0

NSB 239: Functional Anatomy of the Human Brain

The Anatomy of Addiction

The nucleus accumbens: anatomy, function, and its role in the mesolimbic circuit.

Raghu Kiran Appasani

12/15/2010

In this review, I hope to demonstrate the current understanding of the brain structures and circuitry involved in the formation of an addiction as well as a brief overview of where the field stands in terms of understanding the molecular mechanisms of long-term addiction.

1

Addiction can be best defined as the loss of control over drug use, or the compulsive

seeking and taking of drugs despite adverse consequences. Addiction continues to impose

enormous human and financial costs on society, but available treatments remain inadequate.

Addiction is caused by the actions of a drug of abuse on a vulnerable brain and generally

requires chronic use, repeated exposure. This process is strongly influenced by many factors

including genetic makeup, epigenetic makeup, psychological context, and social context in

which the drug use occurs. Unfortunately, once an addiction is formed, it can last life-long in

which individuals show intense drug cravings and increased risk for relapse after years and even

decades of abstinence. Researchers have inferred from this result that addiction involves

extremely stable changes in the brain and especially in specific circuits and regions of the brain.

In this review, I hope to demonstrate the current understanding of the brain structures and

circuitry involved in the formation of an addiction as well as a brief overview of where the field

stands in terms of understanding the molecular mechanisms of long-term addiction.

THE MESOLIMBIC CIRCUIT

Figure 1 | Key neural circuits of addiction. Dotted lines indicate limbic afferents to the nucleus accumbens (NAc). Blue lines represent efferents from the NAc thought to be involved in drug reward. Red lines indicate projections of the mesolimbic dopamine system thought to be a critical substrate for drug reward. Dopamine neurons originate in the ventral tegmental area (VTA) and project to the NAc and other limbic structures, including the olfactory tubercle (OT), ventral domains of the caudate-putamen (C-P), the amygdala (AMG) and the prefrontal cortex (PFC). Green indicates opioid-peptide-containing neurons, which are involved in opiate, ethanol and possibly nicotine reward. These opioid peptide systems include the local enkephalin circuits (short segments) and the hypothalamic midbrain β-endorphin circuit (long segment). Blue shading indicates the approximate distribution of GABAA (γ-aminobutyric acid) receptor complexes that might contribute to ethanol reward. Yellow solid structures indicate nicotinic acetylcholine receptors hypothesized to be located on dopamine- and opioid-peptide-containing neurons. (ARC, arcuate nucleus; Cer, cerebellum; DMT, dorsomedial thalamus; IC, inferior colliculus; LC, locus coeruleus; LH, lateral hypothalamus; PAG, periaqueductal grey; SC, superior colliculus; SNr, substantia nigra pars reticulata; VP, ventral pallidum.) (Nestler EJ 2007)

2

In a world in which the environment is constantly changing, animals must learn new

behavioral strategies in order to successfully retrieve food, sex, and other necessities.

Fortunately, this synaptic plasticity is available and occurs within the mesolimbic system, a key

reward circuit. This synaptic plasticity provides animals the ability to “adapt and perform

essential goal-directed behaviors” (Chen et al 2010). Paradoxically, drugs of abuse can also

induce this synaptic plasticity within the circuit, and these changes are linked to the promotion of

addictive drug-seeking behaviors. The mesolimbic system is formed by two integral parts of the

brain: the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Dopaminergic

neurons in the VTA provide the major source of dopamine (DA) to the limbic structures,

especially the NAc (Hyman et al 2006). The VTA specifically consists of dopaminergic neurons

which respond to glutamate. These cells respond when stimuli indicative of a reward are present.

