Neuroanatomical Mechanisms Involved in Cue Induced Relapse to Alcohol

Drug addiction can be defined as a chronically relapsing disorder due to the difficulty for addicts to maintain abstinent from a particular drug (Koob and Volkow 2010). This is due to an unconscious mechanism within the brain that drives people to seek for a particular drug even when they intend to remain abstinent. In this article I am going to be looking at cue-induced relapse to alcohol.

Alcohol addiction is a major problem in the UK, costing the NHS £3.5billion per year. 9% of adult men and 4% of adult woman in the UK are dependent on alcohol, but only 1% of alcoholics actually seek treatment (statistics on alcohol). Alcohol also causes 4.6% of global disease and injury (Ryan et al, 2013). The current treatments for alcoholism prescribed by the NHS are aimed at preventing relapse or limiting the effects of alcohol. Some examples are naltrexone and acamprosate (NHS). These treatments, however, are unsatisfactory as there are still high relapse rates, in addition to compliance issues (Ryan et al, 2013).

To understand why the treatment of alcoholism is so difficult, the behaviour of an alcohol addicted individual compared to that of a non-addicted drinker needs to be understood. This difference highlights how the seeking of alcohol becomes an unconscious and uncontrollable drive. Addiction occurs once there is a shift from drinking being a goal directed behaviour (going out for a drink with a friend on a night out), to an automatic habitual behaviour (drinking every day). When people start drinking they are seeking positive reinforcement (this is a goal directed behaviour) and have control over their decision to drink alcohol. On the other hand habit-seeking behaviours are not due to the expectation of a positive reward, but are instead driven by the memory of previous, reinforcing, alcohol associated history; thus the action of seeking alcohol becomes automatic and involuntary. This is where environmental cues start to come into play. Cues such as the sight of a pub trigger memories of drinking, causing craving symptoms due to the establishment of habitual pathways in the brain. Therefore, addicts will take a drink when these cues are presented. The other sign that drinking has become habitual is that immediate negative effects associated with drinking have no effect on preventing alcohol seeking behaviours. The brain region involved in mediating these two behaviours is the striatum. Goal-seeking behaviour is mediated by the dorsomedial striatal circuitry whereas habitual control takes place in the dorsolateral striatum, and evidence shows that there is a shift of control from the dorsomedial to the dorsolateral striatum as habitual learning takes place and addiction occurs (Corbit and Janak, 2016).

Relapse is an enduring problem, even once withdrawal symptoms have disappeared and alcohol addicted patients have undergone long periods of abstinence. Although there are many factors involved in relapse (such as stress) a major problem for alcoholics is the constant exposure to alcohol and alcohol related cues, due to the legal nature of alcohol and its wide availability. Some of the main areas in the brain that have been shown to be involved with cue-induced relapse to alcohol-seeking are the medial prefrontal cortex (mPFC), the nucleus accumbens (NAc) core and shell, the ventral tegmental area (VTA), the basolateral and central amygdala and the cornu ammon regions of the hippocampus. Two major neurotransmitters have been implicated in signalling to these brain regions and triggering relapse due to the presentation of an alcohol related cue. These are Orexin-A and relaxin-3.

There are two forms of orexin: orexin A and orexin B, which bind to the receptors orexin-1 (OX1) and orexin-2 (OX2). Orexin A and its cognate receptor OX1 have been identified as being involved in the act of alcohol seeking. Orexins are hypothalamic neuropeptides and their neurones originate in the lateral, dorsomedial and perifornical areas of the hypothalamus. Orexins play a role in many autonomic functions such as feeding and arousal, as well as being implicated in the reward system. Their axons project from the hypothalamus to the mesocortical limbic system.

One experiment (Brown et al) looked at the involvement of orexin A innervation of the prelimbic cortex and the VTA and its involvement in alcohol-seeking behaviour in rats due to reinstatement of alcohol linked triggers. The prelimbic cortex is a brain region located in the prefrontal cortex and has been linked to alcohol seeking behaviour. The VTA is a major brain region involved in the dopaminergic reward pathway (mesolimbic pathway) and also has a role in alcohol-seeking behaviour. For this experiment rats where trained to administer an ethanol containing solution by pressing a lever. The cues present that were to become associated with the reward of alcohol included a light placed above the lever and vanilla essence scent. The rats then underwent extinction of alcohol (they were put in the chamber without alcohol being delivered when the lever was pressed and no cues where present) and then after a period of extinction the cues where reinstated and the rats where either given a vehicle or an OX1 inhibitor (SB-334867) to see whether by preventing orexin signalling there would be a decrease in the tendency of rats to relapse due to cue-induced reinstatement of alcohol. Selective inhibition of either the VTA or the prelimbic cortex both significantly reduced alcohol reinstatement in rats.





