mitogen
Bluelighter
- Joined
- Nov 8, 2004
- Messages
- 127
Here's an essay I wrote a couple months ago for a drug addiction course. Its about 5000 words. Feel free to comment. It only has 1 figure which is the DSMIV criteria for addiction, which you can find anywhere.
Discuss the role of the nucleus accumbens in drug addiction. Does nucleus accumbens dopamine have functions other than reward?
Drug addiction or dependence has been present in human communities since prehistory, and continues today to have detrimental impacts on individuals, those in direct proximity to them, and as a result, society as a whole. In light of this, a significant modern research effort has been initiated in an attempt to reduce the effect on society of the adverse consequences of drug dependence. This modern effort is essentially a ‘three-pronged weapon,’ involving biological, psychological and sociological models of addictive behaviour, but in many cases, theories and data from these diverse fields can not be integrated to form a unifying theory of what causes addiction. The following will be primarily an investigation of the neurobiological aspects of drug addiction, and as such will draw from psychological and physiological paradigms to explain how data concerning the properties of neuronal circuitry can account for observed drug related behaviour in dependent individuals.
Drug dependence and drug related behaviour:
For an investigation into the biology underlying drug dependence to be relevant to actual amelioration of the problem, which is the ultimate goal of addiction research, researchers must start with a comprehensive definition of what drug dependence actually comprises. While “addictive” and “non-addictive” psychoactive substances have been present and used by humans since prehistory, the actual notion of drug dependence became a common notion in the period of early industrialisation of society, referring first to alcohol, and then to opioids and other psychoactive substances [1]. Psychiatric models of drug dependence have evolved throughout the era of modern scientific and medical research, the most common model currently used being the “DSM-IV” index, which was developed by the American Psychiatric Association. Fig.1 details the criteria [1]. This model presents a holistic view of what addiction involves, and each of these criteria may be easier than others to explain using biological, psychological or sociological theories of addiction. For example, tolerance and withdrawal are primarily physiological phenomena, and are the subject matter of many research papers in biology. Biological approaches can be potentially applied to answering questions about all seven criteria, but success is often limited by the extraordinary complexity of assigning complex social behaviours to aspects of neurobiology. The DSM-IV index is by no means the only set of criteria for assessing whether an individual is a ‘drug addict,’ but it provides adequate focus for investigation.
Reward Pathways:
At the dawn of neuroscience was the field of neuroanatomy. Perhaps the single greatest advance in the biology of addiction was the identification and description of a series of interconnecting circuits in the brain termed the ‘reward pathway.’ The principle component of this reward pathway is called the mesocorticolimbic dopamine system [1]. As the name implies, this is a neuronal projection from the mesencephalon to the cortex through the limbic system. Dopaminergic cell bodies in an area called the Ventral Tegmental Area (VTA) project through the ‘medial forebrain bundle’ to a component of the limbic system called the Nucleus Accumbens (NAc.) One of the primary outputs of NAc cells is the cerebral cortex [1]. The NAc has been strongly implicated in initiation of goal directed behaviours
Fig 1. The DSM-IV index. [1]
for both natural rewards such as food and sex [2], and drug rewards such as cocaine and heroin [3]. Rewards increase the rate of release of dopamine in by VTA neurons in the NAc [1,3].
It is still a subject of debate that the activation of this mesocorticolimbic pathway is the actual neural substrate of reward, or the pleasurable feeling obtained from using a drug, or whether it is simply involved in motivation to use a drug [1,3,4]. These concepts are difficult to tease apart. Animals with electrodes inserted into the medial forebrain bundle, for example, will repeatedly self-stimulate [5], but it is impossible to tell whether the animal is actually experiencing ‘pleasurable sensations’ as a direct result of activation of this pathway, and this represents a major problem with using animal models to study drugs of abuse and addiction. To date, the only drugs to which dopamine release has been correlated with measurements of ‘drug liking’ are psychostimulants [4]. However, as experimental animal models can not be made to represent every aspect of the subjective effects of drugs in humans, it is difficult to make a completely valid claim that dopamine release by non-psychostimulant drugs has nothing to do with ‘drug liking.’
Research shows that the NAc is a critical site for integration of information from the limbic system about the nature of rewards and for providing output specific to reward directed goal creation [1,2,3]. However, the NAc must be viewed not as a discrete entity but as an integral part of a circuit dedicated to production of reward related behaviours.
On further examination of the anatomy of the circuitry which the NAc is part of, this proposed function appears logical. Rewarding drug use by its very nature forms sets of different ‘types’ of memories, such as memory of the environment in which the drug is commonly used or obtained, procedural memory involving, for example, the motor pattern required to prepare a drug to be injected, or memory about the emotional state which the drug induces in the individual. These discrete ‘forms’ of memory are proposed to be learned and processed in parallel by discrete structures in the brain [7,8]. The result of this is that learned information of diverse form travels to the NAc where it is integrated and processed. In light of the proposed role for the NAc as an important site of integration of reward related memory, a review of the anatomy of the NAc and the circuitry of which the NAc is an integral part will provide some useful structure/function insight. The rat brain will be used as a model as a significant proportion of researchers in the drug addiction field use rats as model animals.
Neuroanatomy of the Nucleus Accumbens and Associated Structures:
In the rat, the NAc is located in the forebrain, ventral to the rostral end of the dorsal striatum (caudate-putamen) [7]. The NAc is physically and histologically contiguous with the caudate-putamen and the olfactory tubercle on which it rests. At the caudal end, similar poorly defined boundaries exist between the NAc and the bed nucleus of the stria terminalis. The medial border of the NAc distinctly separates it from the septum diagonal band complex, and it is laterally and rostrally delineated by a border with the external capsule [8]. Early descriptions of this area of the brain tended to include the NAc as a part of the striatum, and these interpretations may have been fueled by the observation of a large amount of dopaminergic input from the midbrain to this area, including projections to the dorsal striatum and olfactory tubercle [8].
The NAc is divided functionally and histologically into two primary structures: the NAc core and the NAc shell [9]. Both the core and shell bear similarity to the striatum both histologically and in their connection pattern. Subcortical afferents to the NAc core include various thalamic nuclei, the basolateral amygdala, the globus pallidus, the ventral pallidum, the subthalamic nucleus, and cell groups in the ventral midbrain. The shell receives afferents from the same areas with the exception of the globus pallidus and the subthalamic nucleus, but also from cells in the bed nucleus of the stria terminalus, the preoptic area, the lateral hypothalamus, the medial amygdala and the brainstem reticular formation [8]. Thus the NAc shell has greater input from the limbic system.