The VTA supports learning and sensitization development. The NAc consists mainly of medium-

spiny projection neurons (MSNs), which are GABAergic. The NAc is typically associated with

acquiring and eliciting conditioned behaviors and involved in the increased sensitivity to drugs

as addiction progresses. The NAc is also involved in the mesocortical circuit in which it projects

to the prefrontal cortex to aid with cognitive functions. Overall, the VTA and NAc, along with

other areas, including: the prefrontal cortex, thalamus, and amygdala, are considered to play a

crucial role in the control of motivated and goal-directed behaviors. Virtually all drugs of abuse

that cause addiction increase the dopamine release in the mesolimbic pathway. It has been

hypothesized and much research has shown that drugs of abuse hijack the mesolimbic reward

circuit to induce aberrantly long-lasting forms of synaptic plasticity that may serve to drive the

persistent drug-seeking behaviors which are observed with addicts. People suffering from

3

addiction have this drug-seeking behavior even when they are aware of the severe negative

complications the drug has on their lives and those around them.

The NAc and the VTA both receive extensive glutamatergic inputs from the prefrontal

cortex and other brain areas, and these excitatory inputs have been considered critical for

establishing and expressing addictive and motivated behaviors. This increased glutamate

function onto VTA dopaminergic neurons may alter the generation of firing in these neurons

during goal-directed behaviors and promote repetition of these behaviors. Recent imaging studies

have provided new insights on the role of DA in substance abuse and addiction in the human

brain. These studies have shown that the reinforcing effects of drugs of abuse in human beings

are contingent not just on DA increases per se in the reward circuit, but also on the rate of DA

increases. It has been shown that the faster the increases, the more intense the reinforcing effects

(Volkow et al 2007).

NUCLEUS ACCUMBENS

The NAc specifically plays a central role in the integration of cortical afferent systems

under the modulatory influence of DA. Consequently, the NAc and many of its inputs are also

involved in influencing and regulating DA neuron activity states. As mentioned above, the NAc

receives extensive excitatory afferents from the cerebral cortex and thalamus. All of these

structures networked together form essential circuitry necessary to optimize the behavioral

response to rewards; alterations of elements in this circuitry are strongly associated in the

development of addictive disorders (Sesack and Grace 2010).

The NAc is divided into two major regions: the core is the central portion directly

beneath and continuous with the dorsal striatum and surrounding the anterior commissure and

4

the shell occupy the most ventral and medial portions of the NAc. The core and shell regions

share striatal characteristics in that approximately 90 percent of the cells are typically medium

spiny projection neurons as stated above. The remainder is made up of local circuit interneurons

which include cholinergic and parvalbumin cells (Kawaguchi et al 1995). The core of the NAc

and shell differ in terms of their specific projection patterns, functions, neurochemistry, and

morphology. The shell division, specifically its medial aspect, is often associated with drug

reward. Although, the core is linked to motivated behaviors that are cue-conditioned, it should be

noted that the core is also involved in drug-seeking behaviors (Sesack and Grace 2010). The

NAc has been a difficult structure to define in an organizational sense; patterning of cells and

input-output channels is known to be highly complex.

Afferents

Figure 2 | Principal afferents linking brain centers for goal-directed behavior with the NAc and VTA. Red indicates inhibitory structures and pathways, green excitatory connections, and yellow the modulatory influence of DA. Please refer to the text for detailed explanation. BLA, basolateral amygdala; LHA/LPOA, lateral hypothalamic and lateral preoptic areas; LHb, lateral habenula; Mid/Intral Thal, midline and intralaminar thalamic nuclei; NAc, nucleus accumbens; PAG/RF, periaqueductal gray and reticular formation; PFC, prefrontal cortex; PPTg/LDT, pedunculopontine and laterodorsal tegmentum; RMTg, mesopontine rostromedial tegmental nucleus; VP, ventral pallidum; vSub/Hipp, ventral subiculum of the hippocampus; VTA, ventral tegmental area. (Sesack and Grace 2010)

5

Figure 2 demonstrates the multiple limbic associated areas that provide the excitatory

cortical innervation of the NAc, including medial and lateral divisions of the prefrontal cortex,

entorhinal cortex and ventral subiculum of the hippocampus (vSub), and basolateral amygdala