Figure 1a depicts a significant decrease in alcohol seeking in rats when the SB3 antagonist was applied to the VTA compared to when rats where only given the vehicle. 1b also shows a significant decreased in lever presses when SB3 was injected into the prelimbic cortex.

Orexin neurones project from the lateral hypothalamus to the prelimbic cortex. These neurones are involved in sending appetitive signals to the prelimbic cortex, triggering alcohol-seeking behaviour. The role of the orexin system in the VTA is more centred on reward value, but the results clearly show that this pathway is also implicated in cue-mediated reinstatement of alcohol seeking. Jupp et al also investigated orexin mediated alcohol seeking by examining Fos expression. They also applied the OX1 inhibitor SB-334867, but at two stages, either during immediate reinstatement to alcohol after a period of extinction or after 5 months or extinction. They found that Fos expression increased (when presented with alcohol related cues) in the infra-limbic cortex, the prelimbic cortex, orbitofrontal and piriform cortices, NAc core and shell, basolateral and central amygdala, lateral and dorsomedial hypothalamus and the BNST. SB-3 inhibited Fos expression showing that orexin signalling circuitry is involved in cue-reinstatement, but depending on the time of relapse they found a change in the amount of Fos inhibition, indicating that the orexin circuitry involved in reinstatement may change over time. In immediate reinstatement the brain areas involved are the orbitofrontal and prelimbic cortex and the accumbens core but after protracted abstinence there is a shift to the cortical locus.

The second neurotransmitter involved in cue-reinstatement of alcohol is Relaxin-3. Relaxin-3 is a highly conserved neuropeptide, throughout species, and is the true ancestor of the relaxin peptide family. Its cognate receptor is relaxin peptide 3 receptor (RXFP3). Relaxin-3 networks have been linked with arousal functions such as stress, feeding, sleep/wake states and motivation and reward. Relaxin-3 is expressed in GABAergic neurones in the hindbrain nucleus incertus. These neurones then project to the forebrain areas: the amygdala, bed nucleus of the stria terminalis (BNST), hippocampus and the lateral hypothalamus. The previous experiment was repeated by Ryan and team, however the rats were injected with either an antagonist for RXFP3 called R3(B1-22)R or a vehicle. Rats that were injected with R3(B1-22)R had significantly reduced lever presses then rats injected with the vehicle.



Figure 2a demonstrates that application of the R3(B1-22)R antagonist significantly reduced lever presses when alcohol cues where reinstated.

These experiments demonstrate the importance of orexin and relaxin-3 in drug seeking behaviors and cue induced triggers. These experiments also highlight the importance of understanding these complicated systems so that new pharmaceuticals can be developed to help prevent alcoholics from relapsing again and to make their attempts to remain abstinent easier. Further research into the involvement of these two neurotransmitters and their involvement in relapse is crucial so that our understanding of alcoholism can develop, allowing scientist to help alcoholics, and the treatment they receive, improve.

Author: Lara Cornish 



Alcohol concern (2016). Statistics on alcohol. Available at Accessed on the 5th of September.

Brown, R. M., Kim, A. K., Khoo, S. Y. S., Kim, J. H., Jupp, B. & Lawrence, A. J. (2016) Orexin-1 receptor signalling in the prelimbic cortex and ventral tegmental area regulates cue-induced reinstatement of ethanol-seeking in iP rats. Addiction Biology, 21(3), 603-612.

Corbit, L. H. & Janak, P. H. (2016) Habitual Alcohol Seeking: Neural Bases and Possible Relations to Alcohol Use Disorders. Alcoholism-Clinical and Experimental Research, 40(7), 1380-1389.

Jupp, B., Krstew, E., Dezsi, G. & Lawrence, A. J. (2011) Discrete cue-conditioned alcohol-seeking after protracted abstinence: pattern of neural activation and involvement of orexin(1) receptors. British Journal of Pharmacology, 162(4), 880-889.

