Untitled (3).jpg

Link to article: Brain plasticity: The key for drug addiction?



Introduction


Drug addiction is a complex disorder that cripples the lives of people around the globe. Due to such comlpexity, the disorder displays a wide variety of causes. This research suggests that synaptic anaplasticity contributes to the progressive onset of addiction as a result of continual reinforcement.
The concept of addiction, which was originally thought to only be exerted in humans, can furthermore be explored through the self administration of cocaine in rodents, resulting in the consistent, compulsive consumption of drugs. The article "Brain plasticity:The key for drug addiction?" is based on the research report,Transition to Addiction is Associated with a Persistent Impairment in Synaptic Plasticity, by Fernando Kasanetz et al (2010).
In this article, the author examines the major underlying causes of drug addiction and the journey an individual goes through in becoming drug-dependent. It also aims to provide further information for the development of treatments and therapies in order to control addiction and assist in managing healthy lifestyles of the few that are addicted. (INSERM, 2010), (Kasanetz.F et al, 2010)

Neuroscientific Context



Neuroplasticity refers to changes in grey matter induced by training (Draganski, et al. 2004). As this definition is relatively broad in this piece of literature the focus will be on Neuroplastic changes that occur in discrete cortical pathways and are induced specifically by pharmacological substances.
Pharmacological substances such as addicitive drugs have numerous affects on the brain, so identifying exactly which neuroplastic changes stem from addictive drugs is a major component of research undertaken by neuroscientists working in this area. Involved in this research is also eliminating neuroplastic changes that occur as a result of other environmental stimuli. (Kalivas, Peter. W, 2005)).
‍‍‍‍‍‍‍At a glance, addiction can be viewed as a psychological process that causes modifications to cortical pathways and behavioral responses. It is characterised by an evolution from social to uncontrolled drug administration‍‍‍‍‍‍‍. As is the case with neuroplasiticity, there is an interplay of different factors surrounding addiction. Genetic, developmental and environmental factors all play a role in determining an individual’s current susceptibility to addiction. These factors, when coupled with addictive drugs act to induce changes to the brain circuitry that strengthen drug-associated behaviours at the expense of natural reward seeking. (Kalivas, Peter. W, O’Brien, Charles, 2008)

Drug dependency places medical, social and economic burdens on society (T Robbin’s and B, Everitt 1999). We can see this in Collin and Lapsley’s (2008) estimate of the cost of alcohol, tobacco and illicit drug abuse in Australia using 2004/2005 financial year data, which was the most recent available at the time of research, to be $55.2 billion. These costs pertain to crime, health, loss of production in the workplace and home. To date there are no effective treatments for many kinds of drug addiction.

Kasanetz et al (2010) investigate how addiction impacts on the plasticity of LTD (long term depression) within the nucleus acumens core (NAC) and how this impacts on pathways which facilitate flexible and new learning (Thomas 2008, Chen 2010). Their research draws on prior research which has found that drug induced changes to LTD and LTP [long term potentiation} in different areas of the mesocorticolimbic system leads to a loss of plasticity, establishing the foundation for addiction as the drug seeking behaviour becomes impervious to change despite competing demands. One of the most intransigent problems with treatment of drug addiction is relapse. Therefore, understanding the process for formation of drug related learning and then how this learning is stored and can be modified could provide a powerful contribution to treatments. The hypothesis of Kasanetz et al (2010) is that drug use may have different impacts on the LTD induction in the NAC in individuals, with some prone to a more permanent loss of synaptic plasticity and therefore to changing addictive behaviours. This research has the potential to identify root causes of the loss of synaptic plasticity in drug-dependent individuals.



