of addictive behavior as follows.
1 Activation of receptors and receptors located in different parts of GABAergic neurons can lead to elevation and down-regulation of DA neurotransmitters, resulting in reward and aversion effects, respectively.
2 Activation of opioid receptors can inhibit the secretion of GABA neurons, and the release of DA neurons after depletion of GABA release increases the activation of the reward pathway [11-13].
3DA and opioids synergistically inhibit GABA interneurons in NAc to promote addictive behavior.
Glutamate neurons in 4VTA promote the development of addictive behavior by activating DA neurons, while glutamatergic neurons in NAc inhibit the development of addictive behavior by activating GABAergic neurons.
The 5-HT neurotransmitter in 5NAc regulates addictive behavior by acting on GABAergic neurons through different receptor subtypes [14-15].
In short, the mechanism of substance addiction is still complicated, not only can be completely explained by these neurotransmitter systems, but also may be related to other neural mechanisms [19]. Existing research has only made some initial progress, and most of the doctrines 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 behavior and drug development to truly solve the social problems caused by drug abuse.

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