CNS 27: Neurobiology of Addiction

In this discussion, we will talk about the features of drug addiction, factors that influence the development of drug addiction, the neurobiology of drug addiction, and mechanism of action of highly abused medications.

Features of drug addiction

Drug addiction is a pattern of behavior that individuals develop and maintain that is destructive to their lives. It is unknown why some individuals develop a pattern of compulsive drug use, where others do not.

Factors that Influence the Development and Maintenance of Drug Abuse and Addiction

The development and maintenance of drug abuse is complex, and it involves multiple factors that involves pharmacological, biological and psychological factors. Cumulatively, this is referred to as the biopsychosocial model.

The first factor is the route of administration. Some routes are quicker than others. For examples, intravenous injection or inhalation allow for rapid a drug entry into the brain, leading to a fast onset of drug action. In contrast, oral or transdermal routes have a relatively slow absorption in comparison.

In general, a fast onset of action is associated with shorter duration of active. This can also increase the risk of medication addiction.

The quick onset (strongest euphoric effects) with shorter duration (require more repeated exposure) are why IV and inhalation routes have the greatest risk for addiction. For example, IV heroin is more addictive than snorted heroin, which is much more addictive than oral morphine or methadone.

The second factor is the agent or medication. For example, cigarettes (inhalation) are much more addictive than snorted heroin (inhalation).

Stages of Addiction:

  1. “Bingeing” The extreme exposure to the drug leading to drug intoxication, activating the reward pathway.
  2. “Withdrawal and negative affect” The individual experienced a negative reinforcement and that they to desire more medications.
  3. “Anticipation” This period is when the individual is pre-occupied with the medication and anticipate upcoming uses.

The individual will cycle between experiencing bingeing and the negative affects. Once this preoccupation happens, the individual may start experiencing persistent desire, that leads to tolerance withdrawal. This may compromise the social or work life of the individual, leading to spiraling distress and addiction.

Neurobiology of Drug Addiction

The reward circuit is what responsible for the acute rewarding and reinforcing effects that drive the first stage of addiction (bingeing.) There are lot of moving parts in this circuit, such as the mesolimbic pathway, dopamine, amygdala, opioid, cannabinoid, nicotinic, and GABA.

Different types of drugs activate different receptors. Most of this involves the mesolimbic DA pathway, which when activated, play a central role in drug reward and reinforcement.

Upon a repeated exposure, the affect of the reward system becomes more and more dull due to tolerance development. This is one of the may neuroadaptations in response to repeated exposure to a drug. When this happens, incentive salience becomes a key component that drives drug addiction.

Incentive sensitization is almost a switch between “liking” the drug and “wanting” the drug. Individuals at this stage experience a massive increase in the craving (wanting) the drugs while maintain a stable “liking” of the drug. This is the incentive sensitization theory.

This is another proposal made by Koob and Le Moal on some of the neuroadaptation changes seen with repeated exposures. They proposed that these neuroadaptations result in a down-regulation of activity, which prompted a gradual recruitment of the antireward system.

This activation of the antireward system increases the release of norepinephrine, the neuropeptides corticotropin-releasing factor (CRF), and dynorphin. This put a limit on the reward circuit and mediate some of the aversive effects of stress. All of these lead to aversive affects of withdrawal and negative reinforcement.

Over an extended period of time, individuals started to have structural and functional abnormalities in the prefrontal cortex (PFC) as demonstrated by brain imaging studies. Since PFC has a central role in executive function of emotional and motivational processes, a dysfunction in the PFC is thought to play a key role in the third-stage (anticipation.)

There may also be changes in the transition from the ventral striatum (NAcc) to the dorsal striatum (caudate-putamen) that result in a switch from reward-motivated behavior to automatic, habitual, and compulsive behavior.

In 1970, the U.S. published the Controlled Substances Act to classify risky medications in schedule of controlled substances.

Opioid Receptors and Endogenous Neuropeptides

In the 1970, peptides that can bind to opioid receptors were identified and tagged as endorphins. There are four types of opioid receptors: mu (u), delta (d), kappa (k), and NOP-R. All four types are coupled to inhibitory G-coupled protein (Gi.) This leads to a reduced cAMP in the system. Opioid receptors can be on the postsynaptic neurons or presynaptic neurons. This allows them to perform various types of inhibition, such as postsynaptic inhibition through the opening of potassium channels, axoaxonic inhibition through the closing to calcium channel, and presynaptic autoreceptors through reducing the transmitter release.

