Advanced Psychopharmacology

Impulsivity, Compulsivity, Addiction Lecture 1 Video Transcript

This is the first lecture in a series on impulsivity, compulsivity, and addiction. Impulsivity and compulsivity are seen in a wide variety of psychiatric disorders. Impulsivity can be thought of as the inability to stop the initiation of actions and involves the brain circuit centered on the ventral striatum linked to the thalamus, to the ventromedial prefrontal cortex, and to the Anterior Cingulate Cortex, or the ACC.

Compulsivity can be thought of as the inability to terminate ongoing actions and hypothetically is centered on a different brain circuit, namely, the dorsal striatum, thalamus, and orbitofrontal cortex. Impulsive acts, such as drug use, gambling, and obesity, can eventually become compulsive due to neuroplastic changes that engage the dorsal habit system and theoretically cause impulses in the ventral loop to migrate to the dorsal loop.

This table represents the possible categorization of impulsivity and compulsivity endophenotypes as impulsive-compulsive disorders. You'll want to familiarize yourself with the phrasing in Table 14-2 of these terms that will be used throughout the chapter.

The bottom-up circuit that drives impulsivity is a loop with projections from the ventral striatum to the thalamus, from the thalamus to the ventromedial prefrontal cortex, and from the ventromedial prefrontal cortex back to the ventral striatum. This circuit is usually modulated top down from the prefrontal cortex. If this top-down response inhibition system is inadequate or is overcome by activity from bottom-up ventral striatum, impulsive behaviors may result.

The bottom-up circuit that drives compulsivity is a loop with projections from the dorsal striatum to the thalamus, from the thalamus to the orbitofrontal cortex, and from the orbitofrontal cortex back to the dorsal striatum. This habit circuit can be modulated top down from the orbitofrontal cortex. But if this top-down response inhibition system is inadequate or is overcome by activity from the bottom-up dorsal striatum, compulsive behaviors may result.

The progression from occasional impulsive drug use to compulsive use and addiction involves the dysregulation of bottom-up reward circuits and insufficient top-down inhibition of these circuits. The amygdala and hippocampus provide regulatory input to this system as well.

Drug addiction provides a good example of the shift from impulsivity to compulsivity that comes with migration from ventral to dorsal circuits. The impulse to take a drug initially leads to great pleasure and satisfaction. If this happens infrequently, the behavior may be a bit naughty but will not necessarily progress to compulsivity. With chronic substance use, compulsivity may develop as an individual's drive turns from seeking pleasure to seeking relief from distressing symptoms of withdrawal and anticipation of obtaining the drug.

Dopamine has long been recognized as a major player in the regulation of reinforcement and reward, specifically, the mesolimbic pathway from the ventral tegmental area to the nucleus accumbens, seems to be crucial for reward. Naturally rewarding activities, such as achieving a major accomplishment or enjoying a good meal, can cause fast and robust increases in dopamine in the mesolimbic pathway.

Drugs of abuse also cause dopamine release in the mesolimbic pathway. In fact, drugs of abuse can often increase dopamine in a manner that is more explosive and pleasurable than that which occurs naturally. Unfortunately, unlike a natural high, the activation caused by drugs of abuse can eventually cause changes in the reward circuitry that are associated with a vicious cycle of drug preoccupation, craving, addiction, dependence, and withdrawal.

The final common pathway of reward in the brain is hypothesized to be the mesolimbic dopamine pathway. This pathway is modulated by many naturally occurring substances in the brain in order to deliver normal reinforcement to adaptive behaviors. This table here shows the probability of becoming dependent once you have tried a substance at least once.

Here we have a slide on stimulants. These drugs are inhaled, snorted, or injected, thus entering the brain in a sudden and explosive manner. The faster the drug's entry into the brain, the stronger its reinforcing effects. Among the stimulants, we can see prescribed psychostimulants like amphetamine, dextroamphetamine, Ritalin or methylphenidates, along with cocaine, crack cocaine, and methamphetamines among others.