Cortical inputs to the NAc are also region (core/shell) specific [8]. It is important to note the anatomical juxtaposition and functional similarity of the mesocorticolimbic pathway to the nigrostriatal pathway. The presence of extensive projections from the NAc core to the substantia nigra pars compacta (SNc) also illustrate the interconnectivity of these two dopaminergic pathways [9]. These outputs from the NAc core to the SNc can affect processing of motor sensory information and behaviour in the cortex through the basal ganglia. Similarly, not only does the NAc receive afferents from the VTA, but efferents from the NAc shell also project to the VTA. The efferent pathways from the NAc shell are similar to its afferent inputs, and this region innervates structures in the limbic system. In addition, an important efferent pathway from the NAc shell is that to the ventral pallidum. Neurons in this region in turn project to the mediodorsal thalamic nucleus, which in turn contains neurons which synapse in the prefrontal cortex. Alternatively, NAc efferents can project directly to the prefrontal cortex [9].
The basolateral amygdala is linked to memory consolidation and emotional memory [10,11] and the hippocampus has been implicated by many studies in episodic memory formation [11]. As such, the anatomical interconnectivity of the NAc with other components of the limbic system and the cortex is essential when considering the neural substrates of addictive behaviour. Similarly, the role of the NAc in modulating expression of motor functions is an important feature of the neural systems underlying goal directed behaviour [4].
One theory is that memories and cues regarding a drug or natural reward are integrated in the NAc: the output may result in the expression of goal directed behaviour, the goal being a reward [3]. In the case of a drug dependent individual, this goal will likely be to obtain and use their drug of choice. This is termed drug seeking behaviour. The neural basis of production of goal-directed behaviour towards natural rewards in non-dependent individuals is significantly different to drug seeking behaviour [3,4].
Dopamine Transmission:
Dopamine is a crucial modulator of the function of the NAc. Having examined the role of the NAc and its associated structures in addiction related behaviour and memory from an anatomical point of view, it will now be useful to give a basic description of the dynamics of dopamine transmission. This will provide a basis to explain how drugs of abuse affect dopamine and therefore the function of the NAc.
Dopamine is released into the synapse and acts on G-protein coupled receptors. These receptors do not directly affect the electrical properties of the cell as do ligand gated ion channels – rather they act in a ‘neuromodulatory’ fashion and affect the response of the cell to inputs from other neurons. This action requires signalling events to occur, which means that dopamine action occurs on a much longer timescale than neurotransmission involving ligand gated ion channels [4,7,13].
In addition, the action of dopamine on a cell is heterogeneous and depends on the particular receptor subtype that it binds to. Dopamine transmission is terminated by its reuptake through membrane localised dopamine reuptake transporters (DAT). Enzymes such as COMT (catechol o-methyl transferase) and members of the MAO (monoamine oxidase) family also aid in degradation of dopamine and termination of dopamine transmission [7].
Dopamine is a member of a group of neurotransmission systems which are referred to as ‘diffuse modulatory systems.’ As the name implies, if levels of synaptic dopamine build up sufficiently, for example after repeated drug administration, it can diffuse into the extracellular fluid and affect receptors distant from its site of release. Dopamine therefore acts over an extended time period compared to neuronal firing rates and often with low spatial specificity [4,7].
Two different modes of synaptic dopamine release have been identified – the ‘phasic’ and ‘tonic’ responses. Imbalance between these firing modes caused by repeated administration of drugs of abuse is thought to be crucial in drug craving, in anhedonia associated with drug withdrawal and in relapse to drug administration under stress or in response to a low priming dose of the drug on which the individual has been dependent [14].
Modulation of Dopaminergic Activity by Drugs of Abuse:
This section will deal with the pharmacology of several different drugs of abuse, and specifically how these drugs affect the mesocorticolimbic dopamine system, and hence disrupt the normal function of the NAc. Addiction to these drugs can be categorised by a set of common behaviours observed in drug dependent individuals which are present across the whole spectrum of addictive drugs. When each drug’s mechanism of action is examined, the common effect of all addictive drugs is their ability to increase dopamine release in the mesocorticolimbic pathway [1,15]. As mentioned previously, it is difficult to distinguish between the role of dopamine in ‘drug wanting’ and ‘drug liking,’ particularly in non-psychostimulant drugs. Because of these similarities between drugs in releasing dopamine, it is possible to use a comparative approach between diverse drugs to further implicate the involvement of dopamine release in the NAc as the primary reason that individuals become addicted to these drugs. Following is a comparison of five drugs which are commonly known to be addictive:
Cocaine:
Cocaine blocks the dopamine reuptake transporter (DAT) which is responsible for terminating dopamine action. This results in dopamine remaining in the synapse at higher concentrations than normal, for longer. [1]
Amphetamines:
Amphetamines induce release of dopamine from the presynaptic cell. [1]
Opioids:
Opioids inhibit GABAergic inhibition of VTA dopamine neuron firing. [1,15]
Alcohol:
Alcohol’s effects are thought to be mediated by activation of GABAA receptors and inhibition of NDMA glutamate receptors. Rising plasma concentrations of alcohol induce dopamine release in the NAc. [1]
Nicotine:
Nicotine’s effect is mediated by nicotinic acetylcholine receptors which are located on dopaminergic and opioidergic neurons. Activation of these receptors results in an increase in dopamine release in the NAc. [15]
The above is by no means a comprehensive list of addictive drugs but is intended to provide a comparison between several drugs with differing mechanisms of action.
Biobehaviouralism and its physiological substrates:
What are some psychological theories of drug dependence and drug related behaviour, and how do neurobiological paradigms meld these theories with physiological observations about the role of dopamine in the function of the NAc?
Two important psychological models which are of use in dissecting the behaviour of drug dependent individuals are “classical conditioning” (also known as Pavlovian or associative learning,) and “operant conditioning.” Dopamine release in the NAc is proposed to underlie both of these processes. Recent psychological models of drug dependence such as incentive sensitisation draw on these basic concepts of conditioning [1,3,17].
Classical conditioning [1,7] results in the pairing of two stimuli. The first stimulus is termed the ‘conditioned stimulus,’ usually a light or sound, which by definition must not elicit any response from the subject. The second stimulus is the ‘unconditioned stimulus,’ and is chosen for its ability to produce a consistent response. These two stimuli are paired, and eventually the conditioned stimulus will elicit a response even in the absence of the unconditioned stimulus. This type of learning is important in drug related behaviours such as cue induced craving [1,17]. For example, the sight of a needle, or a drug dealer may induce drug craving. The sight of the needle would be the conditioned stimulus, in that it becomes paired with the state induced by injection of the drug (the state produced by the drug being the unconditioned stimulus.) Thus the addict would form an association between seeing a needle and using the drug.
According to incentive motivational theory, which will be elaborated on later, needle is in fact an ‘incentive,’ in that it induces motivation to obtain the reward [1,17].