(BLA). The shell of the NAc is primarily innervated by the ventral portions of the infralimbic,

prelimbic, medial orbital, and ventral agranular insular cortices. On the other hand, the core of

the NAc is primarily innervated from the dorsal parts of the prelimbic cortex and dorsal

agranular insular areas. The vSub projects caudomedially with a preference for the NAc shell

while the dorsal subiculum projects to more rostrolateral regions such as the core. The BLA

generates a complex rostral to core and caudal to shell topography. Much research shows that the

cortical neurons are the promoters of goal-directed behaviors, in which the vSub provides

contextual and spatial information, the prefrontal cortex supplies executive control such as task

switching and response inhibition, and the BLA provides information regarding conditioned

associations. The NAc is the primary site for many of these cortical structures; however, they

also maintain many other interconnections with one another. Many afferents from the thalamus

also exist including: the paraventricular, paratenial, intermediodorsal, central medial, rhomboid,

reunions, and rostral parafascicular nuclei (Sesack and Grace 2010). In the primate and rodent

models, the NAc core is innervated mainly by the intermediodorsal, the shell by the

paraventricular, and the rostral pole by the paratenial nucleus. In addition to innervating the

NAc, some thalamic neurons also project to the prefrontal cortex. These neurons are not well

understood, but some research has shown that they are likely to operate in arousal and directing

attention to significant events (Smith et al 2004).

The NAc receives very few strong inhibitory afferents. There are GABA projections from

the VP, other parts of the basal forebrain, and the VTA. The shell portion of the NAc receives a

6

projection from orexin (hypocretin) neurons in the lateral hypothalamus. Orexin is a peptide that

is generally reported to be excitatory, but in this case it appears to have inhibitory actions on

neurons within the NAc (Martin et al 2002). The NAc receives modulatory afferents from the

brainstem, including DA and GABA projections from the medial substantia nigra zona compacta

(SNc) and VTA. The DA innervation forms the essential component of reward circuitry and is

recruited by both natural rewards and drugs (Koob 1992). The NAc also receives serotonin and

non-serotonin inputs from the dorsal raphe nucleus. There is a small norepinephrine projection

from the locus coeruleus (LC) and nucleus of the solitary tract directed towards the NAc shell.

There are also additional afferents from other brainstem regions such as the parabrachial nucleus,

the pedunculopontine tegmentum (PPTg), and the periaqueductal gray (Sesack and Grace 2010).

As mentioned earlier, there are many dopamine afferents to the NAc which synapse onto

GABA neurons with medium spiny morphology. These medium spiny neurons have dendritic

spines that receive excitatory synapses from cortical axon terminals which sometimes also

display inhibitory or modulatory–type synapses from DA axons. In the rodent model, DA and

thalamostriatal projections have also been reported for the midline paraventricular innervation to

the NAc shell (Pinto et al 2003).

7

Efferents

Figure 3 | Hypothetical direct and indirect output pathways whereby the NAc core and shell may disinhibit or inhibit, respectively, adaptive motor pathways for maximizing reward acquisition. Only major projections are shown. Red indicates inhibitory structures and pathways, whereas green indicates excitatory connections. BF Hypoth, basal forebrain and hypothalamus; MD Thal, mediodorsal thalamic nucleus; NAc, nucleus accumbens; PFC, prefrontal cortex; SNr, substantia nigra zona reticulata; STN, subthalamic nucleus; VP dl/vm, ventral pallidum, dorsolateral, and ventromedial; VTA, ventral tegmental area. (Sesack and Grace 2010)

As depicted in figure 3, there are major projections from the NAc which lead to the VP,

substantia nigra, VTA, hypothalamus, and brainstem. The core of the NAc projects mainly to the

dorsolateral portion of the VP, the substantia nigra zona reticulate (SNr), and the entopeduncular

nucleus. The shell primarily innervates the ventrome-dial VP division, lateral hypothalamic area,

later preoptic area, substantia innominate, SNc, VTA, periaqueductal gray, parabrachial nucleus,

and PPTg. The VP regions also project to some of the same targets, with the subthalamic nucleus

and the ventromedial VP projecting to the VTA, basal forebrain, and preoptics areas while the

dorsolateral VP innervates primarily the SNr. A study by Nauta in 1978 showed that projections

from the shell of the NAc to the VTA influence DA cells that in turn project to the NAc core,

sequentially creating a medial to lateral series of spiraling projections that allow limbic

associated structures to influence transmission in motor-related parts of basal ganglia circuitry

(Nauta et al 1978).

