Nestler Lab

Laboratory of Molecular Psychiatry

Molecular Basis of Addiction and Depression

Introduction to Drug Addiction

Like most psychiatric disorders, drug addiction is defined today solely on the basis of behavioral terms. For example, addiction can be defined as a loss of control over drug intake, or the compulsive seeking and taking of drugs despite adverse consequences. The devastating consequences of addiction are well known. Addiction is the leading cause of AIDS, lung cancer, and cirrhosis of the liver and costs society hundreds of billions of dollars due to loss of life and productivity. Unfortunately, today’s treatments for addiction are inadequate for many addicts.

Addiction is complex, and involves many types of social and psychological factors. However, it is, at its core, a biological process: the effect of a biological substance (drug of abuse) on a biological substrate (a vulnerable brain). Addiction is also highly heritable: about 50% of the risk for an addiction is genetic, and this holds true for many different addictions, including to heroin, cocaine, alcohol, and nicotine. However, the specific genes which comprise that risk remain unknown.

Over the past several decades, the behavioral abnormalities that are used to define addiction have been modeled with increasing accuracy in animal models. The availability of such models has made it possible to investigate the neurobiological basis of the addiction process. Upon initial exposure, a drug of abuse enters the brain and binds to its initial protein target. This binding perturbs synaptic transmission at particular synapses in the brain, which in turn causes the acute behavioral effects of the drug (e.g., high, euphoria, sedation, activation, etc.). These acute actions of a drug of abuse do not per se explain addiction, which requires adaptations to repeated drug administration. These adaptations presumably involve molecular and cellular changes in particular neurons in the brain, which alter the functioning of the neural circuits in which those neurons operate to lead ultimately to the behavioral abnormalities that characterize an addicted state. As a result, the process of addiction can be viewed as a form of drug-induced neural plasticity.

We now know the acute protein targets for most drugs of abuse and understand in considerable detail how those actions perturb synaptic transmission after initial exposure to the drugs. In addition, considerable progress has been made in identifying the molecular and cellular adaptations that are induced in the brain in response to chronic drug administration, and in relating individual adaptations to the behavioral abnormalities that define addiction. One of the major gaps in our knowledge is understanding how altered functioning of individual nerve cells, as a result of those molecular and cellular adaptations, leads to abnormalities in complex behavior. Such an understanding will require a more sophisticated comprehension of brain function at a neural circuit level, which is not currently available.

The fact that structurally diverse drugs all cause a similar behavioral abnormality (addiction) can be explained by the fact that each drug, despite many distinct actions in the brain, converge in producing some common actions, prominent among which is activation of the brain’s reward circuitry. The most important part of this circuitry is the mesolimbic dopamine system, comprised of dopamine neurons in the ventral tegmental area (VTA) and their projections to the limbic forebrain, in particular the nucleus accumbens (NAc). Drugs of abuse affect the VTA-NAc pathway with a power and persistence not seen in response to natural rewards. One likely mechanism of addiction, then, is that repeated, extreme perturbation of these neurons changes them in a way that leads to dramatic alterations in reward mechanisms and motivational state that underlie addiction.

Several types of functional alterations have been described in the addiction field. Tolerance, or reduced drug responsiveness with repeated exposure to a constant drug dose, may contribute to the escalation of drugcocaineintake seen during the development of an addiction. Dependence, or an altered physiological (functional) state that develops to compensate for persistent drug exposure. Dependence gives rise to a withdrawal syndrome upon ceasing of drug exposure, and may contribute to the dysphoria (negative or aversive emotional state) and high rates of relapse seen during early phases of withdrawal. Sensitization, or enhanced drug responsiveness with repeated exposure to a constant dose, may contribute to the increased risk of relapse after longer withdrawal periods.

Drug addiction likely involves changes in many brain structures. Changes in the VTA and NAc increase or decrease an individual’s sensitivity to the rewarding effects of drug exposure and lead to withdrawal symptoms when the drug is stopped. Changes in the amygdala and hippocampus are important in mediating drug craving and relapse triggered by cues associated with past drug use (e.g., drug paraphernalia, locations of past drug use), while changes in frontal cortex may be particularly critical for the loss of control over drug use, an essential feature of addiction.

Introduction to Depression

Depression is among the most common form of mental illness. It affects up to 15% of the population and has been described by mankind for several millennia. The term melancholia (meaning black bile in Greek) was first used by Hippocrates around 400 B.C. Most of the major symptoms of depression observed today were recognized in ancient times, as were the contributions of innate predispositions and external factors in causing the illness. The ancients also recognized a large overlap of depression with anxiety and excessive alcohol consumption, both of which are well established today. Indeed, similarities between ancient descriptions of depression and those of the modern era are striking, yet it wasn’t until the middle part of the 19 th Century that the brain became the focus of efforts to understand the pathophysiology of this disorder.

While many brain regions have been implicated in regulating emotions, we still have a very rudimentary understanding of the neural circuitry underlying normal mood and the abnormalities in mood that are the hallmark of depression. This lack of knowledge is underscored by the fact that even if it were possible to biopsy the brains of patients with depression, there is no consensus in the field as to the site of the pathology and hence the best brain region to biopsy. This is in striking contrast to other neuropsychiatric disorders (e.g., Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis) where pathologic lesions have been identified in specific regions of the central nervous system.

It is likely that many brain regions mediate the diverse symptoms of depression. This is supported by human brain imaging studies-still in relatively early stages-which have demonstrated changes in blood flow or related measures in several brain areas. Similarly, studies of the brains of depressed patients obtained at autopsy have reported abnormalities in many of these same brain regions. Much work remains, however, since some of the imaging and autopsy studies have yielded contradictory findings; still, this work has underscored the need to investigate mechanisms of mood regulation and dysregulation in numerous brain areas.

Knowledge of the function of these brain regions under normal conditions suggests the aspects of depression to which they may contribute. Frontal cortex and hippocampus may mediate cognitive aspects of depression, such as memory impairments and feelings of worthlessness, hopelessness, guilt, doom, and suicidality. The VTA-NAc, amygdala, and related brain areas are important in reward, motivation, and emotional memory, as mentioned earlier, and could as a result mediate the anhedonia (decreased drive and reward for pleasurable activities), anxiety, and reduced motivation that predominate in many patients. Given the prominence of so-called neurovegetative symptoms of depression, including too much or too little sleep, appetite, and energy, as well as a loss of interest in sex and other pleasurable activities, a role for the hypothalamus has also been speculated.

It is striking that the brain regions implicated prominently in depression are the same as those implicated in addiction. This is not surprising, since key features of both conditions involve abnormalities in the same behavioral domains (e.g., reward, pleasure, motivation, neurovegetative functions). The involvement of common neural substrates of addiction and depression is a major driving force of our research. Thus, we are interested in understanding the molecular constituents of the brain’s reward regions that control the functioning of these circuits under normal conditions as well as the molecular changes that drugs and stress induce these circuits that contribute to symptoms of addiction and depression.