Operant conditioning involves goal directed behaviour. The behaviour is elicited as a function of the perceived consequences. Operant conditioning schedules can be divided into three groups: positive reinforcement, negative reinforcement and punishment, all of which are important in drug dependence [1]. In positive reinforcement schedules, the individual learns that a behaviour will result in presentation of a pleasurable stimulus, and therefore learns to repeat the behaviour. Negative reinforcement schedules dictate that the behaviour will eliminate presentation of an unpleasurable stimulus, encouraging repetition of the behaviour. Punishment schedules extinguish a behaviour by presenting an unpleasurable stimulus when the behaviour is performed [1,7].
An elegant demonstration of the role of dopamine transmission in operant conditioning was published by Reynolds et al. from Otago University in their Nature paper “A Cellular Mechanism of Reward Related Learning” [16]. A ‘reward’ can be defined as “a stimulus that provides positive motivation for behaviour,” and therefore can be generalised as a reinforcer, in the sense of the operant conditioning model [1]. Reynolds et al. paired lever pressing with electrical stimulation of dopaminergic neurons in the substantia nigra (the reward.) These dopaminergic neurons synapse on neurons in the striatum in close proximity to inputs from the cerebral cortex on the same striatal neurons. This pathway is an essential component of the brain’s motor learning system [16].
The rate at which the animals learnt the behaviour (lever pressing, as measured by presses per minute) was closely correlated with the degree of potentiation of corticostriatal synapses. It was shown pharmacologically that this potentiation was dopamine dependent. Although this study involved the substantia nigra and the striatum, the nigrostriatal pathway is very similar anatomically and functionally to the mesolimbic dopamine pathway [4,16]. Repetition of the goal directed behaviour increased as a result of reinforcement, and the neural substrate of this function was dopamine release into the striatum by neurons in the substantia nigra.
It was originally thought that drug dependence occurred as a result of two factors, both of which are components of the operant conditioning model: the first being the desire to experience the pleasurable effects of the drug (positive reinforcement,) and the second being the desire to avoid the unpleasant consequences of discontinuing drug use (negative reinforcement) [17].
These two factors are differentially important when studying addiction to drugs with different mechanisms of action. For example, negative reinforcement is an important contributor to continuation of opiate use, since discontinuation results in an exceptionally unpleasant withdrawal phase, with both emotional and physical components. In the case of cocaine, the addict may experience an unpleasurable emotional resposnse to withdrawal of their drug, but the power of negative reinforcement in maintaining drug use will not be as strong as for the opiate addict. In addition, some drugs, such as neuroleptics, can produce a withdrawal syndrome but are not considered to be ‘addictive’ [1,17].
The positive reinforcement model of drug addiction claims that repetition of drug taking behaviour increases because drugs are acting as a positive reinforcer, and that this positive reinforcement is experienced as euphoria, or hedonia. However, studies demonstrating that addicts will seek and perform work for doses of morphine or cocaine that are not high enough to produce any subjective pleasurable state whatsoever, imply a separation between motivation to take drugs or “drug wanting,” and the pleasurable effects experienced by drugs, or “drug liking” [17].
Thus, the addict may have progressed past the stage where drug wanting and liking are intrinsically linked. Formation of memories of pleasurable drug induced experiences is an essential part the initiation phase of drug dependence; the pleasurable effects of the drug are necessary to begin the process of dependency, but are not sufficient to explain maintenance of dependence. At this point, the positive reinforcement model of drug dependence is unable to explain the biological and behavioural processes which are occurring [17]. This observed separation of drug wanting and drug liking in the addict is likely to have a neural basis, and is further evidence for the role of the NAc as an initiator of goal directed, (or more specifically, drug seeking) behaviour causing drug wanting, but not as the actual substrate of drug liking or euphoria caused by the drug [4].
Electrophysiological studies in behaving animals [3] have shown that NAc cell firing changes during operant responding for juice reinforcement in monkeys. In addition, in a different experiment [3], VTA dopamine cell firing increases during operant responding for sucrose reinforcement. A synthesis of these two results shows that during operant responding for reinforcers, dopamine transmission increases and alters NAc cell firing patterns. These studies used sucrose as their reinforcer, but the results can also be applied to other natural and drug reinforcers. It is however important to note the difference between natural and drug reinforcers with respect to their effect on dopamine transmission in the NAc. For example, a study by Hernandez and Hobel in 1988 showed that food increased dopamine release by 45%, whereas amphetamine increased dopamine release by 500% [1]. Drug reinforcement also lacks the adaptive response to natural rewards, whereby dopamine transmission is usually only stimulated by unexpected reward [4].
With respect to the function of associative learning in attribution of motivational value to stimuli that predict drug availability, increases in dopamine transmission in the NAc were also observed on presentation of conditioned stimuli that had been repeatedly paired to the impending administration of cocaine [3].
While neither positive nor negative reinforcement models of drug dependence are definitive, a relatively new concept in drug dependence theory called the ‘incentive sensitisation’ model gives a more valid explanation of how compulsive drug seeking behaviour may be maintained in both the absence of desire to experience pleasurable sensations and the absence of desire to alleviate withdrawal.
The precepts of this incentive sensitisation model are that addictive drugs induce long lasting changes in regions of the brain whose function is involved with goal directed behaviour and reward, such as the NAc and the rest of the limbic system, and that these changes hypersensitize these regions of the brain to drugs and stimuli. Finally, this model necessitates that the brain regions which undergo these neuroadaptations to use of addictive drugs mediate drug wanting, but not drug liking [17].
Essentially, incentive sensitisation is the process by which the brain becomes more sensitive to stimuli conditioned by pairing with drugs, and is directly dependent on dopaminergic transmission in the NAc. Consistent with observations that dopamine release also increases during operant responding for rewards, the incentive sensitisation model also describes the sensitisation of the brain to the motivational value of performing a behaviour directed at obtaining reward [1,17].
To conclude this investigation, and as a means of bringing together the concepts and principles involved in behavioural and physiological studies of the addicted brain, we will consider a fictional situation. A cocaine addict passes through an alleyway, at the end of which he will often find his dealer. Through repeated pairing, this alleyway has become associated in his mind, via a dopamine dependent mechanism termed ‘incentive salience attribution,’ with the impending acquisition of cocaine. Walking through the alleyway, which is now an ‘incentive,’ has now reminded the addict of the drug. His brain has been sensitised, again via a dopamine dependent mechanism, to operant responding reinforced by cocaine; the operant response being to approach his dealer and purchase the drug. The sight of the alleyway cues memories of cocaine by association, which are likely stored in parts of the limbic system such as the amygdala or the hippocampus. Inputs to the NAc from other parts of the limbic system signal the possibility of impending cocaine reward. The NAc would then co-ordinate goal directed behaviour to obtain the reward. The entire process by which the incentive (the sight of the alleyway,) induces the motivational response to buy the drugs is called ‘incentive motivational responding’ [1]. The process of incentive sensitisation strengthens synaptic efficacy in this pathway, in much the same way that the stimulation of dopaminergic neurons in the substantia nigra of a mouse increases corticostriatal synaptic efficacy, resulting in the mouse learning the lever-pressing behaviour required to obtain dopaminergic reward [16].