Koob, G. F. & Volkow, N. D. (2010) Neurocircuitry of Addiction (vol 35, pg 217, 2010). Neuropsychopharmacology, 35(4), 1051-1051.

NHS choices (2015) alcohol misuse – treatment. Available at Accessed on the 5th of Spetember 2016.

Ryan, P. J., Kastman, H. E., Krstew, E. V., Rosengren, K. J., Hossain, M. A., Churilov, L., Wade, J. D., Gundlach, A. L. & Lawrence, A. J. (2013) Relaxin-3/RXFP3 system regulates alcohol-seeking. Proceedings of the National Academy of Sciences of the United States of America, 110(51), 20789-20794.





Addictive Drugs and Their Reinforcing Capabilities


Almost every person in his or her lifetime will have taken some sort of drug, whether this is caffeine, nicotine or perhaps a recreational drug, such as cocaine. The taking of drugs seems to be a natural phenomenon within humans because as well as targeting the reward pathway within the brain, they provide an effect that is appealing to people; whether this is just a caffeine kick or the euphoria produced that allows people to escape from their usual way of thinking. The reward pathways within the brain are an evolutionary advantage that ensures that when a positive action is carried out (such as drinking water, eating food or having sex) it is repeated. Drugs target this pathway producing reinforcing affects. They do this by releasing dopamine, a neurotransmitter that activates the reward pathway, making the brain believe the effects of taking the drug are good, ‘rewarding’. In this article I will be talking about the reinforcing effects of cocaine, alcohol (ethanol) and nicotine.

The Reward Pathway: 

First the terms ‘rewarding’ and ‘reinforcing’ require definition. A rewarding stimulus is one in which, through activation of dopamine, the brain understands to be not only positive but a stimulus that must be approached. Reinforcement means that the action produces the increasingly intense feeling that repetition is necessary. The pathways within the brain that induce reinforcement are a set of forebrain structures, connected through a series of neural pathways. These include the nucleus accumbens (which is part of the ventral striatum), the basal forebrain (which includes the amygdala) and regions within the medial prefrontal cortex (Eric J. Nestler et al, 2001). These areas of the brain receive dopaminergic innervation from the ventral tegmental area (which is part of the midbrain). Reinforcing drugs induce a sense of reward by increasing that release of dopamine within these forebrain structures, via activation of the mesocorticolimbic dopaminergic system. The euphoric state of the drug also plays a role in their reinforcing nature, but without this release of dopamine they would not necessarily be addictive. This is seen in LSD which does not provide this rapid onset of positive reinforcement, so although the drug does produce a state of euphoria, this alone is not enough to cause chronic use and abuse (Eric J. NEstler et al, 2001).
The mesocorticolimbic pathway originates in the ventral tegmental area of the midbrain and the dopaminergic neurone efferents that synapse in the ventral tegmental area are the most important in reinforcement.


Figure 1: The dopaminergic pathways of the brain.
Source: Bear et al., Neuroscience, 3rd edition.


Cocaine is a psychostimulant which produces a state of euphoria that induces a state of extreme pleasure and gratification, which is accompanied by a separation from reality. Cocaine is highly addictive due to its capability to produce strong reinforcement. Cocaine’s affects are fast acting but short lasting which also adds to its reinforcing nature, and is why users will continuously take the drug throughout a short period of time. Although cocaine is reinforcing, addicts of cocaine are more likely to go through sessions of binges on the drug rather than continual use. This may be due to the fact that withdrawal of cocaine does not necessarily produce major adverse effects on the body, (although there are emotional withdrawal symptoms) such as the shakes that would cause users to need the drug to function normally. The psychostimulant effects of cocaine results from the increased level of monoamine neurotransmitter release, including: dopamine, serotonin and noradrenaline. Cocaine targets the reuptake proteins of these neurotransmitters, binding to them and antagonising them, inhibiting their action. This decreases the amount of neurotransmitter being removed from the synaptic cleft, causing an increased level of neurotransmitter and enhancing the response. The prevention of the removal of dopamine is the most important for the reinforcing nature of cocaine. Dopamine release is increased in the nucleus accumbens.

