After decades of efforts, a series of important progress has been made in the research on the reward effect of psychoactive substances and the neurobiological mechanism of regular medication, and the research on the mechanism of forced medication has also begun in recent years.

The core feature of drug addiction is compulsive drug seeking. Understanding the mechanism of compulsive drug seeking will help us to understand the neurobiological basis of drug addiction more accurately.

(A) the mental dependence related nerve nuclei and neural circuits

Mental dependence caused by psychoactive substances involves multiple nuclei and brain regions, and * * * together constitute the cortex-striatum-thalamus loop (color figure 3-3), in which the reward loop and the learning and memory-related loop play an important role.

Third, the neurobiological basis of mental dependence.

Figure 3-3 Cortical-Striatum-Thalamic Circuit Related to Drug Addiction

? Red arrow: dopaminergic projection; Blue arrow: GABA can project; Black arrow: glutamic acid can be projected.

1. Midbrain reward circuit.

Psychoactive substances can cause mental dependence, which is closely related to their special psychoactive functions, including pleasure, excitement, increasing awakening, improving mood and exercise, increasing exploration behavior, and even hallucinating, among which the most important thing is reward.

Reward has two main functions: one is to activate behavior and immediately change the direction and activity of behavior;

Another function is reinforcement, which can change future behavior through the process of learning and memory.

The reward system in the brain is mainly composed of dopamine system at the edge of midbrain.

Dopaminergic neurons are located in VTA, and nerve fibers project to NAc, PFC, hippocampus, bed nucleus of stria terminalis, septal nucleus, olfactory tubercle and amygdala.

Among them, VTA-NAc loop is considered as the main neural loop encoding the acute reward effect of addictive drugs, which is closely related to the reward effect caused by drugs.

In addition, VTA in this loop is also regulated by PFC, glutamate projection in amygdala and hippocampus and GABA projection in NAc. NAc not only receives dopaminergic projections from VTA, but also is regulated by glutamate projections from PFC, amygdala and hippocampus.

NAc is the main component of ventral striatum and the key nucleus for information convergence and integration. NAc is divided into shell and kernel. The shell region mainly mediates the reward effect of drugs, and the nuclear region mainly mediates conditional reinforcement.

Almost all addictive substances can directly or indirectly increase the dopamine concentration outside NAc cells, and NAc-encoded individuals get euphoria (reward) and have the desire (motivation) to experience this euphoria again.

Therefore, the dopaminergic reward circuit of VTA-NAc is the same as the pathway initiated by addiction.

At the beginning of taking the drug, psychoactive substances activated the function of dopamine system in the midbrain margin, which significantly increased the dopamine level in NAc area, thus producing euphoria;

After long-term medication, it leads to the continuous adaptive changes of dopamine system-related nuclei or synapses in the midbrain margin.

Although the reward effect of drugs will gradually weaken with the extension of medication time (reward tolerance), it will be sensitive to drug-related clues, which is the main factor leading to craving and relapse.

At the same time, the role of dopamine has become more extensive, from simply generating euphoria to highlighting the significance of new and unusual signals, predicting whether reward factors will come, generating driving force (motivation) and promoting relevant learning.

2. Learning and memory related circuits

Drug addiction is a stubborn stimulus-response habit established by abnormal learning. Neural circuits related to learning and memory have been proved to play an important role in the formation and maintenance of addictive behavior.

Studies have shown that the dorsal striatum (dStr), which participates in normal habit learning and memory, may play a special role in compulsive drug-seeking behavior.

The behavioral basis of the change from regular medication to forced medication is the change from purposeful behavior to habitual behavior, and its neurobiological structure is the migration from NAc to dStr function.

DStr can be divided into two subregions: dorsal lateral striatum (dlStr) and dorsal medial striatum (dmStr).

DmStr accepts the loop formed by PFC projection (its function is similar to NAc nucleus), which mainly participates in behavior-result coupling learning and affects purposeful behavior, which is related to regular medication; The sensorimotor cortex is related to dlStr, which is mainly involved in stimulus-response coupling learning and affects habitual behavior, which may be related to compulsive medication. At the initial stage of the establishment of cocaine self-administration model in rats, the amount of dopamine released by NAc putamen increased significantly, and the intervention of NAc function affected the drug use and drug seeking behavior. With the extension of medication time, dStr replaced NAc to dominate the regulation of addiction behavior.

