Nestler Lab

Laboratory of Molecular Psychiatry



Loss of control over drug use or the compulsive seeking and taking of drug despite adverse consequences.

A brain region particularly important for conditioned forms of learning. This region is critical for establishing associations between aversive and rewarding stimuli and environmental cues.


Basal Transcription Complex
A complex comprised of RNA polymerase (which transcribes the new RNA strand) and numerous regulatory proteins (some of which unwind nucleosomes via histone acetyl transferase activity).

Brain Derived Neurotrophic Factor (BDNF)
A type of neurotrophic factor which regulates neuronal growth, survival, and function during development and in the adult brain.


CREB (cAMP Response Element Binding Protein)

A type of transcription factor implicated in learning and memory, depression, and drug addiction.


An altered physiological state that develops to compensate for persistent drug exposure and that gives rise to a withdrawal syndrome upon cessation of drug exposure. Dependence may contribute to the dysphoria (negative or aversive emotional state) and high rates of relapse seen during early phases of withdrawal.

A mental state of depressed mood characterized by feelings of sadness, despair and discouragement. Depression ranges from normal feelings of the blues through dysthymia to major depression. Symptoms of depression include sadness, inactivity, difficulty in thinking and concentration, a significant increase or decrease in appetite and time spent sleeping, feelings of dejection and hopelessness, and sometimes suicidal tendencies.

Dorsal raphe
This is the primary site of serotonergic neurons in the brain, which, like noradrenergic neurons, pervasively modulate brain function to regulate the state of activation and mood of the organism.

Drug Addiction
See Addiction.

Negative or aversive emotional state.


A type of transcription factor that appears to play an important role in drug addiction. It is unique due to its prolonged stability.

Frontal cortex
Frontal regions of cerebral cortex, which mediate executive functions and exert control over the subcortical structures that are targets of natural and drug rewards as well as of stressful situations. Such regions include the medial prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex.


G proteins
GTP-binding membrane proteins that couple many extracellular receptors to intracellular effector proteins.


This region is critical for declarative memory, the memory of persons, places, and things. Along with the amygdala, it establishes memories of drug experiences which are important mediators of relapse. It may also contribute to cognitive abnormalities seen in depression.


This region integrates brain function with the physiological needs of the organism. The hypothalamus is important for coordinating an individual’s interest in rewards with the body’s physiological state.


Locus coeruleus
This is the primary site of noradrenergic neurons in the brain, which pervasively modulate brain function to regulate the state of activation and mood of the organism. The locus coeruleus is located on the floor of the fourth ventricle in the anterior pons. It also is an important mediator of physical dependence on opiates.


Those factors which cause an organism to behave or act in either a goal-seeking or satisfying manner. They may be influenced by physiological drives or by external stimuli.


A tightly wound span of DNA that is bound to histones and other nuclear proteins. Transcription of a gene requires the unwinding of a nucleosome, which makes the gene accessible to a basal transcription complex.

Neurons – or – nerve cell
A cell specialized to transmit electrical nerve impulses. A typical neuron consists of dendrites (fibers that receive stimuli and conduct them inward), a cell body (a nucleated body that receives input from dendrites), and an axon (a fiber that relays the nerve impulse from the cell body outward to its terminals, the synaptic knobs). Impulses are conducted by neurotransmitter chemicals released by the axon’s synaptic endings across the synapses (junctions between) or, in some cases, pass directly from one neuron to the next.

A substance released from the axon terminal or ending of a presynaptic neuron to either excite or inhibit a target cell. Examples of neurotransmitters include: glutamate, GABA ( g -amino-butyric acid), dopamine, serotonin, acetylcholine, norepinephrine, epinephrine (adrenaline), glycine, substance P, and enkephalin.

Neurotrophic Factor
Nerve growth factors that regulate the birth and survival of neurons during development and modify their functioning and survival in the adult brain. Neurotrophins are a major type of neurotrophic factor, an example of which is BDNF (Brain Derived Neurotrophic Factor).

Norepinephrine (noradrenaline)
Catecholamine neurotransmitter, used by the sympathetic nervous system and in the brain.

Nucleus Accumbens (NAc)
Also called ventral striatum, this region is a principle target of VTA dopamine neurons and mediates the rewarding effects of natural rewards and drugs of abuse. Together, the VTA-NAc pathway, also called the mesolimbic dopamine system, is the most important reward circuit in brain. It is also highly responsive to stress.


Originally, a term denoting synthetic narcotics resembling opiates but increasingly used to refer to both opiates and synthetic narcotics.


Protein phosphorylation
A process wherein phosphate groups are added to proteins by protein kinases or removed from proteins by protein phosphatases. The addition or removal of phosphate groups dramatically alters protein function and leads to the myriad of biological responses in question.


Reinforcing Stimulus
A stimulus that increases the probability that behaviors paired with it will be repeated.

A stimulus that the brain interprets as intrinsically positive, or as something to be approached.

Reward Regions
Regions of the brain that mediate reward and reinforcement. See Amygdala, Dorsal Raphe, Frontal Cortex, Hippocampus, Hypothalamus, Locus Coeruleus, Nucleus Accumbens, and Ventral Tegmental Area.


Second Messengers
Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. Second messengers include cAMP [cyclic AMP], calcium, phosphatidylinositol, and nitric oxide.

Enhanced drug responsiveness with repeated exposure to a constant dose. May be referred to as a reverse tolerance. Sensitization may contribute to the increased risk of relapse after longer withdrawal periods.


Reduced drug responsiveness with repeated exposure to a constant drug dose. Tolerance may contribute to the escalation of drug intake seen during the development of an addiction.

Transcription factors
Proteins that bind to specific sites (response elements; also called promoter or enhancer elements) present within the regulatory regions of certain genes and thereby increase or decrease the rate at which those genes are transcribed. Transcription factors act by enhancing (or inhibiting) the activity of the basal transcription complex, in some cases by altering nucleosomal structure through changes in histone acetyl transferase or distone deacetylase activity of the complex.


Ventral Tegmental Area (VTA)
Located in the ventral midbrain, this is the site of dopaminergic neurons, which tell the organism whether an environmental stimulus (natural reward, drug of abuse, stress) is rewarding or aversive. These neurons are also highly responsive to stress.