While the incentive sensitisation model is obviously theoretical, it does provide an integration of operant conditioning aspects of drug addiction and other observations that operant conditioning models can not account for, such as relapse after long periods of abstinence; sensitisation to incentives at the molecular level is extremely stable and can persist for a long time after the last time the ‘dependent’ individual stopped taking their drug [15].
Does Nucleus Accumbens dopamine have functions other than reward?
This is a particularly difficult question to address. Researchers in the drug addiction field, particularly those involved in psychopharmacological studies of dopamine function and how these physiological processes produce specific behaviours associated with drug dependence, have disagreed for decades about the actual role of dopamine release into the nucleus accumbens. These disagreements are centred around what the actual nature of ‘reward’ is, and whether it might in fact be a misnomer, and instead should be replaced by the dual concepts of ‘drug liking’ and ‘drug wanting,’ the latter, but not the former of which has been shown conclusively to be dependent on the mesolimbic dopamine system.
Dopamine release in the nucleus accumbens mediates some processes and behaviours that can not be directly defined as ‘reward.’ Most of these processes are, however, intrinsically related to ‘reward’ and goal directed behaviour. The confusion inherent in attempting to define processes mediated by the dopamine release in the NAc that are not ‘reward,’ comes from the inadequate biobehavioural definition of reward.
The most important of these processes attributable to dopamine release in the NAc is called ‘appetitive conditioning.’ Appetitive conditioning, or the disruption thereof also plays a significant role in drug addiction. The general principle is that the NAc integrates information input from various components of the limbic system and other parts of the brain (as detailed in the “Neuroanatomy of the Nucleus Accumbens and Associated Structures” section,) and that this information concerns the value of a certain stimulus to the organism. The authors of one study [18] propose that “activity in this distributed network (including D1 receptor activity) computes coincident events and thus enhances the probability that temporally related actions and events (e.g. lever pressing and delivery of reward) become associated.”
The NAc can also mediate fear conditioning. In another study, the experimenters temporarily inactivated neuronal function in the NAc using tetradoxin, a drug which blocks neuronal sodium channels, and therefore blocks action potential propagation. During this time, they investigated acquisition and expression of conditioned fear, as measured by “fear-potentiated startle,” or “FPS.” Injection of tetradoxin into the NAc completely inhibited acquisition and significantly decreased expression of conditioned fear to a visual conditioned stiumulus. Additionally, this temporary inactivation of the NAc did not have an effect on shock sensitisation of startle. This may indicate that both the perception of the shock and the short term contextual conditioning was not affected by injection of tetradoxin into the NAc. These results indicate that the function of the NAc in fear conditioning is that of acquisition and expression of long-term conditioned fear (measured by fear-potentiated startle, to a conditioned stimulus,) but that the NAc is not involved in short term conditioning of fear to a ‘context’ [19].
Thus nucleus accumbens dopamine is primarily involved in strengthening relationships between stimuli and other stimuli, and relationships between stimuli and ‘affective states,’ such as, but not limited to, drug states and the states induced by other natural rewards. Dopamine release by mesencephalic neurons into the nucleus accumbens is essential for modulation of the function of this region, and is essential to all current models of obsessive drug related behaviours. The interaction of the nucleus accumbens with other regions of the brain such as other components of the limbic system, the hypothalamus and the prefrontal cortex is also an essential component of current biobehavioural models of drug dependence.
REFERENCES:
1.) Wolrd Health Organisation Report: The Neuroscience of Psychoactive Substance Use & Dependence, 2004
2.) Salmone JD, Correa M, Mingote S, Weber SM “Nucleus accumbens dopamine and the regulation of effort in food-seeking behavior: implications for studies of natural motivation, psychiatry, and drug abuse.” J Pharmacol Exp Ther. 2003 Apr;305(1):1-8. Review.
3.) Carelli R. “Nucleus accumbens cell firing and rapid dopamine signalling during goal-directed behaviours in rats.” Neuropharmacology 47 (2004) 190-189
4.) Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, Acquas E, Carboni E, Valentini V, Lecca D. “Dopamine and drug addiction: the nucleus accumbens shell connection.” Neuropharmacology 47 (2004) 227-241
5.) Boye SM. “Mesencephalic substrate of reward: lesion effects.” Behav Brain Res. 2005 Jan 6;156(1):31-43
6.) Brog JS, Salyapongse A, Deutch AY, Zahm DS. “The patterns of afferent innervation of the core and shell in the "accumbens" part of the rat ventral striatum: immunohistochemical detection of retrogradely transported fluoro-gold.” J Comp Neurol. 1993 Dec 8;338(2):255-78
7.) Kandel ER, Schwartz JH, Jessel TM. “Principles of Neural Science.” McGraw-Hill Medical 4th Edition, Jan 5th 2000
8.) Zahm DS, Brog JS, “On the significance of subterritories in the “accumbens” part of the rat ventral striatum.” Neuroscience, Volume 50, No. 4, pp. 751-767, 1992.
9.) Otake K, Nakamura Y, “Possible pathways through which neurons of the shell of the nucleus accumbens influence the outflow of the core of the nucleus accumbens.” Brain & Development 22 (2000) S17-S26
10.) Pare D, “Role of the basolateral amygdala in memory consolidation.
Prog Neurobiol. 2003 Aug;70(5):409-20. Review.”
11.) White NM, “Addictive drugs as reinforcers: multiple partial actions on memory systems.” Addiction (1996) 91(7), 921-949.\
12.) Girault JA, Greengard P, “The neurobiology of dopamine signaling.” Arch Neurol. 2004 May;61(5):641-4. Review.
13.) Greengard P. “The neurobiology of slow synaptic transmission.” Science, Nov 2 2001, Vol294
14.) Grace A, “The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving.” Addiction (2000) 95 (Supplement 2), S119-S128
15.) Nestler EJ “Molecular basis of long term plasticity underlying addiction.” Nature Reviews Neuroscience. 2001 Feb;2(2):119-28
16.) Reynolds DN, Hyland BI, Wickens JR, “A cellular mechanism of reward related learning.” Nature. 2001 Spec 6;413(6851):67-70
17.) Robinson TE, Berrige KC, “The psychology and neurobiology of addiction: an incentive-sensitization view.” Addiction. 200 Aug;95 Suppl 2: S91-117
18.) Kelley AE. “Appetitive conditioning Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning.” Neurosci Biobehav Rev. 2004 Jan;27(8):765-76.