After 45 days of cocaine self-administration training, the release of DA (but not NAc) in rats' dlStr increased significantly. Inactivated dlStr can restore the target-oriented cocaine drug-seeking behavior, but inhibit the forced drug-seeking behavior. In addition, using positron emission tomography (PET), it was found that the changes of glucose utilization rate in rhesus monkeys' brains were limited to NAc only five days after cocaine self-administration training, but after 100 days, these changes had spread to most areas of caudate putamen (equivalent to dStr of rodents).

Clinical research also found that dopamine function of dStr (but not ventral striatum) of cocaine addicts was positively correlated with cue-induced craving.

Therefore, the transformation of ventral and dorsal functions of striatum is one of the important reasons for compulsive drug-seeking behavior. This conversion process is regulated by glutamate energy in different brain regions of prefrontal cortex.

In the process of developing from regular medication to forced medication, the functions of NAc and dStr do not exist in isolation, but form a functional relationship through the spiral ring of striatum-substantia nigra-striatum (SNS). The cascade of NAC and DSTR may participate in the development of drug-seeking behavior of forced medication.

In addition, as the key nucleus of emotional memory, amygdala also plays an important role in addictive behavior. The central amygdala is mainly involved in compulsive drug-seeking behavior, and the lateral amygdala plays a key role in drug-related conditional cues-related learning and memory and relapse induction.

As a memory center, hippocampus plays an important role in learning and memory related to situational clues and inducing recurrence.

The above subcortical structure is very important in the formation of addiction and pathological learning and memory, although it is not all the elements, it is an essential prerequisite.

The most powerful biological evidence is that nematodes can also be addicted to psychoactive substances and form some relatively simple memory behaviors, while nematodes do not have complex central brain structures.

Therefore, it is necessary to attach importance to the above research results and fully consider its value and significance in addiction intervention.

3. The extensive regulation of the prefrontal cortex on addictive behavior.

PFC is also the key brain region of drug addiction, which is involved in many aspects of drug addiction, including craving, motivation and decision-making.

At present, it is considered that the middle prefrontal cortex (mPFC), orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) of PFC are closely related to compulsive drug use.

Drug addicts often show cognitive dysfunction such as attention bias, decision-making obstacles and impulse suppression defects. Stimulation of drugs and drugs, which leads to compulsive drug-seeking behavior.

The main reason is that the structure and function of PFC have changed.

PFC receives dopaminergic projections from VTA and glutamatergic projections from hippocampus and lateral basal amygdala, and emits glutamatergic fibers to dominate VTA, NAc, hippocampus and lateral basal amygdala.

The adaptive change of glutamate ring function projected by mPFC to NAc leads to control function defect and sensitization to drug-related stimuli.

MPFC includes dorsal medial prefrontal cortex (PrL) and ventral medial prefrontal cortex (IL), in which PrL mainly projects to NAc nucleus and IL mainly projects to NAc shell. PrL-NAc nuclear projection mainly regulates drug-seeking motivation, while IL-NAc shell projection mainly regulates the expression of drug-seeking behavior.

Long-term and large-scale use of addictive drugs leads to the weakening of the projection function of PrL to NAc and promotes the formation of compulsive drug-seeking behavior.

OFC predicts events through neural connections with lateral basal amygdala and NAc, and guides decision-making by comparing values and expectations.

After OFC is damaged, it will lead to the wrong judgment of the reaction result and the emergence of forced reaction. The downward adjustment of OFC function caused by long-term drug abuse makes addicts have decision-making obstacles and causes compulsive drug-seeking behavior.

In addition, destroying ACC will destroy the ability to select attention and distinguish different conditional signals, and the loss of these abilities will lead to the inability to provide timely and accurate information to start the behavior inhibition mechanism.

In a word, cognitive dysfunction of PFC caused by long-term medication is another important reason for compulsive medication. in addition

PFC also participates in drug addiction behavior by enhancing the value prominence and motivation significance of stimulation.

4. Neural circuits related to recurrence

Even after long-term withdrawal, drug-related clues and environment, small-dose drug ignition and stress can induce relapse, which is also the difficulty of drug treatment.