LTD, LTP plasticity and addiction


Long term potentiation (LTP) and long term depression (LTD) are processes in which activity dependent plasticity is created through increasing or lowering the effectiveness of synaptic pathways and functions in different parts of the brain. Romany Cajal, a Nobel laureate and pioneer of neuroscience hypothesized an association between learning and synaptic connections between neurons a century ago ( Kauer and Malenka 2007). Long term potentiation was discovered in 1973 and subsequently an enormous effort has been dedicated to researching the science of synaptic plasticity (Kauer and Malenka 2007). A significant body of research suggests that LTD and LTP are related to the learning of addictive behavior and the resistance experienced by addicts to changing this behavior. Kasanetz et al (2010) study compared the glutamate-dependant long term depression (LTD) in the nucleus acumens core (NAC) of cocaine addicted and non addicted rats. The NAC is an integral part of the brains reward circuitry and seen as the limbic-motor mediator in which seemingly relevant stimuli are processed to influence behavior. In vitro brain slice modeling has demonstrated that glutamatergic synapses in the VTA and NAC can express plasticity. Many studies have found that long-term potentiation (LTP) and long-term depression (LTD) of evoked alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) currents can be induced in the VTA and NAC (Thomas, Kalivas, & Shaham 2008),

The AMPA receptor which mediates synaptic messages is made of four types of proteins called GluR1, GluR2, GluR3 and GluR4. An increase in GlUr1 and decrease in GluR2 type receptors has been associated with drug usage.For example tetrahydrocannabinoids (cocaine) induced LTP in the VTA is associated with an increase in the proportion of GluR1 and a reduction in GluR2 within AMPARs. When cocaine is self administered the changes to the AMPAR receptors in VTA DA neurons can be observed for at least 3 months after the drug is no longer used although the same impact is not observed when the drug is not self administered. Further, in contrast to drug induced stimulation, LTP induction with natural rewards resulted in VTA DA neurons only present for up to 7 days. (Thomas, Kalivas, & Shaham 2008) These research findings suggest with respect to cocaine usage that:

• learning in relation to natural rewards stimulates LTP in a more transient way than cocaine induced stimulation in the VTA

• The sustained increase in LTP when drug induced is related both to the pharmaceutical properties of the drug and the learning and memory mechanisms triggered through self administration.

The induction of LTD and LTP in the NAC is different to that in the VTA. Much less is known about the synaptic plasticity in the NAC compared with the VAC ( Kauer and Malenka 2007) The NAC is comprised of spiny neurons which receive messages from dopaminergic neurons in the VAT and the glutamatergic neurons of the hippocampus, amygdala, and the medial prefrontal cortex. Researchers generally agree that repeated drug exposure and protracted abstinence alter AMPAR signaling in the NAC. After 5 days of self administration of cocaine LTD induction is observed in the NAC (Thomas, Kalivas, & Shaham 2008) The induction of LTD through cocaine uses a different path to that which occurs through natural rewards. Cocaine induced LTD induction uses a mGluR2/3-dependent mechanism compared with the mGluR5 mechanism which induces LTD in the NAC through natural rewards. Cocaine self-administration leads in some rats to a long-lasting disruption to the induction of LTD in the NAC core. Further, use of chemicals which interfere with GluR1 or GluR2 in the NAC reduces the re usage of cocaine, suggesting that NAC GluR1s and GluR2s may be associated with reward and motivation learning related to cocaine addiction. While research demonstrates the induction of LTD in the NAC through cocaine use, the precise mechanisms within the core and the shell of the NAC through which this induction takes place are still being researched. Kasanetz et al's (2010) found that after 17 days of self administration of cocaine NMDAR dependant LTD in the NAC was eliminated in all the rats. However, after 8 to 10 weeks it was recovered by the rats which had controlled cocaine intake but not by those, which using an established protocol, had been identified as addicts. The difference between the plasticity of NMDAR dependent LTD in the NAC of addict rats compared with non addict rats, after self administered exposure to cocaine for 8 to 10 weeks, offers a promising path for research into treatment for cocaine addiction.

