The Common Reward Pathway

The common reward pathway for substances of abuse, specifically relating to neuroanatomy and neurophysiology.

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Although substances of abuse have varied and diverse primary targets and acute effects neurochemically, research has shown that almost all substances of abuse lead to an increase in dopamine in the mesocorticolimbic dopaminergic system. The understanding of this common reward pathway is important as it could (i) lead to the development of a single medication that works for various classes of substances of abuse in addiction treatment; and (ii) give a better understanding as to why all those suffering from addiction experience similar psycho-social devastation in spite of the variety of drugs of choice.

The Reward System

As humans we are prepared to allocate time, effort and energy in the acquisition of the “things” that are essential for our survival. These “things” can be considered the fruit, or reward, of our labour.

The human brain has a complex system of ‘reward’ that has evolved to assist in the mediation of pleasurable behaviour (Esch & Stefano, 2004). Primary reward is designed to ensure human survival by directing us toward beneficial behaviours such as eating and procreating and then reinforcing such essential behaviours (Goldstein, 2002) (Nestler E. , 2005) (World Health Organisation, 2004). Secondary reward deals with more abstract concepts such as achieving life goals (Taber, Black, Porrino, & Hurley, 2012).

Box 1:  Brief description of main areas involved in the reward system
Ventral Tegmental Area (VTA)	The VTA is situated in the evolutionary old area called the midbrain. It consists of a group of neurons and is the origin of the dopaminergic cell bodies. Although there are relatively few neurons (about 5000) these dopaminergic neurons can have an axonal length of 74cm and 500,000 terminals per individual neuron. As a result the dopaminergic neurons have an extensive reach to multiple areas and modulate diverse brain functions (Arias-Carrion et al, 2010). FMRi Image Source: Princeton University
Nucleus Accumbens (NAc)	The NAc forms the main portion of the ventral striatum and consists of two bodies, one for each hemisphere, and each of these consists of two structures, the core and the shell. The neural cells produce the neurotransmitter gamma-aminobutyric acid (GABA), and these neurons project from the NAc. Projecting into the NAc are the dopaminergic neurons from the VTA. The VTA is a part of the cortico-striato-thalamo-cortical loop.          CMRi Image Source: Wikimedia
Limbic System	The limbic system consists of the set of brain structures that “line” the cortex. In some literature the NAc is considered part of the limbic system. The areas of the limbic system closely linked to reward are the Amygdala and, because of the link between memory and reward, the Hippocampus and the Mammillary body.
Prefrontal Cortex (PFC)	This is the anterior part of the frontal lobes. The prefrontal cortex is primarily credited with executive function: the ability to make decisions, determine good from bad, prediction of consequences, salience and inhibition amongst other things.

At the centre of the reward system are the mesolimbic and mesocortical pathways (World Health Organisation, 2004) (Esch & Stefano, 2004). The mesocortic pathway projects from the ventral tegmental area (VTA) to the perirhinal, cingulate and prefrontal cortex and is thought to be important for reward processing. The mesolimbic pathway links the VTA with the limbic system via the nucleus accumbens (NAcc) and is thought to be important for the reinforcement of reward (Taber, Black, Porrino, & Hurley, 2012). See Figure 1

In response to a motivationally relevant event, the VTA is stimulated. Nerve cells are excited and they send an electronic impulse along the axons that project into the NAcc. This causes dopamine to be released into the synapse and then latches onto receptors on the NAcc neurons. The activation of this system produces changes ranging from slight mood elevation to euphoria. In this way we develop an adaptive behaviour response in the case recurring events or stimuli (Kalivas & Volkow, 2005).

It is important in terms of addiction that the “motivationally relevant event” in initial stages is the actual receipt of the reward, while after time it is the repeated precursor to the reward that triggers the release of dopamine and acts as the “motivationally relevant event”. Should the reward exceed the anticipated level of reward, this can result in further dopamine release and even further enhance the learning and reward process.