Kalivas put forward the neural circuit of relapse after a lot of research (color picture 3-4). The projection of VTA to lateral basal amygdala and then to PFC is a drug-related clue pathway to induce relapse;

The projection of extended amygdala (including central amygdala, bed nucleus of stria terminalis and NAc shell) to VTA and then to PFC is the pathway of stress-induced recurrence.

The projection of PFC to NAc nucleus and then to ventral globus pallidus is the same pathway of stress, drug-related clues or drug-induced relapse.

Compared with dopamine, glutamate system is dominant in recurrence.

? Figure 3-4 Recurrent Neural Circuits

? Red: relapse induced by drugs, clues or stress;

? Green: the way of clue-induced recurrence

Blue: the way stress causes recurrence.

(2) Neurotransmitter system related to mental dependence

Neurotransmitters are the material basis for realizing the function of neural circuits. According to the existing research results, almost all known central neurotransmitters are involved in drug addiction to varying degrees.

Among them, dopamine and glutamate neurotransmitter systems are the most studied and the most important.

1. dopamine system

The reward effect mediated by VTA-NAc dopaminergic neural pathway is the first step of addiction initiation. Almost all psychoactive substances can directly or indirectly activate this dopaminergic neural pathway, but their initial mechanisms of action are different.

Opioid drugs inhibit the activity of GABAergic neurons by activating μ opioid receptors on GABAergic intermediate neurons of VTA GABA thus relieving the inhibition of GABAergic neurons on VTA dopaminergic neurons, increasing the amount of dopamine released by NAc in the projection target area, activating GABAergic projection neurons in NAc, and realizing the coding of reward effect;

Cocaine and amphetamine-type stimulants act on dopaminergic nerve endings of NAc, and cocaine blocks dopamine reuptake by inhibiting dopamine transporter in plasma membrane;

Amphetamine stimulants can not only inhibit dopamine transporter in plasma membrane from blocking dopamine reuptake, but also reverse the functions of vesicular monoamine transporter 2 and plasma membrane monoamine transporter, promote reverse dopamine transport and increase extracellular dopamine content, thus up-regulating the function of dopamine pathway in VTA-NAc.

Cannabis can increase the discharge of VTA dopaminergic neurons and dopamine concentration in NAc by activating CB 1 receptors on GABAergic neurons and glutamate neurons.

Nicotine can activate α4β2 nicotinic acetylcholine receptor located in VTA dopaminergic neurons, thus increasing the dopamine release of VTA dopaminergic neurons in NAc.

Ethanol can increase the dopamine release of NAc in some indirect way by acting on GABAA receptor and NMDA receptor.

In the early days, dopamine was thought to be the material basis of reward (euphoria), but in recent years, it has been found that dopamine also mediates reward expectation error and reward-related correlation learning.

Schultz et al. systematically studied the response of VTA dopaminergic neurons to reward stimuli.

In the experimental model of classical conditioned reflex training in rhesus monkeys, they found that natural reward (such as juice and food) stimulation increased the phase discharge frequency of dopaminergic neurons in VTA brain region, while unnatural reward stimulation could not increase the phase discharge frequency of dopaminergic neurons, suggesting that dopaminergic neurons can distinguish reward stimulation from non-reward stimulation.

Further research shows that there is no significant difference in the discharge patterns of the above dopaminergic neurons for different natural reward stimuli, suggesting that dopaminergic neurons cannot distinguish the nature of natural rewards.

In addition, dopaminergic neurons are also involved in reward learning, which shows that Pavlov conditioned reflex can be established in response to reward stimulation. When the sound or light signal is repeatedly paired with the original reward (fruit juice), a single conditioned stimulus (sound or light signal) can also cause the phase discharge frequency of dopaminergic neurons to increase, indicating that dopamine not only responds to the reward itself (fruit juice), but also responds to the expectation of the reward (conditioned stimulus).

This kind of response to reward and matching conditional stimulation changes gradually with the increase of matching training times. At the beginning of training, only the original reward can cause the discharge frequency of dopaminergic neurons to increase; In the middle of training, both reward and conditioned stimulus can increase the discharge frequency of dopaminergic neurons; After training (the connection between conditioned stimulus and reward has been firmly established), only conditioned stimulus can cause the discharge frequency of dopaminergic neurons to increase.