In Kasanetz et al's (2010) study the reason for certain rats having an impotence to fighting addiction was correlated with not being able to regain normal levels of LTD in the NAC, this suggested a loss of plasticity and inability to change motivational circuitry. More broadly the learning that causes the development of this change in motivational circuitry can be understood in the context of how drugs activate the reward circuitry of the brain

Changes to motivational pathways


The cortical changes that occur to the brain during progression into an addictive-state heavily rely on the motivational circuitry of the brain. This circuitry is responsible for cueing the organism to seek out biological rewards, and so it enhances learning and memory for that particular stimulus.
Research into drug addiction has highlighted that habitual drug use causes changes to how a person interprets and responds to motivationally relevant stimuli. By causing changes to this circuitry, drugs alter the way the person is able to learn about the environment and adapt to important environmental stimuli.
Addictive drugs are known to cause an increased activation of this circuitry when compared to natural rewards. This impairment causes the individual to behaviourally adapt in such a way that increases drug-seeking and drug-taking strategies, inevitably leading to a decline in the seeking of natural rewards.
In this sense, addiction can be viewed as a pathological alteration to neural mechanisms that control the hierarchy of adaptive behaviours towards environmental stimuli. This pathological alteration manifests in two ways:
  1. Impairment to the ability to seek-out and use drugs (relapse).
  2. Inhibit the motivation towards natural-reward seeking.
(Kalivas, Peter. W, O’Brien, Charles, 2008)

Dopamine in the reward circuit (between PFC, VTA, NA and VP)


Fundamental in the aforementioned motivational circuitry is the neurotransmitter dopamine. All addictive drugs release dopamine via different mechanisms, which enables the individual to flag an environmental stimulus or event as important to survival. In this process, Dopamine aids to facilitate learning of the adaptive response to the important stimuli. It also ensures that this memory is stored in such a way that allows quick retrieval should the appropriate environmental cues be presented.
This capability is further enhanced by the drugs capacity to continually release large amounts of dopamine after each presentation, as opposed to the tolerance that is built to natural rewards. (Jay, 2003; Kelley, 2004; Nestler, 2005 in Kalivas, Peter. W, O’Brien, Charles, 2008) It can therefore be expected that this repeated release of dopamine will continually promote new learning and therefore consolidate the drug-seeking and drug-taking behaviours more rapidly and to a greater degree than physiological rewards. As a result, these behaviours are hard to expel and cause stronger motivation towards re-consolidation, exemplified by addictive drug relapse. It is via this continual reinforcement of drug-seeking behaviours that addictive drugs are able to form associations with life events and therefore encroach upon all aspects of a person’s life, resulting in drug-dependency.
In the brain, the region that controls the release of dopamine is the Ventral Tegmental Area (VTA). From this region, the Dopamine is released to the Prefrontal cortex (PFC), Amygdala and Nucleus Accumbens (NA). The basic role of this circuit (Fig. 1) is to control motivation; therefore an increase in dopamine leads to increased activation of this neural circuit and the subsequent actions associated with the neurotransmitter dopamine, such as enhanced learning capacity.

Activation of D1, CREB and deltaFosB


The increased release of Dopamine that is caused by the consumption of addictive drugs triggers changes in the excitatory and inhibitory mechanisms, particularly those associated with D1 (Dopamine 1) receptors situated in the striatum cortex (as seen in figure 1).
03_01.gif
Fig 1. Important structure of the brain related to motivational circuitry.



The mechanisms by which the D1 receptors act is thought to involve gene transcription. It has been further identified that changes to the signalling directed towards D1 receptors initiates changes to chromatin remodelling and cause activation/deactivation of particular genes. It is these changes associated with gene transcription that are believed to play an integral role in consolidating the transition from social to compulsive drug taking.
This subsequent alteration to the neurophysiology of D1 receptors is believed to be important for the establishment of adaptive behaviours associated with motivational learning. The transition to compulsive drug-taking is in essence a mutation to the motivational circuit (Fig 1), therefore changes to the neurophysiology of D1 receptors plays a vital role in the consolidation of maladaptive drug-seeking behaviours.