8

The direct pathway from the NAc core involves primarily projections to the SNr and

from there to the mediodorsal thalamus. The dorsolateral VP (targeted by the NAc core) has

minor porjections to the mediodorsal thalamus, but still mediates direct actions on thalamic

activity (Lavin and Grace 1994). Through the direct route, cortical activation of NAc neurons

leads to disinhibition of action plans that facilitate reward acquisition. The indirect circuit travels

through the dorsolateral VP and subthalamic nucleus before reaching the SNr. Activation of this

circuit most likely leads to inhibit motor plans that are maladaptive, either for avoiding

punishment or for obtaining reward (Redgrave et al 1999).

A division of the NAc shell neurons into indirect and direct pathways is complicated

because of its hybrid structure containing part limbic region and part basal ganglia. In addition to

being a ventral extension of the striatum, the shell is also an extended part of the amygdala

complex that has projections to hypothalamic and brainstem structures which are crucial for

visceral motor control and affect (Waraczynski 2006). However, it has been hypothesized that

both direct and indirect projections might involve the ventromedial VP, with the direct circuit

contacting cells that project to the mediodorsal thalamus (Nicola et al 2000; O’Donnell et al

1997) and the indirect projections involving VP neurons that then project to the subthalamic

nucleus. Parts of the basal forebrain and hypothalamus receive projections from the NAc and

serve the role of output structures for visceral motor functions. Another hypothesis is that the

direct and indirect pathways from the NAc shell converge on the VTA. From this the VTA may

act as a basal ganglia output structure via projections to the mediodorsal thalamus. The direct

pathway would proceed from the NAc to the VTA and the indirect pathway would be first

involved the connection to the ventromedial VP and then project to the VTA.

9

ADDICTIVE DISORDERS

Drug addiction is defined as the progressive and often fatal behavioral syndrome

characterized by compulsive drug-seeking and consumption despite serious negative

consequences (Nestler et al 2009). The lives of these addicts are centered around their drug use

such that it can cost them their personal relationships, jobs, happiness, and in some cases, their

lives. Many drug addicts have lost their ability to make their own choices and those who seek

treatment report that they realize the negative consequences of their addiction but are unable to

alter their behavior. Why do people associate themselves with the use of addictive drugs? In both

animals and humans, about 50 percent of the risk for addiction is genetic. Pleasurable states

induced by drug use are very crucial motivators for initial drug use. These actions in turn cause

undesirable changes in brain reward circuitry which promotes future drug use. Sensory cues

produced by natural reinforcers activate reward pathways under normal circumstances and help

humans to have an evolutionary advantage; however addictive drugs hijack this system,

bypassing the need for evolutionarily useful behaviors and causing cellular and molecular

changes within neurons of the circuitry.

Many people including some physicians believe that drug addiction is psychological and

not neurobiological. This population of citizens is mistaken; in a laboratory setting in which

social and environmental variables are controlled, normal animals with access to addictive drugs

typically engage in self-administration of them. In this self-administration paradigm, the amount

of work (number of lever presses or nose pokes) an animal does to gain access to a given amount

of drug indicates the strength of reinforcement induced by the drug. This research clearly shows

a relationship between neurobiological changes and the chronic use of addictive drugs; the same

self-administration paradigm is mimicked by humans in the real world. Once dependence is

10

formed in an animal, tolerance is increased and leads to increased drug use. In this case,

tolerance is experienced when a specific dose taken previously to generate a certain kind of

psychological state is no longer effective when taken subsequently, thus it becomes necessary to

increase the dose of the substance to maintain the same psychological effect of the drug (Siegel

and Sapru 2011).