Acute drug use causes dopamine release in the striatum. However, the reinforcing effects of the drug are largely determined not only by the presence of dopamine but also by the rate at which dopamine increases in the brain, which in turn is dictated by the speed at which the drug enters and leaves the brain, in this case, targeting the dopamine transporter.

An abrupt and large increase in dopamine mimic the phasic dopamine firing associated with conveying information about reward and saliency. The rate of drug uptake is subject to the route of administration with IV administration and inhalation producing the fastest drug uptake followed by snorting. In addition, different drugs of abuse have different reward values.

Nicotine directly causes dopamine release in the nucleus accumbens by binding to alpha-4 beta-2 nicotinic postsynaptic receptors on dopamine neurons in the Ventral Tegmental Area, or the VTA. In addition, nicotine binds to alpha-7 nicotinic presynaptic receptors on glutamate neurons in the VTA, which in turn leads to dopamine release in the nucleus accumbens.

In the resting state, alpha-4 beta-2 nicotinic receptors are closed. Nicotine administration as by smoking a cigarette causes the receptor to open, which in turn leads to dopamine release. Long-term stimulation of these receptors leads to their desensitization such that they temporarily can no longer react to nicotine. This occurs in approximately the same length of time it takes to finish a single cigarette. As the receptors resensitize, they initiate craving and withdrawal due to the lack of release of further dopamine.

Full agonists at alpha-4 beta-2 receptors, such as acetylcholine and nicotine, cause the channels to open frequently. In contrast, antagonists of these receptors stabilize them in a closed state such that they do not become desensitized. Nicotinic partial agonists stabilize the channels in an intermediate state, causing them to open less frequently than a full agonist but more frequently than an antagonist.

Varenicline is a nicotinic partial agonist selective for the alpha-4 beta-2 receptor subtype. Its actions of alpha-4 beta-2 nicotinic receptors located on dopamine neurons and GABA interneurons in the VTA are all shown.

A regular smoker delivers reliable nicotine, releasing dopamine in the limbic area at frequent intervals, which is rewarding to the limbic dopamine D2 receptors on the right. However, during attempts at smoking cessation, dopamine will be cut off when nicotine no longer releases it from the mesolimbic neurons. This upsets the postsynaptic D2 limbic receptors and leads to craving or what some call a nicotine fit.

A therapeutic approach to diminishing craving during the early stages of smoking cessation is to deliver a bit of dopamine itself by blocking dopamine reuptake directly at the nerve terminal with bupropion. Although not as powerful as nicotine, it does take the edge off and can make abstinence more tolerable. Benzodiazepines and barbiturates both act at GABAA receptors but at different binding sites. Benzodiazepines do not act at all GABAA receptors.

Opioid neurons synapse in the VTA with GABAergic interneurons and presynaptic nerve terminals of glutamate neurons. Inhibitory actions of opioids at mu opioid receptors there cause disinhibition of dopamine release in the nucleus accumbens. Alcohol either directly acts upon mu receptors or causes release of endogenous opioids. Alcohol also acts at presynaptic metabotropic glutamate receptors and presynaptic voltage-sensitive calcium channels to inhibit glutamate release.

Opioid neurons from synapses in the VTA with GABAergic interneurons and with presynaptic nerve terminals of glutamate neurons-- alcohol either acts directly upon mu receptors or causes release of endogenous opioids. In either case, the result is increased dopamine release to the nucleus accumbens. Naltrexone is a mu opioid receptor antagonist. Thus, it blocks the pleasurable effects of alcohol mediated by the mu opioid receptors.

Acamprosate seems to block glutamate receptors, particularly the metabotropic glutamate receptors and perhaps also NMDA receptors. When alcohol was taken chronically and then withdrawn, the adaptive changes that it causes in both the glutamate system and the GABA system create a state of glutamate overexcitation as well as GABA deficiency. By blocking glutamate receptors, acamprosate may thus mitigate glutamate hyper-excitability during alcohol withdrawal.