Another important factor in the development of maladaptive drug-seeking behaviours is CREB (cAMP response element binding protein). CREB is a transcription factor that binds to regions known as cAMP response elements (CRE) and therefore affects the transcription of the DNA downstream. This transcription factor is known to promote gene transcription related to drug-addiction and is necessary in the reinforcement of motivationally relevant learning. (Jin et al, 2005; Walters et al, 2005; Choi et al, 2006, In Kalivas, Peter. W, O’Brien, Charles, 2008)
A consequence of CREB expression is the activation of deltaFosB . DeltaFosB is another transcription factor that accumulates in the dopamine terminal fields and striatum as a result of exposure to motivationally relevant stimuli. (Nestler et al, 2001; McClung and Nestler, 2003, In Kalivas, Peter. W, O’Brien, Charles, 2008) .This demonstrates that deltaFosB is inextricably related to the development of motivational learning and the consolidation of drug-seeking behaviours.

Brain derived neurotrophic factors (BDNF)


Brain-derived neurotrophic factors are molecules that play a role in growth, development, maintenance and function of the nervous system (Russo, Nestadt A. 2008). The actions of these molecules are known to be dependent on dopamine levels in the brain and are responsible for initiating neuroplastic changes related to the survival of the organism.
Recent research that supports this information is suggestive that stimulating BDNF receptors in the Amygdala, Nucleus Accumbens or Ventral Tegmental Area (Fig 1) promote drug-seeking behaviours ,(Horger et al, 1999; Lu et al, 2004b; Graham et al, 2007; Pu et al, 2006, In Kalivas, Peter. W, O’Brien, Charles, 2008) whereas increasing the expression of BDNF in the Prefrontal cortex inhibits drug seeking (Berglind et al, 2007, In Kalivas, Peter. W, O’Brien, Charles, 2008). The prefrontal cortex is associated with voluntary control over actions whereas the Amygdala, Nucleus Accumbens or Ventral Tegmental Area is associated with the motivational circuit and is largely involuntarily controlled.
This research highlights that BDNF serves as a supporting factor of neuroplastic changes that occur in the progression from social to compulsive drug-taking.
The implication of this evidence is that the transition from social to compulsive drug-taking is a shift from declarative processes (PFC) to habitual processes involving the motivational circuitry. Due to the continual release of Dopamine, this change is progressive. However, as more dopamine is released via the mechanisms of addictive drugs the ability for the declarative processes to intrude on the habitual processes becomes more impaired. The result is a pattern of continual drug-seeking and drug-taking behaviours that are driven largely by involuntary mechanisms.

Critical Analysis:


The media article being discussed is taken from Science Daily a news site aimed at individuals with an interest in science. The article is written so that anybody with a general interest in neuroscience can understand the experiment being discussed.

Science Daily has been branded a scientific source with a wide range of information, covering all different fields of science. Articles published in Science Daily have been selected from universities and other research institutions, and some are written by Science Daily staff. Although Science Daily has not always held a reliable source title, most articles published prove unbiased and relay factual information retrieved straight from an institute of research. The 'story source' listed down the bottom of this particular article states that it was retrieved from INSERM (institut national de la sante et de la recherche medicale). It does however, state that materials may be edited for content and length, which, may prove unreliable. Underneath that, the 'journal reference' is listed and through comparing the journal and this article, little changes were found.

Because this article's primary focus is to inform and entertain the scientific content contained needs to be looked at in a very critical manner. Although the information in the article can be regarded as accurate, due to it being sourced by a journal article, it must also be recognized that there is no information in regards to the experiment that was conducted or any of the experimental results that were previously obtained. Furthermore the article does not provide information from other sources about neuroplasticity therefore cannot be considered objective.
Although this article does not contain any information about the experiment or any experimental results the information it sourced from a peer reviewed journal. As such the article does contain some valid information. The article also explains scientific concepts that not all people may know, including neuroplasticity, and does educate readers.

By scanning through various journals related to the relationship of drug and brain plasticity, it was evident that most institutes agree with the information found in the article. This is yet another indication of its validity. However it should be not the article does not source any of this information itself.

