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.





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