In articles published in Science in 2007 and 2009, Han et al. showed that about 20% of neurons in the lateral amygdala of mice were involved in the formation of a fear memory, and that selective deletion of these neurons could erase the fear memory. Using the same methodology, Josh Sullivan et al. identified neurons that were active in the mouse brain during cocaine conditioning. Amygdala activity showed that the mice preferred an environment where they received cocaine to an environment where they didn’t. The researchers noticed increased cyclic AMP, a messenger that led to increased production of calcium responsive element binding protein (CREB). When the researchers targeted the neurons in the lateral amygdala that were overexpressing CREB, they found that selective destruction of the overexpressing neurons disrupted the cocaine-induced place preference.
The research team further documented this effect by temporarily, rather than permanently, knocking out neuronal function. They could reversibly turn off neurons with an inert compound that promotes neuronal inhibition. Silencing the neurons that were overexpressing CREB before the conditioned place preference testing also limited cocaine-induced place preference memory.
Editor’s Note: While this type of intervention is not feasible in humans with cocaine addiction, these data do shed more light on the mechanisms behind cocaine conditioning.
We have written before that if extinction training to break a cocaine habit or neutralize a learned fear is performed within the brain’s memory reconsolidation window (five minutes to one hour after memory recall), it can induce long-lasting alterations in cocaine craving or conditioned fear.
It is possible that properly timed extinction of cocaine- or fear-conditioned memories might work similarly to the selective silencing of neurons that was carried out in the mice using a drug that inhibited CREB-activated neurons. Determining the commonalities between these ways of eliminating conditioned memories could lead to a whole new set of psychotherapeutic approaches to anxiety disorder, addictions, and other pathological habits.
At a recent scientific meeting, Jennifer E. Murray et al. presented findings about the amygdala’s role in habitual cocaine seeking. The amygdala is the part of the brain that makes associations between a stimulus and a response. When a person begins using cocaine, a signal between the amygdala and the ventral striatum (also known as the nucleus accumbens), the brain’s reward center, creates a pleasurable feeling for the person. The researchers found that in mice who have learned to self-administer cocaine, as an animal progresses from intermittent use to habitual use, the amygdala connections shift away from the ventral striatum toward the dorsal striatum, a site for motor and habit memory. If amygdala connections to the dorsal striatum are severed, the pattern of compulsive cocaine abuse does not develop.
Editor’s Note: These data indicate that the amygdala is involved in cocaine-related habit memory, and that the path of activity shifts from the ventral to the dorsal striatum as the cocaine use becomes more habit-based—automatic, compulsive, and outside of the user’s awareness.
As we’ve reviewed before, the amygdala also plays a role in context-dependent fear memories, such as those that occur in post-traumatic stress disorder (PTSD). The process of retraining a person with PTSD to view a stimulus without experiencing fear is called extinction training. A study by Agren et al. published in Science in 2012 demonstrated that when extinction training of a learned fear took place within the brain’s memory reconsolidation window (five minutes to one hour after active memory recall), the training was sufficient to not only “erase the conditioned fear memory trace in the amygdala, but also decrease autonomic evidence of fear as revealed in skin conductance changes in volunteers.”
The preclinical data presented by Murray and colleagues suggest the possibility that amygdala-based habit memory traces could also be revealed via functional magnetic resonance imaging (fMRI) in subjects with cocaine addiction. Attempts at extinction of cocaine craving, if administered within the memory reconsolidation window, might likewise be able to erase the cocaine addiction/craving memory trace, as Xue et al. reported in Science in 2012.
N-acetylcysteine (NAC) is a drug available over-the-counter in health food stores that seems to be effective for a variety of disorders, including depression and many different habits and addictions. Preventing relapse of cocaine abuse is one of its uses. Researcher Kathryn Reissner at the Medical University of South Carolina found that NAC increases the expression of a glial glutamate transporter (GLT-1) that helps clear excessive glutamate in the nucleus accumbens, and that this mechanism is critical to preventing the reinstatement of cocaine self-administration in rodents.
As we have previously described in the BNN, NAC also decreases cued release of glutamate in the nucleus accumbens by potentiating the cystine-glutamate exchanger. This initially increases extrasynaptic glutamate, but subsequently downregulates glutamate release in the nucleus accumbens through actions at an inhibitory presynaptic metabotropic glutamate receptor.