19.) Schwienbacher I, Fendt M, Richardson R, Schnitzler HU. “Temporary inactivation of the nucleus accumbens disrupts acquisition and expression of fear-potentiated startle in rats.” Prog Neurobiol. 2004 Jun;73(3):179-226
Discuss the role of the nucleus accumbens in drug addiction. Does nucleus accumbens dopamine have functions other than reward?
Drug addiction or dependence has been present in human communities since prehistory, and continues today to have detrimental impacts on individuals, those in direct proximity to them, and as a result, society as a whole. In light of this, a significant modern research effort has been initiated in an attempt to reduce the effect on society of the adverse consequences of drug dependence. This modern effort is essentially a ‘three-pronged weapon,’ involving biological, psychological and sociological models of addictive behaviour, but in many cases, theories and data from these diverse fields can not be integrated to form a unifying theory of what causes addiction. The following will be primarily an investigation of the neurobiological aspects of drug addiction, and as such will draw from psychological and physiological paradigms to explain how data concerning the properties of neuronal circuitry can account for observed drug related behaviour in dependent individuals.
Drug dependence and drug related behaviour:
For an investigation into the biology underlying drug dependence to be relevant to actual amelioration of the problem, which is the ultimate goal of addiction research, researchers must start with a comprehensive definition of what drug dependence actually comprises. While “addictive” and “non-addictive” psychoactive substances have been present and used by humans since prehistory, the actual notion of drug dependence became a common notion in the period of early industrialisation of society, referring first to alcohol, and then to opioids and other psychoactive substances [1]. Psychiatric models of drug dependence have evolved throughout the era of modern scientific and medical research, the most common model currently used being the “DSM-IV” index, which was developed by the American Psychiatric Association. Fig.1 details the criteria [1]. This model presents a holistic view of what addiction involves, and each of these criteria may be easier than others to explain using biological, psychological or sociological theories of addiction. For example, tolerance and withdrawal are primarily physiological phenomena, and are the subject matter of many research papers in biology. Biological approaches can be potentially applied to answering questions about all seven criteria, but success is often limited by the extraordinary complexity of assigning complex social behaviours to aspects of neurobiology. The DSM-IV index is by no means the only set of criteria for assessing whether an individual is a ‘drug addict,’ but it provides adequate focus for investigation.
Reward Pathways:
At the dawn of neuroscience was the field of neuroanatomy. Perhaps the single greatest advance in the biology of addiction was the identification and description of a series of interconnecting circuits in the brain termed the ‘reward pathway.’ The principle component of this reward pathway is called the mesocorticolimbic dopamine system [1]. As the name implies, this is a neuronal projection from the mesencephalon to the cortex through the limbic system. Dopaminergic cell bodies in an area called the Ventral Tegmental Area (VTA) project through the ‘medial forebrain bundle’ to a component of the limbic system called the Nucleus Accumbens (NAc.) One of the primary outputs of NAc cells is the cerebral cortex [1]. The NAc has been strongly implicated in initiation of goal directed behaviours
Fig 1. The DSM-IV index. [1]
for both natural rewards such as food and sex [2], and drug rewards such as cocaine and heroin [3]. Rewards increase the rate of release of dopamine in by VTA neurons in the NAc [1,3].
It is still a subject of debate that the activation of this mesocorticolimbic pathway is the actual neural substrate of reward, or the pleasurable feeling obtained from using a drug, or whether it is simply involved in motivation to use a drug [1,3,4]. These concepts are difficult to tease apart. Animals with electrodes inserted into the medial forebrain bundle, for example, will repeatedly self-stimulate [5], but it is impossible to tell whether the animal is actually experiencing ‘pleasurable sensations’ as a direct result of activation of this pathway, and this represents a major problem with using animal models to study drugs of abuse and addiction. To date, the only drugs to which dopamine release has been correlated with measurements of ‘drug liking’ are psychostimulants [4]. However, as experimental animal models can not be made to represent every aspect of the subjective effects of drugs in humans, it is difficult to make a completely valid claim that dopamine release by non-psychostimulant drugs has nothing to do with ‘drug liking.’
Research shows that the NAc is a critical site for integration of information from the limbic system about the nature of rewards and for providing output specific to reward directed goal creation [1,2,3]. However, the NAc must be viewed not as a discrete entity but as an integral part of a circuit dedicated to production of reward related behaviours.
On further examination of the anatomy of the circuitry which the NAc is part of, this proposed function appears logical. Rewarding drug use by its very nature forms sets of different ‘types’ of memories, such as memory of the environment in which the drug is commonly used or obtained, procedural memory involving, for example, the motor pattern required to prepare a drug to be injected, or memory about the emotional state which the drug induces in the individual. These discrete ‘forms’ of memory are proposed to be learned and processed in parallel by discrete structures in the brain [7,8]. The result of this is that learned information of diverse form travels to the NAc where it is integrated and processed. In light of the proposed role for the NAc as an important site of integration of reward related memory, a review of the anatomy of the NAc and the circuitry of which the NAc is an integral part will provide some useful structure/function insight. The rat brain will be used as a model as a significant proportion of researchers in the drug addiction field use rats as model animals.
Neuroanatomy of the Nucleus Accumbens and Associated Structures:
In the rat, the NAc is located in the forebrain, ventral to the rostral end of the dorsal striatum (caudate-putamen) [7]. The NAc is physically and histologically contiguous with the caudate-putamen and the olfactory tubercle on which it rests. At the caudal end, similar poorly defined boundaries exist between the NAc and the bed nucleus of the stria terminalis. The medial border of the NAc distinctly separates it from the septum diagonal band complex, and it is laterally and rostrally delineated by a border with the external capsule [8]. Early descriptions of this area of the brain tended to include the NAc as a part of the striatum, and these interpretations may have been fueled by the observation of a large amount of dopaminergic input from the midbrain to this area, including projections to the dorsal striatum and olfactory tubercle [8].
The NAc is divided functionally and histologically into two primary structures: the NAc core and the NAc shell [9]. Both the core and shell bear similarity to the striatum both histologically and in their connection pattern. Subcortical afferents to the NAc core include various thalamic nuclei, the basolateral amygdala, the globus pallidus, the ventral pallidum, the subthalamic nucleus, and cell groups in the ventral midbrain. The shell receives afferents from the same areas with the exception of the globus pallidus and the subthalamic nucleus, but also from cells in the bed nucleus of the stria terminalus, the preoptic area, the lateral hypothalamus, the medial amygdala and the brainstem reticular formation [8]. Thus the NAc shell has greater input from the limbic system.