Figure 4 | Highly simplified scheme of converging acute actions of drugs of abuse on the VTA-NAc. Stimulants directly increase dopaminergic transmission in the NAc. Opiates do the same indirectly: they inhibit GABAergic interneurons in the VTA, which disinhibits VTA dopamine neurons. Opiates also directly act on opioid receptors on NAc neurons, and opioid receptors, like D2 dopamine receptors, signal via Gi, hence the two mechanisms converge within NAc neurons. The actions of the other drugs remain more conjectural. Nicotine activates VTA dopamine neurons directly via stimulation of nicotinic cholinergic receptors on those neurons, and indirectly via stimulation of its receptors on glutamatergic nerve terminals that innervate the dopamine cells. Ethanol, by promoting GABAA receptor function, may inhibit GABAergic terminals in VTA and hence disinhibit VTA dopamine neurons. It may similarly inhibit glutamatergic terminals that innervate NAc neurons. Cannabinoid mechanisms involve activation of CB1 receptors (which, like D2 and opioid receptors, are Gi linked) on glutamatergic and GABAergic nerve terminals in the NAc and possibly on NAc neurons themselves. PCP may act by inhibiting postsynaptic NMDA glutamate receptors in the NAc. Finally, evidence suggests that nicotine and ethanol may activate endogenous cannabinoid pathways. (Nestler EJ 2009)

There are many classes of drugs that act in various ways on the reward circuit and

interact with various structures of the system (Figure 4). Substances that activate CNS functions,

which may result in heightened alertness, agitation, mild improvement of mood, increased heart

rate, loss of appetite, and aggression are called stimulants and include substances such as:

caffeine, amphetamines, cocaine, and nicotine. On the other hand sedatives have a depressive

effect on CNS, quite possibly by activating GABAergic inhibitory systems and include

11

substances such as: alcohol, barbiturates, and benzodiazepines. They might produce a mild

elevation of mood, sedation, sleep, behavioral disinhibition, and a decrease in anxiety. Other

classes of drugs include: (1) narcotics or opioid drugs (e.g. heroin and morphine) and (2)

hallucinogens such as LSD, phencyclidine (“angel dust”), bromocriptines (when used to treat

Parkinson’s), and cannabis (marijuana). The effects of short-term drug exposure on extracellular

DA concentrations in the human brain is studied using positron emission tomography (PET) and

D2 DA receptor radioactive ligands that are sensitive to competition with endogenous DA. A

research group used stimulant drugs methylphenidate and amphetamine to study the relationship

between reinforcing properties and effects of drugs on DA. Methylphenidate, like cocaine,

increases DA by blocking DA transporters, whereas amphetamine, like methamphetamine,

increases DA by releasing it from the terminal via DA transporters. Many synaptic increases in

DA concentration occur during drug intoxication in both non-addicted and addicted subjects.

Inasmuch as it is the loss of control and compulsive drug taking that characterizes addiction, the

short-term drug-induced DA level increase alone does not explain this condition. Hence, it is

hypothesized that repeated perturbation of DA-regulated brain circuits involved with

reward/saliency, motivation/drive, inhibitory control/executive function, and

memory/conditioning lead to addiction (Volkow et al 2007).

Molecular Mechanisms

The rodent model has been extensively used in drug addiction research. Previous research

has shown that regulation of gene expression is one mechanism that leads to stable changes

within neurons. The idea is that repeated exposure to a drug will eventually lead to changes at a

cellular level that then causes altered rates of transcription. Ultimately, an increase of these

changes will lead to long-term changes in the neural circuit and long-term behavioral effects. At

12

the transcriptional level, two particular factors have been associated with addiction: the cyclic-

AMP response-element-binding protein (CREB) and ΔFosB.

CREB has been found to have a very important role with respect to opiate addiction (i.e

morphine). With the abuse of opiates, there is an upregulation of the cAMP pathway observed

leading to lower levels of the activated CREB gene. The inhibition of CREB leads to an increase

of tyrosine hydroxylase (TH). TH is a very important enzyme in the production of the chemical

dopamine. As stated before, drugs of abuse cause an increase in the release of dopamine

throughout the reward circuit. An overexpression of CREB within this pathway decreases the

rewarding effects of opiates and cocaine. On the other hand, inhibiting CREB seems to have the

opposite effect by promoting rewarding effects. Understanding the detailed mechanistic role and

function of CREB in addiction will lead scientists to the development of diagnostic screening for

specific substances abuses (Nestler 2007).

