Brain Mechanism of Addiction Drug Psychological Dependence and Recurrence

Brain Mechanism of Addiction Drug Psychological Dependence and Recurrence

Focusing on the relationship between psychological factors such as learning, memory, emotion and stress and recurrence, applying opioid psychological dependence to study conditional position preference, conditional position aversion, Morris water maze quantification of drug motivation model, behavioral and conditional behavior sensitivity Various animal behavior models, such as emotion-related learning, memory in addictive behavior, changes in the activity of different nucleus and neurotransmitter systems, susceptibility to stress-related factors, natural rewards In the comparative study of memory related to addiction drug rewards, a series of studies on the psychological dependence of stress and memory-related drugs and the brain mechanism of recurrence were conducted.

Keywords learning and memory, stress, psychological dependence, addiction susceptibility, drug motivating, natural reward.

With the gradual deepening of the understanding of the biological basis of addictive behavior, the psychological dependence of drug addiction-related craving and relapse behavior has received more and more attention. Under the action of addictive drugs, the long-term adaptive changes of the nervous system, this long-term neurological adaptive changes, become the material basis of dependent behaviors characterized by compulsive drug withdrawal and relapse. In particular, the rapid formation, long-term maintenance and high arousal of abnormal learning and memory have an important relationship with the occurrence and development of addictive behavior. This connection is reflected in different aspects of behavior, cellular molecules and gene expression and regulation. This topic focuses on the relationship between psychological factors such as learning, memory, emotion and stress and recurrence, and establishes a variety of animal behavior models of opioid dependence. On this basis, the role of emotion-related learning, memory in addictive behavior, the changes in the activity of different nucleus and neurotransmitter systems, the susceptibility to addiction to stress-related factors, natural rewards and addiction In the comparative study of drug reward related memories, a series of studies on the psychological dependence of stress and memory related drugs and the brain mechanism of recurrence were conducted. The research content mainly includes the following aspects: 1) The relationship between spatial and positive and negative emotion-related learning and memory and the acquisition and maintenance of the addictive behavior and the environmentally-regulated complex engine; 2) habitualized learning and habit formation and opioid psychology Dependent relationship; 3) the influence of environmental stress on the acquisition and maintenance of addictive behavior and its central mechanism; 4) the behavioral genetic basis of susceptibility to addiction and its interaction with acquired environmental factors; 5) learning and memory activities and Comparative study of drug psychological dependence in rats and chick models; 6) Functional imaging studies of emotional abnormal activation in human addiction patients. Exploring the essential relationship between environmental memory or stress events and the development and activation of heart addiction, and studying its biological nature to find effective methods of confrontation.

1 The role of learning and memory in addictive behavior and its related brain structure

1.1 The relationship between spatial learning and memory ability and addictive behavioral effects shows that long-term adaptive changes in the neurotransmitter system in the brain caused by addictive drugs, most of which are important for activation and molecular changes in the learning and memory loops in the brain. Coincident. The abnormal learning hypothesis of drug addiction believes that the formation, maintenance and relapse behavior of compulsive drug-seeking behavior have an important relationship with the abnormal learning and memory formed by the action of addictive drugs. While the drug produces its addictiveness, it also changes the learning and memory molecules in the brain of the animal and affects the learning ability of the animal. This ability to learn and remember under the influence of addictive drugs can make the environmental cues and medication motives of addiction prominent, affecting the retention and relapse behavior of addictive behavior. Our laboratory work has shown that rats with high spatial learning ability have significantly higher CPP effects than those with low spatial learning ability, suggesting that at least some of the same neural mechanisms exist in the two [1]. The study also showed that the drug affected the animal's ability to acquire Morris water maze learning tasks in a dose-dependent manner. The effect of drugs on the spatial learning ability of animals is partly regulated by the choline system of the hippocampus-sept. Scopolamine aggravated the damage of spatial learning ability by 10 mg/kg drug. This effect can be partially reversed by the cholinesterase inhibitor physostigmine [2], suggesting that the drug-induced damage to the spatial learning ability of the animal is partially affected by choline M. Therapeutic effects and prospects of systemic drugs in addictive behaviors and learning and memory impairment (Figure 1, Figure 2)