Cortical inputs to the NAc are also region (core/shell) specific [8]. It is important to note the anatomical juxtaposition and functional similarity of the mesocorticolimbic pathway to the nigrostriatal pathway. The presence of extensive projections from the NAc core to the substantia nigra pars compacta (SNc) also illustrate the interconnectivity of these two dopaminergic pathways [9]. These outputs from the NAc core to the SNc can affect processing of motor sensory information and behaviour in the cortex through the basal ganglia. Similarly, not only does the NAc receive afferents from the VTA, but efferents from the NAc shell also project to the VTA. The efferent pathways from the NAc shell are similar to its afferent inputs, and this region innervates structures in the limbic system. In addition, an important efferent pathway from the NAc shell is that to the ventral pallidum. Neurons in this region in turn project to the mediodorsal thalamic nucleus, which in turn contains neurons which synapse in the prefrontal cortex. Alternatively, NAc efferents can project directly to the prefrontal cortex [9].
The basolateral amygdala is linked to memory consolidation and emotional memory [10,11] and the hippocampus has been implicated by many studies in episodic memory formation [11]. As such, the anatomical interconnectivity of the NAc with other components of the limbic system and the cortex is essential when considering the neural substrates of addictive behaviour. Similarly, the role of the NAc in modulating expression of motor functions is an important feature of the neural systems underlying goal directed behaviour [4].
One theory is that memories and cues regarding a drug or natural reward are integrated in the NAc: the output may result in the expression of goal directed behaviour, the goal being a reward [3]. In the case of a drug dependent individual, this goal will likely be to obtain and use their drug of choice. This is termed drug seeking behaviour. The neural basis of production of goal-directed behaviour towards natural rewards in non-dependent individuals is significantly different to drug seeking behaviour [3,4].
Dopamine Transmission:
Dopamine is a crucial modulator of the function of the NAc. Having examined the role of the NAc and its associated structures in addiction related behaviour and memory from an anatomical point of view, it will now be useful to give a basic description of the dynamics of dopamine transmission. This will provide a basis to explain how drugs of abuse affect dopamine and therefore the function of the NAc.
Dopamine is released into the synapse and acts on G-protein coupled receptors. These receptors do not directly affect the electrical properties of the cell as do ligand gated ion channels – rather they act in a ‘neuromodulatory’ fashion and affect the response of the cell to inputs from other neurons. This action requires signalling events to occur, which means that dopamine action occurs on a much longer timescale than neurotransmission involving ligand gated ion channels [4,7,13].
In addition, the action of dopamine on a cell is heterogeneous and depends on the particular receptor subtype that it binds to. Dopamine transmission is terminated by its reuptake through membrane localised dopamine reuptake transporters (DAT). Enzymes such as COMT (catechol o-methyl transferase) and members of the MAO (monoamine oxidase) family also aid in degradation of dopamine and termination of dopamine transmission [7].
Dopamine is a member of a group of neurotransmission systems which are referred to as ‘diffuse modulatory systems.’ As the name implies, if levels of synaptic dopamine build up sufficiently, for example after repeated drug administration, it can diffuse into the extracellular fluid and affect receptors distant from its site of release. Dopamine therefore acts over an extended time period compared to neuronal firing rates and often with low spatial specificity [4,7].
Two different modes of synaptic dopamine release have been identified – the ‘phasic’ and ‘tonic’ responses. Imbalance between these firing modes caused by repeated administration of drugs of abuse is thought to be crucial in drug craving, in anhedonia associated with drug withdrawal and in relapse to drug administration under stress or in response to a low priming dose of the drug on which the individual has been dependent [14].
Modulation of Dopaminergic Activity by Drugs of Abuse:
This section will deal with the pharmacology of several different drugs of abuse, and specifically how these drugs affect the mesocorticolimbic dopamine system, and hence disrupt the normal function of the NAc. Addiction to these drugs can be categorised by a set of common behaviours observed in drug dependent individuals which are present across the whole spectrum of addictive drugs. When each drug’s mechanism of action is examined, the common effect of all addictive drugs is their ability to increase dopamine release in the mesocorticolimbic pathway [1,15]. As mentioned previously, it is difficult to distinguish between the role of dopamine in ‘drug wanting’ and ‘drug liking,’ particularly in non-psychostimulant drugs. Because of these similarities between drugs in releasing dopamine, it is possible to use a comparative approach between diverse drugs to further implicate the involvement of dopamine release in the NAc as the primary reason that individuals become addicted to these drugs. Following is a comparison of five drugs which are commonly known to be addictive:
Cocaine:
Cocaine blocks the dopamine reuptake transporter (DAT) which is responsible for terminating dopamine action. This results in dopamine remaining in the synapse at higher concentrations than normal, for longer. [1]
Amphetamines:
Amphetamines induce release of dopamine from the presynaptic cell. [1]
Opioids:
Opioids inhibit GABAergic inhibition of VTA dopamine neuron firing. [1,15]
Alcohol:
Alcohol’s effects are thought to be mediated by activation of GABAA receptors and inhibition of NDMA glutamate receptors. Rising plasma concentrations of alcohol induce dopamine release in the NAc. [1]
Nicotine:
Nicotine’s effect is mediated by nicotinic acetylcholine receptors which are located on dopaminergic and opioidergic neurons. Activation of these receptors results in an increase in dopamine release in the NAc. [15]
The above is by no means a comprehensive list of addictive drugs but is intended to provide a comparison between several drugs with differing mechanisms of action.
Biobehaviouralism and its physiological substrates:
What are some psychological theories of drug dependence and drug related behaviour, and how do neurobiological paradigms meld these theories with physiological observations about the role of dopamine in the function of the NAc?
Two important psychological models which are of use in dissecting the behaviour of drug dependent individuals are “classical conditioning” (also known as Pavlovian or associative learning,) and “operant conditioning.” Dopamine release in the NAc is proposed to underlie both of these processes. Recent psychological models of drug dependence such as incentive sensitisation draw on these basic concepts of conditioning [1,3,17].
Classical conditioning [1,7] results in the pairing of two stimuli. The first stimulus is termed the ‘conditioned stimulus,’ usually a light or sound, which by definition must not elicit any response from the subject. The second stimulus is the ‘unconditioned stimulus,’ and is chosen for its ability to produce a consistent response. These two stimuli are paired, and eventually the conditioned stimulus will elicit a response even in the absence of the unconditioned stimulus. This type of learning is important in drug related behaviours such as cue induced craving [1,17]. For example, the sight of a needle, or a drug dealer may induce drug craving. The sight of the needle would be the conditioned stimulus, in that it becomes paired with the state induced by injection of the drug (the state produced by the drug being the unconditioned stimulus.) Thus the addict would form an association between seeing a needle and using the drug.
According to incentive motivational theory, which will be elaborated on later, needle is in fact an ‘incentive,’ in that it induces motivation to obtain the reward [1,17].