Figure 5 |From the Rush to the Addiction, Cocaine’s Effects in the Brain: (Brain inset) Cocaine causes euphoria in the short term and addiction in the long term via its effects on the brain’s limbic system, which consists of numerous regions, including the ventral tegmental area (VTA) and nucleus accumbens (NAc), centers for pleasure and feelings of reward; the amygdala and hippocampus, centers for memory; and the frontal cortex, a center for weighing options and restraint. (Main panel) Cocaine causes the neurotransmitter dopamine to build up at the interface between VTA cells and NAc cells, triggering pleasurable feelings and NAc cellular activities that sensitize the brain to future exposures to the drug. Among the activities are increased production of genetic transcription factors, including ΔFosB; altered gene activity; altered production of potentially many proteins; and sprouting of new dendrites and dendritic spines. (Graph inset) The time courses of cocaine-induced buildup of ΔFosB and cocaine-related structural changes (dendrite sprouting) suggest that these neurobiological effects may underlie some of the drug’s short-term, medium-term, and long-term behavioral effects. (Hyman 2006)

13

Acute administration of many classes of drugs of abuse (including cocaine, amphetamine,

opiates, nicotine, and alcohol) causes the activation of a transcription factor, ΔFosB within the

NAc. There is a correlation between increased levels of ΔFosB with increased levels of

‘addictive’ cocaine seeking behavior. Many users of drugs of abuse use the drug chronically over

long periods of time. Hence, discovering biomarkers such as ΔFosB can lead the way for a

biological diagnostic test for screening patients with chronic drug addiction.

Morphological Adaptations

Morphological studies provide a qualitative look at the effects of drugs of abuse on the

brain. Many people ask do drugs really alter the brain biologically? Yes, they do. Drugs of abuse

physically change the size of your neurons and as explained above also alter cellular and

molecular activities throughout one’s brain. Ethanol, one of the most abused substances

worldwide has some of the most drastic effects on neurons within the human brain with surface

area decreases of ~30% per neuron (Appasani et al 2010)! Morphine, another drug that is

commonly used as a pain reducer in medical and non-medical venues causes a decrease of ~25%

mean surface area per neuron (Russo et al 2007). The list of various drugs of abuse that decrease

the cell size of neurons within the human brain continues to grow. Recent research has shown

that chronic use of cannabinoids decreases the dopaminergic cell soma size within the VTA.

Preliminary results have shown that cocaine does not affect the dopaminergic cell soma size

within the VTA. This could be due to the dopamine transporter being in the NAc and hence

cocaine is acting directly on the NAc and not the VTA like other drugs of abuse (Appasani et al

2010). Comparing the morphological properties across various classes of drugs leads to the

discovery of common mechanistic pathways that will eventually lead to treatments which target

specific steps within these pathways. The majority of drugs abusers tend to abuse more than one

14

drug and thus this common mechanistic pathway is vital to the formation of a universal

treatment.

CLINICAL APPLICATIONS

The circuits involved in driving motivated behaviors are implicated in a broad array of

disease states. Disorders of these circuits can lead to depression, hyperactivity, addiction,

obsessive-compulsive disorder, and a number of other psychiatric diseases. For example, the

integration of the frontal cortex into the reward circuit regulates goal-directed behavior and

disruption of this can lead to mental illnesses such as substance abuse and schizophrenia. A

better understanding of structures involved in this pathway and how they integrate with one

another may provide a better neuroanatomical basis for interpreting novel findings from imaging

studies and can lead to an individualized approach to the treatment of psychiatric diseases.