This shows that the response of dopaminergic neurons to the original reward can be transferred to the conditioned stimulus related to the reward through correlation learning. When the conditioned stimulus is not given, the experimental animals can't predict that they may get the reward (the reward is unpredictable), and giving the reward stimulus can increase the discharge frequency of dopaminergic neurons; When conditioned stimulus is given, experimental animals can expect to be rewarded (reward is predicted), and given reward stimulus (reward is consistent with expectation), conditioned stimulus can increase the discharge frequency of dopaminergic neurons, but reward itself does not change the discharge frequency of dopaminergic neurons; When the conditional stimulus is given without reward (reward prediction error), the conditional stimulus leads to the increase of discharge frequency, while the reward that does not appear leads to the decrease of discharge frequency. These results show that dopaminergic neurons do not respond to all rewards, but only to the difference between actual rewards and expected rewards, that is, only to the expected error of rewards.

. When the reward is better than expected or unexpected, dopaminergic neurons react positively, while when the reward is worse than expected or does not appear at the expected time, dopaminergic neurons react negatively.

Psychoactive substances make the dopamine level in synaptic cleft rise excessively and continuously, which makes the brain mistakenly think that the return of drugs is better than expected, thus highlighting the value of drugs and inducing drug-seeking behavior.

Because drug-induced dopamine release is higher and more lasting than natural rewards such as food, on the one hand, the correlation between drug-related stimuli and rewards is stronger, on the other hand, the natural reward target is devalued.

In addition, dopamine also mediates behavior-result related learning and habit learning (stimulus-response related learning).

Extracellular dopamine plays a role by activating dopamine receptors. Dopamine receptors are divided into five subtypes, such as D 1 ~ D5. Subtypes D 1 and D5 are coupled with Gs protein, which are collectively called D 1 dopamine-like receptors, mainly distributed in postsynaptic membranes. Subtypes D2, D3 and D4 are coupled with Gi/o protein, collectively called D2-like receptors, which are distributed in presynaptic membrane and postsynaptic membrane. The functions mediated by D 1 receptor and D2-like receptor and their roles in different stages of addiction are different. D 1 like receptor mainly mediates the reward and motivation sensitization of addictive drugs, and plays a leading role in the compensatory adaptation of the central nervous system in the early stage of drug use; However, D2-like receptors may be more involved in conditioned reinforcement and compulsive drug-seeking behavior, and play a leading role in the compensatory adaptation of the central nervous system in the later period of drug use. In drug addicts and animal models, the density of D2/D3 receptors in striatum decreased. Optogenetics technique was used to inhibit moderate spinous GABA neurons with D2 receptor positive in NAc of mice, and the mice showed compulsive drug-seeking behavior. High-impulse rats (with low D2 receptor density) are more likely to form compulsive drug-seeking, but studies have shown that high-impulse rats delay the habit of drug-seeking in the second intensive training. These studies show that D2 receptor and its neuron pathway play a more important role than D 1 receptor in the later stage of addiction development, and the indirect pathway mediated by D2 receptor dominates the regulation of compulsive drug seeking behavior, but the exact regulation mode is still unclear. In addition, D2 receptor density may also be a biological marker of addiction susceptibility. High-impulse rats use drugs more frequently in the process of cocaine self-administration training, and people with high-impulse personality are more inclined to abuse addictive drugs. The molecular basis behind high impulse may be the decrease of D2 receptor density: D2 receptor mRNA in NAc and VTA of high impulse rats is significantly lower than that of low impulse rats, and D2/D3 receptor density in ventral striatum of high impulse rats is even lower.

2. Glutamate system

As mentioned above, dopamine system mainly mediates drug reinforcement and plays an important role in reward-related associative learning, but has little effect on long-term associative memory.

Glutamate system is not. Although glutamate is also involved in reward-related associative learning, it is most closely related to long-term associative memory and plays a key role.

Therefore, the involvement of dopamine system is necessary in the initiation and formation of addiction.

; In the process of maintenance and relapse of addiction, the participation of glutamic acid system is essential.