Operant conditioning involves goal directed behaviour. The behaviour is elicited as a function of the perceived consequences. Operant conditioning schedules can be divided into three groups: positive reinforcement, negative reinforcement and punishment, all of which are important in drug dependence [1]. In positive reinforcement schedules, the individual learns that a behaviour will result in presentation of a pleasurable stimulus, and therefore learns to repeat the behaviour. Negative reinforcement schedules dictate that the behaviour will eliminate presentation of an unpleasurable stimulus, encouraging repetition of the behaviour. Punishment schedules extinguish a behaviour by presenting an unpleasurable stimulus when the behaviour is performed [1,7].
An elegant demonstration of the role of dopamine transmission in operant conditioning was published by Reynolds et al. from Otago University in their Nature paper “A Cellular Mechanism of Reward Related Learning” [16]. A ‘reward’ can be defined as “a stimulus that provides positive motivation for behaviour,” and therefore can be generalised as a reinforcer, in the sense of the operant conditioning model [1]. Reynolds et al. paired lever pressing with electrical stimulation of dopaminergic neurons in the substantia nigra (the reward.) These dopaminergic neurons synapse on neurons in the striatum in close proximity to inputs from the cerebral cortex on the same striatal neurons. This pathway is an essential component of the brain’s motor learning system [16].
The rate at which the animals learnt the behaviour (lever pressing, as measured by presses per minute) was closely correlated with the degree of potentiation of corticostriatal synapses. It was shown pharmacologically that this potentiation was dopamine dependent. Although this study involved the substantia nigra and the striatum, the nigrostriatal pathway is very similar anatomically and functionally to the mesolimbic dopamine pathway [4,16]. Repetition of the goal directed behaviour increased as a result of reinforcement, and the neural substrate of this function was dopamine release into the striatum by neurons in the substantia nigra.
It was originally thought that drug dependence occurred as a result of two factors, both of which are components of the operant conditioning model: the first being the desire to experience the pleasurable effects of the drug (positive reinforcement,) and the second being the desire to avoid the unpleasant consequences of discontinuing drug use (negative reinforcement) [17].
These two factors are differentially important when studying addiction to drugs with different mechanisms of action. For example, negative reinforcement is an important contributor to continuation of opiate use, since discontinuation results in an exceptionally unpleasant withdrawal phase, with both emotional and physical components. In the case of cocaine, the addict may experience an unpleasurable emotional resposnse to withdrawal of their drug, but the power of negative reinforcement in maintaining drug use will not be as strong as for the opiate addict. In addition, some drugs, such as neuroleptics, can produce a withdrawal syndrome but are not considered to be ‘addictive’ [1,17].
The positive reinforcement model of drug addiction claims that repetition of drug taking behaviour increases because drugs are acting as a positive reinforcer, and that this positive reinforcement is experienced as euphoria, or hedonia. However, studies demonstrating that addicts will seek and perform work for doses of morphine or cocaine that are not high enough to produce any subjective pleasurable state whatsoever, imply a separation between motivation to take drugs or “drug wanting,” and the pleasurable effects experienced by drugs, or “drug liking” [17].
Thus, the addict may have progressed past the stage where drug wanting and liking are intrinsically linked. Formation of memories of pleasurable drug induced experiences is an essential part the initiation phase of drug dependence; the pleasurable effects of the drug are necessary to begin the process of dependency, but are not sufficient to explain maintenance of dependence. At this point, the positive reinforcement model of drug dependence is unable to explain the biological and behavioural processes which are occurring [17]. This observed separation of drug wanting and drug liking in the addict is likely to have a neural basis, and is further evidence for the role of the NAc as an initiator of goal directed, (or more specifically, drug seeking) behaviour causing drug wanting, but not as the actual substrate of drug liking or euphoria caused by the drug [4].
Electrophysiological studies in behaving animals [3] have shown that NAc cell firing changes during operant responding for juice reinforcement in monkeys. In addition, in a different experiment [3], VTA dopamine cell firing increases during operant responding for sucrose reinforcement. A synthesis of these two results shows that during operant responding for reinforcers, dopamine transmission increases and alters NAc cell firing patterns. These studies used sucrose as their reinforcer, but the results can also be applied to other natural and drug reinforcers. It is however important to note the difference between natural and drug reinforcers with respect to their effect on dopamine transmission in the NAc. For example, a study by Hernandez and Hobel in 1988 showed that food increased dopamine release by 45%, whereas amphetamine increased dopamine release by 500% [1]. Drug reinforcement also lacks the adaptive response to natural rewards, whereby dopamine transmission is usually only stimulated by unexpected reward [4].
With respect to the function of associative learning in attribution of motivational value to stimuli that predict drug availability, increases in dopamine transmission in the NAc were also observed on presentation of conditioned stimuli that had been repeatedly paired to the impending administration of cocaine [3].
While neither positive nor negative reinforcement models of drug dependence are definitive, a relatively new concept in drug dependence theory called the ‘incentive sensitisation’ model gives a more valid explanation of how compulsive drug seeking behaviour may be maintained in both the absence of desire to experience pleasurable sensations and the absence of desire to alleviate withdrawal.
The precepts of this incentive sensitisation model are that addictive drugs induce long lasting changes in regions of the brain whose function is involved with goal directed behaviour and reward, such as the NAc and the rest of the limbic system, and that these changes hypersensitize these regions of the brain to drugs and stimuli. Finally, this model necessitates that the brain regions which undergo these neuroadaptations to use of addictive drugs mediate drug wanting, but not drug liking [17].
Essentially, incentive sensitisation is the process by which the brain becomes more sensitive to stimuli conditioned by pairing with drugs, and is directly dependent on dopaminergic transmission in the NAc. Consistent with observations that dopamine release also increases during operant responding for rewards, the incentive sensitisation model also describes the sensitisation of the brain to the motivational value of performing a behaviour directed at obtaining reward [1,17].
To conclude this investigation, and as a means of bringing together the concepts and principles involved in behavioural and physiological studies of the addicted brain, we will consider a fictional situation. A cocaine addict passes through an alleyway, at the end of which he will often find his dealer. Through repeated pairing, this alleyway has become associated in his mind, via a dopamine dependent mechanism termed ‘incentive salience attribution,’ with the impending acquisition of cocaine. Walking through the alleyway, which is now an ‘incentive,’ has now reminded the addict of the drug. His brain has been sensitised, again via a dopamine dependent mechanism, to operant responding reinforced by cocaine; the operant response being to approach his dealer and purchase the drug. The sight of the alleyway cues memories of cocaine by association, which are likely stored in parts of the limbic system such as the amygdala or the hippocampus. Inputs to the NAc from other parts of the limbic system signal the possibility of impending cocaine reward. The NAc would then co-ordinate goal directed behaviour to obtain the reward. The entire process by which the incentive (the sight of the alleyway,) induces the motivational response to buy the drugs is called ‘incentive motivational responding’ [1]. The process of incentive sensitisation strengthens synaptic efficacy in this pathway, in much the same way that the stimulation of dopaminergic neurons in the substantia nigra of a mouse increases corticostriatal synaptic efficacy, resulting in the mouse learning the lever-pressing behaviour required to obtain dopaminergic reward [16].