Opioid drugs act on a variety of opioid receptors. Endogenous opioid-like substances are peptides derived from precursor proteins. Parts of these precursor proteins are cleaved off to form endorphins, enkephalins, or dynorphins, which are then stored in opioid neurons and presumably released during neurotransmission to mediate reinforcement and pleasure.

The primary action of hallucinogenic drugs are shown here, namely agonism of 5HT2A receptors. Hallucinogens may have additional actions at other serotonin receptors. Although food addiction is not yet accepted as a formal diagnosis, it does appear that when external stimuli are triggers for maladaptive eating habits that are performed despite apparent satiety and adverse health consequences, this does define a compulsion and a habit with the formation of aberrant eating behaviors in a manner that parallels drug addiction.

Appetite is regulated by the balance between an appetite stimulating pathway and an appetite suppressing pathway. The appetite suppressing neurons make the precursor POMC, which is broken down into alpha-MSH which in turn binds to melanocortin-4 receptors to suppress appetite.

Phentermine increases dopamine and norepinephrine in the hypothalamus by blocking both the norepinephrine and dopamine reuptake transporters. Topiramate hypothetically inhibits the appetite stimulating pathway on the left by reducing excitatory glutamatergic input and by increasing inhibitory GABAergic input. Combining this with phentermine's actions on the right that stimulate the appetite suppressing pathway, this results in a synergistic and enhanced effect on appetite and on weight loss.

The antidepressant and smoking cessation aid bupropion is thought to have effects in the appetite center of the hypothalamus as well. Bupropion increases dopamine and norepinephrine in the hypothalamus by blocking both the norepinephrine and dopamine reuptake transporters.

Both naltrexone and bupropion alone can lead to some weight loss by themselves. However, the combination of naltrexone and bupropion have a synergistic effect on weight loss that surpasses monotherapy with either agent by dual pharmacologic actions on the appetite suppressing pathway.

The 5HT2C agonist lorcaserin has recently been approved for treatment of obesity. This hypothetically binds to 5HT2C receptors on POMC neurons in the appetite suppressing pathway, activating POMC neurons and leading to the release of alpha-MSH, which binds to melanocortin-4 receptors to robustly suppress appetite.

The anticonvulsant zonisamide has actions in the appetite center of the hypothalamus that are similar to those of topiramate. Zonisamide hypothetically both reduces excitatory glutamatergic input and increases inhibitory GABAergic input onto neurons in the appetite stimulating pathway, leading to less output of neuropeptide Y and AGRP and decreased appetite stimulation.

The combination of histamine-1 antagonism and serotonin 5HT2C antagonism present in many atypical antipsychotics may lead to enhanced appetite and consequential weight gain. Conversely, the actions of a 5HT2C agonist, such as lorcaserin, may lead to appetite suppression and weight loss.

Many impulses can become an impulsive-compulsive disorder when done to excess, and several of these examples are listed in this table. Some experts believe gambling disorders should be classified along with drug addiction as the only non-substance disorder in that category. Many disorders considered to be neurodevelopmental have impulsivity or compulsivity as a symptom dimension. This includes notably ADHD discussed in chapter 12.

Aggression and violence have long been controversial issues in psychiatry. When violence is premeditated, callous, and calculated, it may be criminal, psychopathic, and predatory. And this type of violence would neither be impulsive nor compulsive. However, aggression and violence both to others and to one's self are associated with many psychiatric disorders seen here in table 14-7.

Obsessive-Compulsive Disorder or OCD in many ways is the prototypical impulsive-compulsive disorder, although it's been considered to be an anxiety disorder as well. In OCD, many patients experience an intense urge to perform stereotypic ritualistic acts despite having full insight into how senseless and excessive those behaviors are and having no real desire for the outcome of these actions. The most common types of compulsions are checking and cleaning. Seen here in this table are some of the other impulsive-compulsive related disorders such as skin picking, trichotillomania, which is hair pulling.