A great deal of evidence shows that the initiation of drug-induced euphoria and addiction requires the release of dopamine in NAc. With the repeated use of drugs, PFC and its glutamatergic neurons projected to NAc and other nuclei are also involved. Therefore, some scholars have suggested that the development from accidental drug use to regular drug use, from regular drug use mode to forced drug use mode, has experienced a transition from dopamine system in the limbic cortex of the midbrain to glutamate system in the prefrontal cortex, and then to glutamate system in the cortical striatum.

In the process of drug addiction, glutamate directly or indirectly regulates the function of dopamine system; Similarly, dopamine can also affect the function of glutamate through the projection of midbrain limbic cortex.

The activity of dopaminergic neurons in VTA is dominated by glutamate projections from PFC, amygdala and hippocampus.

On the one hand, glutamate nerve fibers introduced into VTA dominate dopaminergic neurons, which improves the excitability of dopaminergic neurons and promotes the release of dopamine in NAc;

On the other hand, glutamatergic nerve fibers introduced into NAc innervate the terminals of dopaminergic neurons and promote the release of dopamine in NAc through presynaptic mechanism.

Dendritic spines of moderate spinous neurons with GABA energy in NAc form synaptic connections with dopaminergic terminals and glutamate terminals at the same time, and their activities are regulated by these two neurotransmitters.

Therefore, glutamate can also regulate behavioral sensitization dependent on the dopamine system in the midbrain margin.

The formation of behavioral sensitization needs to temporarily increase the glutamate release of VTA, thus activating the dopaminergic neurons of VTA and enhancing their discharge, which in turn leads to the increase of dopamine release in this circuit.

Microinjection of glutamate receptor blocker into VTA can block the sensitization caused by psychoactive substances.

. Similar to NAc, dorsal striatum also receives dopaminergic projection and glutamate projection to control its function, so glutamate system is also involved in the regulation of compulsive drug-seeking behavior.

Generally speaking, there is no adaptive change in glutamic acid system at the initial stage of medication. With the prolongation of medication time and the increase of dosage, the glutamate advantage of PFC on NAc weakened, which enhanced the function of cortical striatum, resulting in compulsive medication and compulsive drug-seeking.

In the training of drug-seeking paradigm, the drug-seeking behavior of rats was significantly reduced after microinjection of AMPA receptor /KA receptor blockers into NAc nucleus, suggesting that the glutamate system of NAc participated in the regulation of drug-seeking behavior at the initial stage of drug use. However, after 45 days of cocaine self-administration training, microinjection of AMPA receptor /KA receptor blockers (instead of NAc) into dlStr significantly reduced the drug-seeking behavior of rats, suggesting that glutamate system in dorsal striatum may participate in compulsive drug-seeking behavior through more stable neuroadaptation changes.

Because the root cause of relapse after long-term withdrawal is extremely stubborn addictive memory, and glutamic acid and its receptor are the key to mediate long-term memory, it is glutamic acid rather than dopamine that plays a decisive role in relapse.

Microinjection of AMPA into NAc of cocaine self-administered rats can rebuild drug-seeking behavior (that is, relapse); Some scholars believe that the reconstruction of drug-seeking behavior induced by AMPA may be related to the increase of local dopamine release, but dopamine receptor blockers can not block the reconstruction of AMPA, indicating that the reason for relapse is the activation of NAc glutamate system.

In addition, by electrically stimulating the ventral inferior hippocampus of cocaine self-administered rats, the drug-seeking behavior was reconstructed by the "recurrence ring" described in Figure 3-4, but it was ineffective for stimulating the middle forebrain bundle rich in dopaminergic fibers.

Glutamate projection from PFC to NAc is considered as a common loop of drug-related clues, low-dose drugs and stress-induced recurrence. The weakening of glutamate system homeostasis produces lasting behavior changes by affecting neuroplasticity, leading to recurrence.

Long-term medication decreased the density of glutamate-cysteine exchanger, which was responsible for maintaining the basic level of glutamate, and decreased the basic level of glutamate in NAc nucleus.

The decrease of basal glutamate level weakens the regulation ability of presynaptic negative feedback mediated by metabotropic glutamate receptor mGluR2/3. Continuous administration of N- acetylcysteine during the regression training period can increase the extracellular basic glutamate level by promoting glutamate-cysteine exchange, thus restoring the presynaptic regulation ability of mGluR2/3, preventing the sharp increase of glutamate level caused by clues or drug ignition, and thus inhibiting the reconstruction of drug-seeking behavior.