While the incentive sensitisation model is obviously theoretical, it does provide an integration of operant conditioning aspects of drug addiction and other observations that operant conditioning models can not account for, such as relapse after long periods of abstinence; sensitisation to incentives at the molecular level is extremely stable and can persist for a long time after the last time the ‘dependent’ individual stopped taking their drug [15].
Does Nucleus Accumbens dopamine have functions other than reward?
This is a particularly difficult question to address. Researchers in the drug addiction field, particularly those involved in psychopharmacological studies of dopamine function and how these physiological processes produce specific behaviours associated with drug dependence, have disagreed for decades about the actual role of dopamine release into the nucleus accumbens. These disagreements are centred around what the actual nature of ‘reward’ is, and whether it might in fact be a misnomer, and instead should be replaced by the dual concepts of ‘drug liking’ and ‘drug wanting,’ the latter, but not the former of which has been shown conclusively to be dependent on the mesolimbic dopamine system.
Dopamine release in the nucleus accumbens mediates some processes and behaviours that can not be directly defined as ‘reward.’ Most of these processes are, however, intrinsically related to ‘reward’ and goal directed behaviour. The confusion inherent in attempting to define processes mediated by the dopamine release in the NAc that are not ‘reward,’ comes from the inadequate biobehavioural definition of reward.
The most important of these processes attributable to dopamine release in the NAc is called ‘appetitive conditioning.’ Appetitive conditioning, or the disruption thereof also plays a significant role in drug addiction. The general principle is that the NAc integrates information input from various components of the limbic system and other parts of the brain (as detailed in the “Neuroanatomy of the Nucleus Accumbens and Associated Structures” section,) and that this information concerns the value of a certain stimulus to the organism. The authors of one study [18] propose that “activity in this distributed network (including D1 receptor activity) computes coincident events and thus enhances the probability that temporally related actions and events (e.g. lever pressing and delivery of reward) become associated.”
The NAc can also mediate fear conditioning. In another study, the experimenters temporarily inactivated neuronal function in the NAc using tetradoxin, a drug which blocks neuronal sodium channels, and therefore blocks action potential propagation. During this time, they investigated acquisition and expression of conditioned fear, as measured by “fear-potentiated startle,” or “FPS.” Injection of tetradoxin into the NAc completely inhibited acquisition and significantly decreased expression of conditioned fear to a visual conditioned stiumulus. Additionally, this temporary inactivation of the NAc did not have an effect on shock sensitisation of startle. This may indicate that both the perception of the shock and the short term contextual conditioning was not affected by injection of tetradoxin into the NAc. These results indicate that the function of the NAc in fear conditioning is that of acquisition and expression of long-term conditioned fear (measured by fear-potentiated startle, to a conditioned stimulus,) but that the NAc is not involved in short term conditioning of fear to a ‘context’ [19].
Thus nucleus accumbens dopamine is primarily involved in strengthening relationships between stimuli and other stimuli, and relationships between stimuli and ‘affective states,’ such as, but not limited to, drug states and the states induced by other natural rewards. Dopamine release by mesencephalic neurons into the nucleus accumbens is essential for modulation of the function of this region, and is essential to all current models of obsessive drug related behaviours. The interaction of the nucleus accumbens with other regions of the brain such as other components of the limbic system, the hypothalamus and the prefrontal cortex is also an essential component of current biobehavioural models of drug dependence.
REFERENCES:
1.) Wolrd Health Organisation Report: The Neuroscience of Psychoactive Substance Use & Dependence, 2004
2.) Salmone JD, Correa M, Mingote S, Weber SM “Nucleus accumbens dopamine and the regulation of effort in food-seeking behavior: implications for studies of natural motivation, psychiatry, and drug abuse.” J Pharmacol Exp Ther. 2003 Apr;305(1):1-8. Review.
3.) Carelli R. “Nucleus accumbens cell firing and rapid dopamine signalling during goal-directed behaviours in rats.” Neuropharmacology 47 (2004) 190-189
4.) Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, Acquas E, Carboni E, Valentini V, Lecca D. “Dopamine and drug addiction: the nucleus accumbens shell connection.” Neuropharmacology 47 (2004) 227-241
5.) Boye SM. “Mesencephalic substrate of reward: lesion effects.” Behav Brain Res. 2005 Jan 6;156(1):31-43
6.) Brog JS, Salyapongse A, Deutch AY, Zahm DS. “The patterns of afferent innervation of the core and shell in the "accumbens" part of the rat ventral striatum: immunohistochemical detection of retrogradely transported fluoro-gold.” J Comp Neurol. 1993 Dec 8;338(2):255-78
7.) Kandel ER, Schwartz JH, Jessel TM. “Principles of Neural Science.” McGraw-Hill Medical 4th Edition, Jan 5th 2000
8.) Zahm DS, Brog JS, “On the significance of subterritories in the “accumbens” part of the rat ventral striatum.” Neuroscience, Volume 50, No. 4, pp. 751-767, 1992.
9.) Otake K, Nakamura Y, “Possible pathways through which neurons of the shell of the nucleus accumbens influence the outflow of the core of the nucleus accumbens.” Brain & Development 22 (2000) S17-S26
10.) Pare D, “Role of the basolateral amygdala in memory consolidation.
Prog Neurobiol. 2003 Aug;70(5):409-20. Review.”
11.) White NM, “Addictive drugs as reinforcers: multiple partial actions on memory systems.” Addiction (1996) 91(7), 921-949.\
12.) Girault JA, Greengard P, “The neurobiology of dopamine signaling.” Arch Neurol. 2004 May;61(5):641-4. Review.
13.) Greengard P. “The neurobiology of slow synaptic transmission.” Science, Nov 2 2001, Vol294
14.) Grace A, “The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving.” Addiction (2000) 95 (Supplement 2), S119-S128
15.) Nestler EJ “Molecular basis of long term plasticity underlying addiction.” Nature Reviews Neuroscience. 2001 Feb;2(2):119-28
16.) Reynolds DN, Hyland BI, Wickens JR, “A cellular mechanism of reward related learning.” Nature. 2001 Spec 6;413(6851):67-70
17.) Robinson TE, Berrige KC, “The psychology and neurobiology of addiction: an incentive-sensitization view.” Addiction. 200 Aug;95 Suppl 2: S91-117
18.) Kelley AE. “Appetitive conditioning Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning.” Neurosci Biobehav Rev. 2004 Jan;27(8):765-76.
19.) Schwienbacher I, Fendt M, Richardson R, Schnitzler HU. “Temporary inactivation of the nucleus accumbens disrupts acquisition and expression of fear-potentiated startle in rats.” Prog Neurobiol. 2004 Jun;73(3):179-226