However, the new data indicate that this action at the cystine-glutamate exchanger is not required for NAC’s effects on cocaine reinstatement, but the induction of GLT-1 is. Furthermore, another compound, propentofylline, which increases glutamate GLT-1, is also effective in suppressing cocaine reinstatement. Cocaine decreases a marker of glial activity, glial fibrillary acidic protein (GFAP), in the nucleus accumbens, suggesting that deficient glial functioning and uptake of glutamate could be another target of therapeutics in cocaine addiction.
Editor’s Note: There are also glial deficits in depressed patients, so it is conceivable that NAC’s effect on GLT-1 glutamate clearance is also involved in the antidepressant effects of NAC.
Glutamate is the major excitatory neurotransmitter in the brain, while GABA is the main inhibitory neurotransmitter. Too much or too little of one or the other can lead to an imbalance in neuronal communication. In a 2012 study by Schmaal et al. published in the journal Neuropsychopharmacology, cocaine-dependent patients were found to have high levels of glutamate in the dorsal anterior cingulate cortex. A single administration of N-acetylcysteine (NAC) at a dose of 2400mg lowered these levels.
Healthy (non-addicted) participants who received the same administration of NAC did not show the same drop in glutamate levels.
The study also observed levels of impulsivity in the patients. Higher baseline levels of glutamate were associated with greater impulsivity, and both higher baseline level of glutamate and greater impulsivity were predictive of a larger drop in glutamate levels following NAC administration.
The researchers suggest that these findings may eventually be used in the treatment of cocaine-addicted people, since abnormal glutamate levels are related to risk of relapse. In drug-dependent rodents, NAC was found to normalize hyper-responsive glutamate release in the nucleus accumbens (the brain’s reward center) and prevent cocaine-reinstatement or relapse.
Editor’s Note: When these data from the lab of Peter Kalivas at the Medical University of South Carolina were initially collected, it was thought that NAC’s effect on a cystine-glutamate exchanger in the nucleus accumbens explained its treatment success, but new data suggest that NAC may actually facilitate glutamate clearance by increasing the number of glutamate transporters in glial cells.
New research shows that cocaine, defeat stress, the rapid-acting antidepressant ketamine, and learning and memory can change the size, shape, or number of spines on the dendrites of neurons. Dendrites conduct electrical impulses into the cell body from neighboring neurons.
Several researchers, including Peter Kalivas at the Medical University of South Carolina, have reported that cocaine increases the size of the spines on the dendrites of a certain kind of neurons (GABAergic medium spiny neurons) in the nucleus accumbens (the reward center in the brain). This occurs through a dopamine D1 selective mechanism. N-acetylcysteine, a drug that can be found in health food stores, decreases cocaine intake in animals and humans, and also normalizes the size of dendritic spines.
Depression in animals and humans is associated with decreases in Rac1, a protein in the dendritic spines on GABA neurons in the nucleus accumbens. Rac1 regulates actin and other molecules that alter the shape of the spines.
In an animal model of depression called defeat stress, rodents are stressed by repeatedly being placed in a larger animal’s territory. Their subsequent behavior mimics clinical depression. This kind of social defeat stress decreases Rac1 and causes spines to become thin and lose some function. Replacing Rac1 returns the spines to a more mature mushroom shape and reverses the depressive behavior of these socially defeated animals. Researcher Scott Russo has also found Rac1 deficits in the nucleus accumbens of depressed patients who committed suicide. Russo suggests that decreases in Rac1 are responsible for the manifestation of social avoidance and other depressive behaviors in the defeat stress animal model, and that finding ways to increase Rac1 in humans would be an important new target for antidepressant drug development.
Another animal model of depression called chronic intermittent stress (in which the animals are exposed to a series of unexpected stressors like sounds or mild shocks) also induces depression-like behavior and makes the dendritic spines thin and stubby. The drug ketamine, which can bring about antidepressant effects in humans in as short a time as 2 hours, rapidly reverses the depressive behavior in animals and converts the spines back to the larger, more mature mushroom-shape they typically have.
Learning and Extinction of Fear
Researcher Wenbiao Gan has reported that fear conditioning can change the number of dendritic spines. When animals hear a tone paired with an electrical shock, they begin to exhibit a fear response to the tone. In layer 5 of the prefrontal cortex, spines are eliminated when conditioned fear develops, and are reformed (near where the eliminated spines were) during extinction training, when animals hear the tones without receiving the shock and learn not to fear the tone. However, in the primary auditory cortex the changes are opposite: new spines are formed with learning, and spines are eliminated with extinction.