Alcohol (ethanol):

Ethanol is a depressant within the central nervous system. This does not mean that taking alcohol makes the users depressed; in fact most of us know this is quite the contrary as alcohol usage is associated with increased happiness and a loss of social awkwardness, perhaps why people find it so pleasurable. What ‘depressant’ means in the case of ethanol is that it facilitates the action of GABAA receptors and inhibits glutamatergic NMDA receptors (Eric J. Nestler et al, 2001). The release of GABA within the brain acts to hyperpolarize the cell, making it more negative on the inside and decreasing the amount of action potential (hence depression). Glutamate is the main excitatory neurotransmitter within the brain and its release causes an increase in action potential firing. By inhibiting this, ethanol is again reducing the amount of action potential firing within the brain. If high doses of ethanol are taken then most ligand and voltage gated ion channels are affected. This is why alcohol has such a wide spread affect within the brain. The reinforcing nature of ethanol is not understood completely but is thought to be due to its effects on the NMDA receptors and its ability to activate the mesocorticolimbic pathway, although it is not yet know whether this reinforcing effect takes place in the ventral tegmental area or the nucleus accumbens. How dopamine is realised due to ethanol is also not confirmed as it could either be due to the facilitation of GABAA receptors or due to the inhibition of NMDA receptors (Eric J. Nestler et al, 2001). What is clear though it that one or both of these mechanism plays a role in inhibiting the tonic inhibition of the release of dopamine. Ethanol also reduces serotonergic function, which is thought to add to the reinforcing nature of ethanol. The fact that ethanol does affect so many systems within the brain is probably the main reason why it is so hard to find out why the drug is reinforcing, but it must be remembered that in many cases of drug abuse (this is very different from drug use) people are wanting to remove themselves from reality due to some underlying cause, and for some people this may be what motivates them to abuse alcohol or any other drug to such an extent.


Nicotine is the addictive substance within the Tabaco plant and within cigarettes, and now also E-cigarettes. Nicotine is an interesting drug, firstly because it is highly addictive although it does not cause any state of euphoria, showing how this drugs addictive nature is so much to do with how it’s affects on the central and peripheral nervous system. Secondly, as most of us know smoking is not pleasurable and in fact quite deterring the first couple of times people smoke, and it must be taken quite frequently to become pleasurable. This shows how drug taking can be so associated to one’s social environment as without this most people would not force themselves to continue smoking. It is also shown in animal studies that the animals will not choose to take nicotine if they have the choice (Eric J. Nestler et al, 2001). Therefore the reinforcing nature of nicotine is not immediate as it is in cocaine for example, but is instead only reinforcing once the user has become addicted. Nicotine is similar in structure to acetylcholine and is therefore capable to binding to nicotinic acetylcholine receptors (nACh), causing the opening of ion channels, allowing sodium to enter and a response in the postsynaptic neurone to be initiated. In the central nervous system nACh receptors are located on the ventral tegmental dopamine neurones and through binding of nicotine cause a release in dopamine by creating an action potential (Eric J. Nestler, 2001). Nicotine may also cause the release of endogenous opioids adding to its reinforcing nature. Nicotine also causes withdrawal symptoms, such as an agitated mood and shaking of the hands. This could lead to continued use just to remove the uncomfortable symptoms that are accompanied with withdrawal.


There is so much more that could be said on how drugs cause addiction and how the brain of an addict is altered from the normal state. The reinforcing nature of drugs is what causes people to seek the drug and to feel the need to take the drug again, as by hijacking the reward pathway our brains are fooled into thinking that the drug is good for the body and mind. This fact also demonstrates the strength of the reward pathway in its ability to unconsciously control the acts of the conscious mind. Each drug has its own mechanism in causing the release of dopamine but it is through this release that all drugs are reinforcing.

The consuming of drugs is a subjective topic. Whilst considered dangerous, drugs have been demonstrated to open the mind and make people observe the world in a fascinating and euphoric way. Some of the greatest pieces of literature in history, Alice in Wonderland to name an example, have been argued as products of the brain when under the effects of recreational drugs. What has to be understood is that there is a difference between taking and trying drugs and abusing them. It is the process of taking a drug regularly that causes long term alterations to the brain and enhances the reinforcing nature of the drug.

Eric J. Nestler, Steven E. Hyman and Robert C. Malenka, 2001, Molecular Neuropharmacology A foundation for Clinical Neuroscience, The McGraw-Hill companies, Inc. Medical Publishing Division.

Article by Lara Cornish.
Edited by Molly Campbell.