Recent imaging studies have corroborated that the role of DA in reinforcing effects of

drugs of abuse in human beings and have extended traditional views of DA involvement in drug

addiction. These novel findings suggest multicomponent strategies for the treatment of drug

addiction that include strategies to (1) decrease the reward value of the drug of choice and

increase the reward value of nondrug reinforcers, (2) weaken conditioned drug behaviors, (3)

weaken the motivational drive to take the drug, and (4) strengthen frontal inhibitory and

executive control (Volkow et al 2007).

By understanding these complex adaptations that can be elicited in the brain due to drug

treatment, they can be related to specific behavioral features of addiction and be directed to the

development of new treatments of addictive disorders. Through the integrated approach that

establishes the causal links between molecular, cellular, morphological, behavioral, and

15

anatomical levels will it be possible to understand the permanent neural and behavioral basis of

addiction.

16

Works Cited

Appasani RK, Mazei-Robison MS, Nestler EJ. Your brain on drugs: neuronal adaptations within the reward pathway due to chronic drug use. Mount Sinai School of Medicine Poster (2010).

Hyman SE, Malenka RC, Nestler EJ. Neural mechanism of addiction: the role of reward-related learning and memory. Annual Reviews of Neuroscience 29, 565-598 (2006).

Koob GF. Drugs of Abuse: anatomy, pharmacology and function of reward pathways. Trends in Pharmacological Sciences 13, 177-184 (1992).

Lavin A, Grace AA. Modulation of dorsal thalamic cell activity by the ventral pallidum: its role in the regulation of thalamocortical activity by the basal ganglia. Synapse 18, 104-127 (1994).

Martin G, Fabre V, Siggins GR, de Lecea L. Interaction of the hypocretins with neurotransmitters in the nucleus accumbens. Regulatory Peptides 104, 111-117 (2002).

Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nature Neuroscience 2, 119-128 (2001).

Nestler EJ. Molecular mechanisms of opiate and cocaine addiction. Current Opinion in Neurobiology 7, 713-719 (1997).

Nestler EJ. The neurobiology of cocaine addiction. Science & Practice Perspectives 4, 4-10 (2005).

Nestler EJ, Hyman SE, Malenka RC. Molecular neuropharmacology: a foundation for clinical neuroscience. McGraw Hill Medical. Second Edition (2009).

Nicola SM, Surmeier J, Malenka RC. Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens. Annual Reviews of Neuroscience 23, 185-215 (2000).

O’Donnell P, Lavin A, Enquist LW, Grace AA, Card JP. Interconnected parallel circuits between rat nucleus accumbens and thalamus revealed by retrograde transynaptic transport of pseudorabies virus. Journal of Neuroscience 17, 2143-2167 (1997).

Pinto A, Jankowski M, Sesack SR. Projections from the paraventricular nucleus of the thalamus to the rat prefrontal cortex and nucleus accumbens shell: ultrastructural characteristics and spatial relationships with dopamine afferents. Journal of Comparative Neurology 459, 142-155 (2003).

Redgrave P, Gurney K, Reynolds J. What is reinforced by phasic dopamine signals? Brain Research Reviews 58, 322-339 (2008).

Russo SJ, Bolanos CA, Theobald DE, DeCarolis NA, Renthal W, Kumar A, Winstanley CA, Renthal NE, Wiley MD, Self DW, Russell DS, Neve RL, Eisch AJ, Nestler EJ. IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates. Nature Neuroscience 10(1), 9-10 (2007).

Siegel A, Sparu HN. Essential neuroscience. Wolters Kluwer Health. Second Edition (2011).

17

Smith Y, Raju DV, Pare JF, Sidibe M. The thalamostriatal system: a highly specific network of the basal ganglia circuitry. Trends in Neuroscience 27, 520-527 (2004).

Thomas MJ, Kalivas PW, Shaham Y. Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. British Journal of Pharmacology 154, 327-342 (2008).

Volkow ND, Fowlder JS, Wang GJ, Swanson JM, Telang F. Dopamine in drug abuse and addiction. Archives of Neurology 64, 1575-1579 (2007).

Waraczynski MA. The central extended amygdala network as a proposed circuit underlying reward valuation. Neuroscience & Biobehavioral Reviews 30, 472-496 (2006).