1.2 Emotional related learning and memory and drug addiction

1.2.1 Negative emotional memory and addictive behavioral effects and their brain mechanisms to escape the negative emotions caused by drug withdrawal is one of the important reasons for the occurrence of compulsive drug-seeking behavior. The emergence of unconditional negative emotions or the arousal of conditional negative emotions in abstinence plays an important role in the emergence of addictive drug relapse behavior. We used conditional position aversion (CPA) as a behavioral model of negative emotional state in drug withdrawal, studying the brain structure and neurotransmitter basis of CPA formation and expression. The study found that low-dose naloxone can induce CPA effect in rats treated with drugs; meanwhile, the expression of c-fos increased in the central amygdala (CeA), indicating that CeA is involved in the aversion effect induced by drug withdrawal [3]. In addition, in the functional nuclear magnetic resonance study of heroin addiction patients, negative emotion pictures induced abnormal activation of the ventromedial prefrontal cortex (VMPFC), and the central amygdala activation was weakened [4] (Fig. 3). This indicates that the VMPFC-CeA loop participates in the generation of unconditional negative emotions and aversive effects induced by drug withdrawal. To confirm the specific neural mechanisms involved in negative emotions in CeA, we used 6-OHDA-specific DA neurons that destroyed CeA. It was found that the DA system that destroyed CeA significantly inhibited the formation of CPA (Fig. 4), indicating that the dopamine system of CeA is involved in the acquisition of CPA effect [5]. The study also found that antagonizing the D1 receptor of CeA can block the formation of CPA, while blocking the D2 receptor has no significant effect [6] (Fig. 5). These results indicate that the D1 receptor of the central amygdala is involved in the generation of aversive effects caused by drug withdrawal. Studies have also shown that, except for the DA system, the glutamate system is also involved in the process of negative emotions. The NMDA receptor antagonist MK-801 blocks the withdrawal of acute drug substances, resulting in the acquisition of CPA effects, but does not affect this effect. Expression [7]. The results show that the glutamate system promotes drug withdrawal leading to aversive emotions, and when aversive emotions are generated, the conditional arousal is not regulated by the glutamate system, suggesting the arousal of conditional negative emotions. There may be different neural mechanisms for the generation of conditional negative emotions, and the specific mechanism of action remains to be further studied. Depression and drug addiction have significant comorbidities. Although the withdrawal symptoms caused by various addictive drugs are significantly different, their depressive mood and behavioral performance are the same. It suggests that the depressive neurological changes that occur under the withdrawal of addictive drugs may be closely related to the relapse motivation after withdrawal. The study found that the depression state weakened the establishment of drug CPP; the nucleus accumbens injection of D1 receptor agonist SKF38393 significantly reversed the effect of depression on the establishment of drug CPP, and the D2 agonist quinpirole had no significant effect (Fig. 6). There was no significant effect of the D1 agonist SKF38393 and the D2 agonist quinpirole in the globus pallidal area [8]. The results suggest that the weakening effect of depression on drug reward learning is mediated by the D1 receptor in the ventral nucleus of the ventral nucleus of the midbrain, while the nigrostriatal striatum DA neurotransmission pathway is not involved in this process. . More in-depth research on the interactions between depression and addiction and its mechanisms is underway. 1.2.2 Positive Emotional Memory and Drug Addiction Effect The positive emotional experience of pursuing addictive drugs is the initiating factor for the use of addictive drugs. Abnormal learning, memory acquisition and consolidation enhanced by pathological positive emotions are prerequisites for addiction, and the basolateral amygdala plays an important role in emotional related memory. Our experiment used a conditional position preference (CPP) as a positive emotion study model to investigate the role of DA afferent fibers in the basolateral amygdala in memory consolidation of the drug CPP effect. It was found that the selective D1 receptor antagonist SCH23390 was administered to the basolateral amygdala immediately after the drug CPP training. The CPP effect of the drug was significantly inhibited, and the effect was not observed after 2 hours of training, suggesting activation of the D1 receptor system. Participate in the consolidation process of drug CPP memory. Interfering with this memory consolidation process can significantly abolish the addictive behavioral effects of drugs [9]. The role of the DA receptors in the basolateral amygdala and the central amygdala, both in the extraction and re-consolidation of positive emotional memory, is under investigation. There are significant individual differences in the Spiritual Reward CPP effect. We applied gene chip technology to investigate the differences in gene expression in the brain of rats with high and low spiritual reward CPP expression. It was found that 45 gene sequences were involved in the expression of CPP effect, 29 of which were down-regulated by the D1 receptor antagonist SCH23390 and caused a significant decrease in the drug CPP effect in rats (Fig. 7). Among the 29 differentially expressed genes detected, cluster analysis revealed that there are two types of susceptibility genes for rat mental reward effects, one is the sequence encoding cell structure and non-immune function-related protein, and the other is A sequence encoding an immune function-related protein. It suggests that the drug as an exogenous substance can regulate the immune system and neuroendocrine function, which in turn affects the drug-reward CPP effect. Among the above 29 differentially expressed gene sequences, 7 sequences are new gene sequences not registered in GENDBANK [10]. Since there are many common neural foundations for the drug addiction reward and the natural reward process, it is very difficult to find a therapeutic drug that is relatively specific and has no significant effect on the natural reward. The acquisition of positive emotional memory is the precondition for the development of addiction. It is an effective way to control the drug addiction by controlling the metabolism of addictive drugs to reduce the mental reward effect. Cocaine hydrolase (CocE) accelerates the metabolism of cocaine. We transfected CocE cDNA into transgenic rats to investigate the effects of cocaine on the metabolism and behavioral effects of cocaine. The results showed that the enzymatic activity of rat plasma was 5th after transfection. It increased to 3000 times in ~7 days, the concentration reached 100mU/ml, and the half-life was 33 hours. The activity of this enzyme is equivalent to the action of 3mg/kg purified cocaine hydrolase, which can significantly enhance cocaine metabolism, increase drug plasma clearance, and reduce the mental excitability and cardiovascular effects of cocaine (Figure 8) [11]. The above results suggest that gene therapy methods for accelerating the metabolism of addictive drugs through transgenic technology have a good clinical application prospect. 1.3 Brain mechanism of chicken addiction behavior Although mammals are commonly used as experimental subjects in drug addiction studies, the reward and addictive effects of addictive drugs are among other lower organisms (including birds). It also exists. Chicks have strong visual discrimination, premature nervous system, and the striatum dopamine system is very developed, which is convenient for nerve structure research. Previous studies in our laboratory have shown that dark-incubation of chicken embryos, behavioral damage in passive avoidance tasks and discrimination tasks after birth, can be significantly reversed by exposure to light or corticosterone on E19-20 days; corticosterone receptors The antagonist RU38486 and the protein synthesis inhibitor anisomycin can reverse the memory retention promoted by corticosterone or light, suggesting that corticosterone and light-promoted chick memory remain mediated through corticosterone receptors and affect chick growth through corresponding protein synthesis. Completion of post-memory tasks [12~14]. At the same time, our laboratory also established a associative learning and memory model of chickens under the action of drugs, linking the spiritual reward effect produced by drugs with small plastic beads of specific colors, and the psychomotor excitability generated by drugs through the chicks' beads Behavior is used to examine the neurobiological mechanisms of addiction-related learning and memory. Studies have found that day-old chicks can form significant CPP effects and psychomotor excitability and behavioral sensitization effects. The dopamine transporter antagonist nomifenxin significantly increased the spontaneous activity of the drug-treated chicks [15], and the dopamine D1 receptor antagonist SCH23390 blocked the drug-induced chick CPP expression, while the D2 receptor antagonist Lee has no effect [16]. This indicates that dopamine D1 receptors are involved in the association learning of the drug spirit reward effect of chickens. Further studies have found that chicks' olfactory lobes (LPO) and medial medial striatum ventral nucleus (IMHV) play an important role in conditional positional preference and conditional psychoexcitability, in which D1 and glutamate of LPO The NMDA receptor and the NMDA receptor of IMHV are involved in the above two associative learnings (Fig. 9), while the D2 receptor of LPO participates in the associative learning of mental excitability, while the D1 receptor of IMHV participates in the association of spiritual rewards. Learning (Figure 10) [17]. The above results suggest that there is a separation effect between the associative learning of the drug spirit reward and the associative learning of the excitatory drug conditional psychomotor.