Editor’s Note: It appears that we have arrived at a new milestone in psychiatry. In the field of neurology, changes seen in the brains of patients with strokes or Alzheimer’s dementia have been considered “real” because cells were obviously lost or dead. Psychiatry, in comparison, has been considered a soft science because neuronal changes have been more difficult to see and illnesses were and still are called “mental.” Now that new technologies have made a deeper level of precision, observation, and analysis possible, we know that the brain’s 12 billion neurons and 4 times as many glial cells are exquisitely plastic–capable of biochemical and structural changes that can be reversed using appropriate therapeutic maneuvers.
The changes associated with abnormal behaviors, addictions, and even normal processes of learning and memory now have clearly been shown to correspond with the size, shape, and biochemistry of dendritic spines. These subtle, reproducible changes in the brain and body are amenable to therapeutic intervention, and are now even more demanding of sophisticated medical attention.
Among rodents, being subjected to defeat stress (when an intruder mouse is threatened by a larger mouse defending its territory) can make an animal more susceptible to cocaine. This is referred to as cross-sensitization.
Researcher Elizabeth Holly and colleagues have found that compared to males, female rodents are more sensitive to defeat stress and have greater reactions to cocaine and cocaine sensitization following this type of stress. This is probably related to a neuropeptide called corticotropin releasing factor (CRF), which is associated with cross-sensitization. When the mice were exposed to cocaine, there were increases in CRF in a part of the brain called the ventral tegmental area (VTA), which contains cell bodies of dopamine neurons that travel to the nucleus accumbens, the brain’s reward center. Blocking the CRF receptors in the VTA prevented the sensitization to cocaine from occurring in the mice.
Editor’s Note: These data in animals resemble clinical observations in humans that women are more sensitive to stress and are more prone to depression, and can have an exceedingly difficult time stopping cocaine use if they become addicted.
This editor (RM Post) in collaboration with Jacqueline Fleming and Flavio Kapczinski published the article “Neurobiological mechanisms of illness progression in the recurrent affective disorders” in the Journal of Psychiatric Research this year. The article built on several themes about the progression of bipolar illness that had been explored in previous research.
These themes include:
- The likely acceleration of repeated episodes as a function of the number of prior episodes (episode sensitization)
- The increased responsivity of the illness to repeated stressors (stress sensitization)
- The increased behavioral reactivity to repeated use of psychomotor stimulants such as cocaine (stimulant-induced behavioral sensitization)
Not only are these observations well documented in the scientific literature, but recent observations also suggest that each type of sensitization can show cross-sensitization to the other two types. That is, individuals exposed to repeated stressors are more likely both to experience affective illness episodes and to adopt comorbid substance abuse. In a similar way, episodes of an affective disorder and stressors may also be associated with the relapse into drug administration in those who have been abstinent.
In addition to these mechanisms of illness progression in the recurrent affective disorders, the new article reviews the literature showing that the number of affective episodes or the duration of the illness appear to be associated with a variety of other clinical and neurobiological variables.
The number of affective episodes a patient experiences is associated with the degree of cognitive dysfunction present in their bipolar illness, and experiencing more than 4 episodes of unipolar or bipolar depression is a risk factor for dementia in late life. A relative lack of response to most treatments is also correlated with the number of prior episodes, and this holds true for response to naturalistic treatment in general. While most of these data are correlational and the direction of causality cannot be ascertained for certain, it is likely that the number of affective episodes and/or their duration could account for and drive difficulties with treatment and with cognitive function.
If this were the case, one would expect to see a variety of neurobiological correlates with the number of prior episodes or duration of illness, and in the article we summarize those that have been found in unipolar and bipolar disorder. Considerable data indicate that cortical volume and degrees of prefrontal cortical dysfunction can vary as a function of number of prior episodes. There is evidence that increased activity of the amygdala and the nucleus accumbens are also related to episodes or duration of illness. In those with unipolar depression, the volume of the hippocampus is decreased with longer duration of illness. Read more
In last week’s article we discussed how fearful memories can be changed during the window in which they are reconsolidated (5 minutes to 1 hour after active recall of the long-term memory). Now the memory reconsolidation window has been used in animals and people to extinguish an addiction to cocaine or heroin. The results in humans were reported by Xue et al. in the journal Science in April 2012.
In a typical recovery scenario, a cocaine addict is repeatedly presented cocaine cues (such as paraphernalia) without the delivery of cocaine, and craving for cocaine becomes extinguished. While the patient stops craving the drug, some biological signs of the addiction remain, such as autonomic hyper-reactivity (e.g. changes in skin conductance, pulse, or blood pressure) in response to the cocaine cues. When the sober cocaine addict leaves the recovery program, he may believe he is no longer subject to cocaine craving even upon the sight of cocaine-related cues, but this craving can return spontaneously or be reactivated by cocaine-related environments or friends who were also users, and he typically relapses.