Treatment Programs for Opioid Use Disorder

The first step to treat this is to detoxify the individuals. This must be done gradually over 5-7 days. Long-acting opioids, such as methadone, can be used to help with the withdrawal symptoms. In fact, the methadone maintenance program is the most common and effective treatment for heroin addiction.

Another agent that can be used is clonidine, which acts through alpha-2 agonism to reduce NE activity in the locus coeruleus. This is helpful because during withdrawal there is an increased in NE release. Because clonidine only works on the NE release, it does not relieve all symptoms of withdrawal.

The next agent is buprenorphine (Buprenex). This is an opioid partial agonist. The thought behind its usage is the same as methadone except buprenorphine has weaker effects and longer duration than methadone. It is available in combination with naloxone as a SL tablet known as Suboxone. As a SL formulation, the buprenorphine is absorbed, but the naloxone is not. This prevents individual to crushed or injected the tablet because the naloxone will block the euphoric effects of buprenorphine.

The next two agents are narcotic antagonists: naltrexone (trexans) and nalmefene (Revex). Naltrexone has a longer duration than naloxone and fewer side effects. Nalmefene is similar to naltrexone, but is more potent and last longer.

In these methods discussed above, the craving for the drug is not eliminated, which is why it is important for individuals to maintain their level of motivation.

Treatment of Alcohol Use Disorder (AUD)

Similarly to opioid disorder treatment, the first goal is to detoxify the individual. Alcohol withdrawal symptoms are more severe than opioids.

Benzodiazepines are usually given to prevent alcohol withdrawal symptoms.

Aside from benzodiazepines, there are several other pharmacologic agents that are used in AUD, they both work to make drinking unpleasant and reduce alcohol’s reinforcing qualities.

Disulfiram (Antabuse) works by inhibiting ALDH. Even a small quantity of alcohol (1 oz) can results in flushing, pounding heart, nausea, and vomiting.

Naltrexone is another agent used for AUD. Naltrexone reduces the positive feelings by blocking the endorphin released by alcohol. With the same reasoning, nalmefene may be used also.

Interestingly, targeting opioid receptor with naltrexone produced amazing benefit for some individuals but is limited in others. This is probably due to genetic differences.

Acamprosate is a partial antagonist of the NMDA receptor. Because glutamate level increases dramatically during alcohol withdrawal, this medication can help with some withdrawal symptoms. It has been shown that Acamprosate has similar effectiveness as naltrexone.

Nicotine Addiction Treatment

Nicotine primarily works through the activation of nicotinic cholinergic receptors. These receptors are ionotropic receptors made up of five subunits that work with sodium ions.

The most common pharmacological intervention is with nicotine replacement therapy (NRT). The idea behind this therapy is to deliver nicotine to the individual in a safer and controlled way than smoking. Another application of NRT is with electronic nicotine delivery systems (ENDS.)

Other smoking cessation agent includes bupropion (Zyban). This is due to its DA and NE reuptake inhibition as well as a weak nicotinic cholinergic receptor antagonist.

Varenicline (Chantix) is a partial agonist at high-affinity nicotinic cholinergic receptor antagonist. This partial agonism induces moderate amount of nicotine activation. This results in being able to reduce nicotine craving, and with fewer withdrawal reactions.

Cocaine

Cocaine is able to block DAT, NET, and SERT, resulting in an increased in all of these neurotransmitters.

Amphetamine and Methamphetamine

These agents are indirect agonists of the catecholaminergic systems. They cause a reversal of DAT, resulting in a dramatic increased in DA in the synaptic cleft. They also work on increasing the NE release, similar to cocaine.

Marijuana

Cannabinoids are compounds contained within cannabis plant. The major psychoactive compound of cannabinoids is d9-tetrahydrocannabinol (THC.)

Cannabidiol (CBD) is similar in structure to THC. It has lower affinity for the cannabinoid receptor and lacks the intoxicating and dependence-producing effects of THC.

Cannabinoid receptors are in many areas of the brain. CB1 is found mainly in the CNS, and CB2 is mainly in the immune system and other tissues. Cannabinoid receptors are metabotropic. They work through inhibitory G-protein and inhibit cAMP. In general, cannabinoids can inhibit the release of many neurotransmitters.

Endocannabinoids are neurotransmitter-like substance that acts on cannabinoid receptors. There are two main ones: arachidonoyl ethanolamine (AEA, anadamide) and 2-arachidonoylglycerol (2-AG). They are synthesized and released in response to depolarization of the postsynaptic cell due to the influx of calcium.

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