2 Stress, susceptibility and drug addiction

2.1 Novel Seeking and susceptibility to addictive drugs The novel seeking behavior of animals is equivalent to the human sensory seeking state. The novel seeking behavior of animals increases the chances of animals exploring new environmental things and is related to the activity of the midbrain DA system, which is important in the susceptibility to addiction. The amount of animal movement in an animal's novel environment does not represent the level of novel seeking ability, which is mixed with the animal's stress response in a novel situation. In order to better study the relationship between novel seeking and addiction, we used the Morris water maze to eliminate the differences in the stress response of animals through continuous adaptation, and then added novel objects in the maze to establish a behavioral model for measuring novel seeking. Studies have shown that the CPP effect of novelly sought-up rat drugs is stronger, while the spontaneous movement in the novel environment has no significant correlation with drug CPP (Figure 11), indicating that novel seeking behavior can effectively predict animal addiction drug rewards. effect. Further studies have shown that high-innovation-seeking rats have lower CPP effects in their novels, both in their young and mature ages, and are more novel (Fig. 12), indicating that novel approaches to different stages of development can be Predicting the addictive susceptibility of animals [18]. The study also found that the younger and higher-seeking rats in the young age had a stronger CPP effect after the age-inducing period [19]; ​​considering the animal's novel seeking behavior and human sensory seeking behavior, there is an important relationship between the same organism. Based on the basics of research, the above research results provide a basis for early detection, screening and social control of people with addiction.