It is believed that it is this reward system, along with the serotonin systems, that is co-opted and eventually modified by substances of abuse (Dackis & C, 2005).

Box 2: The discovery and evidence of the reward system

During the 1950s a number of experiments were conducted by stimulating various brain areas in a variety of rats (Olds & Milner, 1954). It was discovered that by stimulating the various areas the rats would seek to repeat the experience through self-stimulation, even to the point of physical exhaustion and in spite of physical discomfort. In further animal experiments, if dopamine was blocked they stopped partaking in rewarding activities (Wise, 1998). Paradoxically the elimination of dopamine does not seem to affect the ability to “like” certain things, such as sweetness. (Pecina et al,1997). This would imply that other systems are involved in the “wanting” of things, as per Koob, 1992. In a series of very controversial experiments during the 1960s Heath inserted an electrode into the NAc of patient “B-19”. He then continuously self-stimulated even though he was left frustrated and had “a nervous feeling” (Heath, 1964). These, and further experiments, have certainly strengthened the case for the existence of a “reward pathway” as described in this essay. It is, however, unfortunate that this has sometimes been erroneously labelled the “pleasure”  centre or pathway, which has had some unfortunate implications in the understanding of the development of addiction in those that use substances of abuse.

The effects of substances of abuse

When a substance of abuse is administered it starts a cascade of complex reactions in the brain. The chemistry of substances of abuse is as diverse as there are names, and each one has a specific protein target in the brain.

As discussed, dopamine is central to the reward system and forms the basis of all current models of instrumental responding. Therefore, if there is a common reward pathway for substances of abuse, it would seem logical that all these substances of abuse would have an effect on dopamine.

If we consider the varied acute effects of the multitude of substances of abuse the likelihood of a common reward pathway may seem remote, however, if we examine the actions of many of these substances we find this to be the case. The following table gives a simplified overview:

Substance	PMA	Main Effect	Other
Cocaine	Blocks DA uptake	Inc Dopamine	Directly increase doperminergic transmission in the NAc
LSD	Inc Serotonin
Heroin	Activates Mu & delta receptors	Inc Dopamine through disinhibition in the VTA of dopamine neurons and direct effects on DA terminals
Amphetamines	Inc Dopamine & blocks DA uptake	Inc Dopamine
Nicotine	Acetylcholine	Inc Dopamine
Alcohol	GABA  & Substance P	Inc GABA	Increased MDP activity
Marijuana	Activates Endocannabinoid receptors		Inc Dopamine in MDP
MDMA	Inc Serotonin  and block 5-HT uptake	Inc  Serotonin	Inc Dopamine

I have highlighted the instances where dopamine release is stimulated, and indeed we see that the substances of abuse listed here all seem to have an effect on dopamine levels, which will in turn activate the natural reward pathway. This evidence is further enhanced by the observation that substances of abuse can lead to cross-tolerance and cross-sensatization (Nestler E. , 2005).

Having said this and pointed out the importance of the dopaminergic pathways and the increased levels of dopamine during drug administration, there is evidence that the reward system may collapse under the constant artificial stimulation by drugs of choice and natural dopamine levels may drop significantly causing a variety of negative affective states (Esch & Stefano, 2004) (Nestler E. , 2005). It is at this point that other systems take over.

 

Conclusion

While all the current evidence seems to demonstrate that there is indeed a common reward pathway, it’s not the only place that substances of abuse are active, and it is doubtful that the effects on the reward pathway are identical. It also seems that while this reward pathway is responsible for the development of addiction, the chronic state of addiction probably lies in other systems.

The value in understanding the common reward pathway for substances of abuse and natural rewards is not so that we can block that reward pathway – this would raise serious bio-ethical issues – but rather so we can prevent the hi-jacking and modification of this system that moves an individual from the state of being a substance user or activity partaker to being addicted to it.

Further research in this direction would possibly lead to the development of a medication that could be used to treat all compulsions and addictive behaviours, natural or substance induced, possibly developing an addiction vaccine. The big question is: if such a vaccine were to be developed, who would want to take it?

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