More importantly, continuous administration of N- acetylcysteine in the regression period can reverse the changes of synaptic plasticity in NAc nucleus caused by long-term medication, so it can inhibit the recurrence induced by cue or drugs even if the drug is stopped for more than 20 days. Other means to restore glutamate homeostasis, such as blocking NMDA receptor and mGluR5 after synapse and increasing the expression of glutamate transporter 1, can also prevent recurrence. Glutamate and its receptor are the basis of synaptic transmission plasticity and play an important role in the long-term memory of addiction, which will be introduced in detail in the next part.

3. Other neurotransmitter systems

In addition to dopamine and glutamate, endogenous neurotransmitters such as opioid peptides, GABA and 5- hydroxytryptamine participate in the process of drug addiction by interacting with dopamine and glutamate systems.

For example, endogenous opioid peptides and serotonin regulate the function of dopamine system, and GABA not only regulates the function of dopamine system, but also regulates the function of glutamate system.

GABA is the most important inhibitory neurotransmitter in the brain, which coordinates the normal function of the brain with excitatory neurotransmitters.

GABA receptors are divided into three subtypes: GABAA, GABAB and GABAC, in which GABAA and GABAC belong to transmitter-gated ion channels, and GABAB receptors are G protein-coupled receptors. The activity of VTA dopaminergic neurons is inhibited by γ -aminobutyric acid neurons, which have μ opioid receptors. Opioid drugs can inhibit the function of GABAergic neurons and reduce the release of GABA, thus relieving the tension inhibition of dopaminergic neurons and increasing the dopamine content released to NAc region. Alcohol can act on GABAA receptor and NMDA receptor, thus increasing the activity of dopaminergic neurons in some indirect way. The regulation of GABAergic neurons on VTA dopaminergic neurons is mediated by GABAA receptors and GABAB receptors, and the activation of GABA receptors can inhibit the reward and reinforcement effects of psychoactive substances. GABA neurotransmitter system in hippocampus, amygdala and PFC also participates in psychoactive substance-related scenes and clues-related memory and cognitive dysfunction by affecting the function of glutamatergic pyramidal neurons. In addition, NAc, as the core of reward and motivation, and dStr, the key core of compulsive drug use behavior, their own output neurons are GABAergic neurons.

Therefore, GABA system participates in drug addiction by regulating the functions of limbic cortical pathway and cortical striatum pathway in midbrain.

Endogenous opioid peptides include enkephalin family, endorphin family, dynorphin family and many new opioid peptides isolated later, among which the most important members include β-endorphin, enkephalin and dynorphin, and their receptors are μ, δ and κ opioid receptors respectively. Endogenous opioid peptides and their receptors are widely distributed in the central nervous system, especially in reward and motivation circuits such as VTANAc.

As mentioned above, exogenous opioids can activate μ opioid receptors distributed on GABAergic intermediate neurons of VTA GABA relieve the inhibition of GABAergic neurons on dopaminergic neurons, and increase the release of dopamine in NAc; However, there are also κ opioid receptors at the axonal endings of dopaminergic neurons in NAc, and the activation of κ opioid receptors inhibits the release of dopamine. Therefore, both μ opioid receptor and κ opioid receptor * * * regulate the release of dopamine in NAc.

. At the same time, exogenous opioids can also regulate the function of dopaminergic neurons by acting on μ opioid receptors and δ opioid receptors on moderate and moderate spinal neurons in NAc. Many non-opioid psychoactive substances can also act on endogenous opioid peptide system. Preclinical studies show that alcohol, cocaine and amphetamine-type stimulants can increase the endorphin level of NAc in rats and participate in regulating the extracellular dopamine level of NAc.

In addition, acute treatment with amphetamine can regulate the expression of opioid receptor mRNA in striatum. Long-term drinking will increase the density of μ opioid receptor and δ opioid receptor. Therefore, endogenous opioid peptide system participates in regulating the reward effect of many addictive substances by affecting the release of dopamine in NAc. Endogenous opioid peptide system not only mediates reward effect, but also mediates withdrawal syndrome after drug withdrawal. Maintaining the functional stability of endogenous opioid peptide system is one of the therapeutic strategies for drug addiction.