In order to make the extinction learning more powerful, it must be experienced during the reconsolidation window. In the animal experiments by Xue et al., rodents were trained to press a lever to receive an injection of cocaine or heroin. In the extinction process, the animals were returned for 15 minutes to the same environment where they had learned to press the lever and receive the drug. This was meant to activate memories associated with the drug. Then, after a 10-minute waiting period, a 180-minute extinction training was given. The process was repeated daily for 14 days and resulted in almost complete absence of relapse to drug use with passage of time (spontaneous recovery), exposure to the drug (reinstatement), or exposure to the drug-associated environment (renewal). Moreover, the expected changes in heart rate and blood pressure upon re-exposure to the drug cues were also fully extinguished. Extinction training that began one hour after activation of the memory was also successful.
When the same extinction training was given 6 hours after placing the animal in the drug administration environment, the animal remained prone to drug re-instatement and relapse in the same or different environments or spontaneously. It can be presumed that this occurred because the extinction training took place after the reconsolidation window had closed.
These well-controlled data with both cocaine and heroin self-administration in animals were then taken to the clinic to test their validity in humans.
The same procedure worked in humans addicted to heroin. Two consecutive days of sixty-minute extinction learning within the reconsolidation window, i.e. starting 10 minutes after a 5-minute retrieval of drug-associated memories by watching a video resulted in amelioration of drug craving for at least 184 days, and amazingly, as in the animals, also resulted in the loss of the unconscious biological reactivity in heart rate and to a lesser extent, blood pressure. Patients did not relapse during 6 months of followup. The same extinction process was unsuccessful when it occurred outside of the reconsolidation window, i.e. 6 hours after retrieving the drug-related memories.
Editor’s Note: These results could be of considerable potential therapeutic value in a variety of psychiatric illnesses. This process is conceptual breakthrough that has great promise for clinical use. Psychiatrists, psychologists, and patients should become familiar with these data and the principles of exploiting the reconsolidation window for potentially transformational results.
How quickly these principles can be incorporated into mainstream psychotherapeutic encounters remains to be seen. However, clinicians should begin to familiarize themselves with these data and concepts so that they can soon be put to use for more effective clinical treatment of psychiatric conditions involving pathological learning, conditioning, and habits.
Sherwood Brown and colleagues from the University of Texas Southwestern Medical Center have completed a successful placebo-controlled trial of citicoline for bipolar and unipolar depression with comorbid methamphetamine dependence. Forty-eight participants with methamphetamine dependence and either unipolar or bipolar depression were randomized to either citicoline (2000 mg/day) or placebo for 12 weeks. Those receiving citicoline had significantly greater improvement in scores on the Inventory of Depressive Symptoms compared with those who received placebo, and patients receiving citicoline stayed in the study significantly longer, with completion rates of 41% on citicoline and 15% on placebo.
In 2007, the same team of investigators reported in the Journal of Clinical Psychopharmacology that citicoline had positive effects in bipolar patients with cocaine dependence, who experienced significant decreases in cocaine use and fewer cocaine-positive urine tests while taking citicoline.
In a study of rodents exposed to stress (by being forced to enter another rodent’s territory) and given the opportunity to self-administer cocaine, those exposed to a few brief episodes of stress increased their cocaine use and engaged in binge-like episodes, while those exposed to stress chronically showed suppressed cocaine use.
At the American College of Neuropsychopharmacology meeting in December 2009, Klaus Miczek and colleagues from Tufts University in Boston presented a fascinating study indicating that the temporal aspects of the experience of social stress may have dramatic impact not only on defeat stress behaviors and the associated biochemistry, but also on the likelihood that an animal adopts cocaine self-administration. These investigators compared episodic versus chronic defeat stress in rodents.
Episodic social defeat stress consisted of four brief confrontations between an intruding animal and an aggressive resident rat over the course of a period of ten days. In contrast, chronic subordination stress involved the continuous exposure of the intruder rat to an aggressive resident over five weeks, during which time the intruder lived in a protective cage within the resident’s home cage.
The episodically defeated intruder rats showed increases in intravenous cocaine self-administration and prolonged binge-like episodes, along with increases in brain-derived neurotropic factor (BDNF), which is necessary for long-term learning and memory, in the midbrain ventral-tegmental area (VTA) and increased dopamine release in the nucleus accumbens, the reward area of the brain. In contrast, the continuously subordinate rats showed the opposite pattern of suppressed cocaine intake, suppression of dopamine release in the n. accumbens, and reduced BDNF in the VTA.