Overall, although Science Daily has not always been known to contain reliable and valid information, this article cites a reliable journal and seems to stick closely to the information presented.

References:


  1. Bogdan Draganski et al. (2004). Neuroplasticity: Changes in grey matter induced by training. Nature, 427, 311-312
    Collins, D, J., & Lapsley, H, M,. (2008) The Costs of Tobacco, Alcohol and Illicit Drug Abuse to Australian Society in 2004/05, Commonwealth of Australia.
  2. Institut national de la sante et de la reserche medicale (INSERM). (2010). Addiction: a loss of plasticity of the brain?. Science Daily.
  3. Kalivas, Peter. W, (2005). How do we determine which drug-induced neuroplastic changes are important? Nature Neuroscience, 8, 1440-1441.
  4. Kalivas, Peter. W, O'brien, C. (2008) Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology, 33, 166-180.
  5. Kasanetz, F., Deroche-Gamonet, V., Berson, N., Balado, E.,Lafourcade, M.,Manzoni, O., & Piazza, P, V., (2010) Transition to Addiction Is Associated with a Persistent Impairment in Synaptic Plasticity, Science, June
    vol 328, pp1709 - 1712
  6. Kauer, J, A., Malenka, R, C (2007) Synaptic plasticity and addiction. Nature Reviews/Neuroscience. November, volume 8, pp844-858.
  7. Robbins, T, W., & Everitt B. J,. (1999) Drug addiction bad habits add up, Nature, April vol 398 pp 567 – 570
  8. Russo-Neustadt A, (2003). Brain Derived Neurotrophic factor, behaviour, and new directions for the treatment of mental disorders. Semin Clin Neuropsychiatry, 8, 109-118.
  9. Thomas, M, J., Kalivas, P, W,. & Shaham, Y,. (2008) Neuroplasticity in the mesolimbic dopamine system and cocaine addiction, British Journal of Pharmacology, May; 154(2): 327–342.



Meetings:

5/8/2012
We organised a facebook page where we can upload information and ask each other questions which proved to be very helpful. All members are involved in this.

24/8/2012
Following our lab we met up to discuss the progress of the group and what research we had managed to achieve. All group members were present.

Appendix:


We chose an article on brain plasticity because it seems to be a fascinating frontier of neuroscience in which many novel discoveries are being made. Further drugs and addiction are topical to changing lifestyles of certain groups in our age bracket so this article provided a marriage of interesting themes. As this article examined a novel aspect of neurobiology we had to troll through many abstracts on databases such as Psyc Info and off the meta search section of Sirius from the UNSW library to discriminate between articles that were specific enough to be relevant yet also generalized enough to be helpful for context

The peer review was extremely helpful in assisting our group with what adjustments needed to be made to improve our report. We were provided with many strong points which assisted us with what parts were concise and what parts needed work. In summary the review suggested we proof read our work more carefully as there was a range of grammatical and punctuation errors throughout. It was also suggested that we refer to the marking criteria when addressing the different headings as parts of our report did not make sense or fulfill certain criteria, such as the introduction. In order to address these concerns our group will have to place significant importance on the flow, grammar and punctuation of our report. Furthermore, an appendix and table of contents could be provided to assist the reader with further knowledge and accessibility.



neuroscience group photo.jpg

Enjoy!

Summary:
Strong points:
Theory and topics of interest (LTD in particular) well written
Widely researched
Information paragraphs broken down into sections, making it easy to understand
A concise straight to the point analysis
Weak points:
Introduction doesn't fulfill criteria
No draft appendix?
Introduction paragraph at neuroscience context is a little confusing

General improvement:
Could add in analysis if you agree with the proposed research
Flow between information paragraphs or introduction sentence in neuroscientific context to explain what is to be discussed

Spec. Improvements:
Links to paragraphs at top of page
Grammar in some sentences
Punctuation in references
Refer to provided figures (eg. As seen in fig.1)