2.2 The impact of environmental stress on drug addiction and its mechanism

2.2.1 Stress and addictive drugs The mental excitatory exercise effect stress can not only induce relapse of addicted animals after withdrawal, but also promote the occurrence and development of addiction. Our study showed that rats with higher spontaneous motility (HR and LR rats) in a mildly stressed environment had higher acute psychomotor motility and the animals were more sensitive in a shorter period of time. Reaction. At the same time, the animals remain in a state of higher mental excitement under continuous administration. After long-term withdrawal, animals with higher stress response still maintain a higher level of psychomotor excitatory effects [20]. The above findings consistently suggest that animals with a higher susceptibility to stress are more addictive and more likely to relapse. The study also found that exogenous behavioral stress, such as social crowding procedures, can significantly increase the acute excitatory effects of the drug, but there are significant individual differences, in which HR rats have a greater increase in the drug excitatory effect, while LR is larger. This effect does not exist in rats (Figure 13). The results showed that the stress program not only facilitated the psychotic stimulatory effect of the drug as a whole, but also expanded the individual differences in HR and LR rats in the pharmacokinetic excitatory effect [21] (Fig. 14). These findings suggest that the combined effects of innate and acquired factors determine the ultimate susceptibility of animals to addictive drugs.

2.2.2 Central mechanism of stress regulation and drug motivation

Compulsive drug-seeking behavior is an essential feature of addiction. Animals pursue drug use at all costs after developing drug-dependent behavior. Our laboratory established the Morris Maze quantification motivation model for the first time based on the principle of anti-vigor and anti-vibration. The model measures the intensity of compulsive drug behavior in addicted rats by confrontation with survival and drug motivation. The results showed that in the early stage of addiction, the drugs and corticosterone were repeatedly administered at the same time, the latency of the rats looking for the platform was significantly prolonged, the escape behavior of the rats was weakened, and the drug continued to increase the drug behavior after withdrawal (Figure 15). [twenty two]. It is suggested that the stress state enhances the animal's motivation for drug use. Hippocampus is a key brain region regulating stress response. The changes in synaptic plasticity of hippocampal neurons play an important role in the generation and triggering of compulsive drug-seeking behavior. We further investigated the effects of stress and drugs on synaptic potency in the hippocampal CA1 region of living animals, and explored the central nervous mechanisms of stress-regulating drug-drug motivation. The results showed that stress facilitated the reduction of synaptic efficacy caused by low-frequency stimulation, while acute drugs led to increased synaptic efficacy. It is worth noting that stress shifts the effects of acute drugs from increased synaptic potency to synaptic potency inhibition and impedes the reduction of synaptic potency induced by low frequency stimulation. This synaptic plasticity can be blocked by the glucocorticoid receptor antagonist RU38486 or the NMDA receptor antagonist AP-5. After slow drug addiction, the synaptic potency and stress-synaptic synaptic efficacy caused by acute drugs decreased, but the decrease in synaptic efficacy caused by acute drugs after stress did not change (Figure 16). twenty two]. These results suggest that under stress conditions, hippocampal synaptic plasticity plays a key role in the formation and development of abnormal memory of opioid addiction.

2.2.3 Corticosterone participates in stress regulation drug addiction process

Stress can affect the mental excitability of addictive drugs at different levels of the hypothalamic-pituitary-adrenal axis (HPA). Our study shows that acute injection of corticosterone promotes acute psychomotor activity, and multiple injections of corticosterone have no effect on the behavioral sensitization of the drug [23]; restraint stress increases the psychomotor excitability of the drug, but the conditions of the drug Sexual excitability and behavioral sensitization had no significant effect [24]. The results suggest that corticosterone plays an important role in acute psychomotor activity, but does not participate in the behavioral sensitization process. The mechanism by which stress regulates the behavioral effects of addictive drugs at other levels of the HPA axis remains to be further studied.

2.2.4 Unconditional neuronal sensitization and addiction susceptibility of addictive drugs

Although the effects of addiction-related behavior are greatly regulated by the drug-related environment, this effect is still based on the unconditional sensitization of neurons in the brain under the influence of addictive drugs. This effect is manifested in behavior as the animal's mental excitability gradually increases with continuous administration. And the unconditional neuronal sensitization and behavioral sensitization formed by continuous administration have an important relationship with the final formation of compulsive drug-seeking behavior. Our study showed that the drug gradually increased the animal's mental excitability in a dose-dependent manner [25] (Fig. 17), and this gradual increase in mental excitability showed significant individual differences. Rats with a higher motility response in a weak stress environment have higher behavioral sensitization effects than low-response rats, and their behavioral sensitization effects remain longer after long-term drug withdrawal. (Figure 18). According to the theory of mental excitability of drug addiction, its longer-term neurological adaptation and behavioral sensitization effects should have an important causal relationship with the relapse behavior of animals after withdrawal.

3 Comparative study on the memory of natural reward and addictive drug reward

A comparative study of natural rewards and addictive drug rewards can reveal specific neurological processes of addiction and find both together with the neural mechanisms of separation. Selective intervention in the abnormal reward effect of addictive drugs, avoiding the impact on the natural reward function, can provide a basis for clinical addiction behavior treatment. Our study showed that rats were conditionally trained, and there was no significant difference in the acquisition of drug and food reward memory, but the retention of drug reward memory was longer [26]. Addiction drug

Abnormal learning and memory caused by things may be an important cause of long-term addiction. The study also found that naloxone significantly enhanced the drug CPP effect in rats, but had no effect on food CPP; NMDA receptor antagonist MK-801 completely inhibited the expression of drug CPP, but enhanced the expression of food CPP (Figure 19); MK-801 can significantly reduce the effect of naloxone on the expression of drug CPP [27]. These evidences suggest that there is a mechanism for the separation of the regulation of natural and drug-rewarding memory by endogenous opioid or glutamate systems. Figure 19 Peripheral MK-801 promotes CPP expression inhibition of food CPP expression [28]

The study of the central mechanism further indicates that the promotion of food CPP expression by MK-801 is regulated by the NMDA receptor in the lateral hypothalamus, while the MK-801 inhibitory drug craving is achieved by regulating the NMDA receptor in the nucleus accumbens [28] ]. It has also been found that melanin-concentrating (MCH) projection from the lateral hypothalamus to the nucleus accumbens has an opposite regulation of food and drug cravings. Activation of the nucleus accumbens MCH receptor promotes food CPP and inhibits drug CPP (Figure 20). The results suggest that MCH projection from the lateral hypothalamus to the nucleus accumbens participates in the expression of food and addictive drug cravings [26]. It is speculated that the MCH projection of the lateral hypothalamus may be one of the important links in the food craving and ending the negative feedback loop. MCH has certain application potential in the treatment of opioid addiction and obesity.

4 Research outlook

Numerous studies have shown that long-term adaptive changes in the brain are the basis for drug-dependent behavior under the influence of addictive drugs. The subsequent changes in drug formation after drug withdrawal have become the essence of drug dependence and drive relapse. The abnormal expression of learning and memory related to environmental stress and emotion is an important reason for the long-term existence of drug addiction [25]. The change of reversibility of addiction-related memory and the facilitation of addiction-related environmental stress on the addictive behavior and the awakening behavior and its neural mechanism have become hotspots in current addiction research, including the following aspects. The problem, first, since the occurrence of addictive behavior is based on the unconditional sensitization of neurons, and environmental factors only play a role in whether or not this sensitization is expressed and expressed, then environmental cues-induced relapse What is the relationship between behavioral and unconditional neuron sensitization and its neural mechanism? Second, under the action of addictive drugs, what is the relationship between the abnormal formation of emotion-related learning and memory and the sensitization of unconditional neurons formed during expression and drug dependence? Third, since the formation of addictive memory is a dynamic process, what factors can promote the consolidation of memory, what is the specific mechanism of action? Fourth, based on the significance of clinical treatment, what state of addictive memory has been formed can be weakened or deleted? What is the specific mechanism of action? 5. Is the neural mechanism of addiction-related memory specific to the memory associated with natural rewards? Significant progress has been made in researching these issues [28-34]. However, there are still differences on the clarification of the specific mechanism of action, which needs further study.