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My community placement was at a homeless shelter in Stockton called Bridge House Hostel. Bridge House accepts men from wide range of backgrounds, but one common feature that I saw again and again in these men's lives was the prevalence of drug and alcohol dependency. I witnessed first-hand promising attempts by residents to succeed at rehabilitation, only for efforts to be sabotaged by relapse, sending them back to square one. As a result, not many men were able to break out of the homelessness cycle.
Cycles of relapse and remission are common in all drug addictions and can occur months or years after physical dependency on the drug has been lost. Cravings are often context dependent, being triggered by cues such as places, smells and objects that are associated with old drug taking practices meaning constant vigilance and determination are needed for the long and laborious journey of rehabilitation.
Pharmacological treatment of addiction has thus far focused mainly on replacement therapies for the physical dependency and there is currently no treatment that can effectively 'cure' a patient from addiction. In this review I am going to discuss current knowledge about the molecular basis for the psychological aspects of addiction and some possible pharmacological targets for future intervention.
Virtually every drug of abuse enhances dopaminergic neurotransmission in the reward system of the brain. The reward system consists of a set of structures interconnected by the dopamine and glutamate modulated mesolimbic and mesocortical pathways (Fig. x). The mesolimbic pathway plays the major role in the system. Dopaminergic neurons in the ventral tegmental area (VTA) modulate information flow through the limbic circuit via reciprocal projections to the nucleus accumbens (Nac), amygdala, hippocampus and pre frontal cortex. Increased dopaminergic transmission in limbic nuclei, particularly the nucleus accumbens is thought to underlie the reinforcing effect of drugs of abuse that results in addiction.
The physiological state of cells in the Nac is controlled by signal transduction mechanisms which regulate the balance between protein kinase and protein phosphatase activities. It has been suggested that disruptions in the dynamic balance of dopamine-receptor-mediated signals which mediate these activities, which can occur from recreational drugs, could account for long lasting changes in synaptic plasticity in areas associated with the VTA and Nac. Synaptic plasticity, the ability of a synapse to change in strength, is the foundation of modern theory of learning and memory. As the Nac and VTA are directly connected to many structures throughout the brain including those normally associated with memory (such as the hippocampus and amygdala) this has given rise to the hypothesis that addiction could be the result of a pathological form of learning and memory. In order to develop potential drug therapies for the treatment of addiction the molecular mechanisms underlying this process have been the target of numerous studies over the past few years.
[Studies have shown however that rats that have had their ventral tegmental area and nucleus accumbens removed don't lose their ability to learn, but rather lose the motivation to work for a reward suggesting further that motivation is a learned activity dependent on the reward system. ]
In 2004, XXXX et al identified extracellular signal-regulated kinase (ERK) as a possible starting candidate for mediation of drug induced changes in synaptic plasticity. ERK is an enzyme that acts as an intracellular signalling molecule in cells throughout the body. Activation of the ERK signalling cascade can regulate gene expression through a protein pathway between cell surface receptors and the cell nucleus.
They focused on ERK for two reasons. Firstly, it has long been known to be important for long-term synaptic plasticity, and secondly, it depends on both glutamate and dopamine receptors for functionality- a key property of neuronal cells in the Nac. In their paper, the team demonstrate in mice models that d-amphetamine selectively activates ERK in a subset of medium-size spiny neurons of the striatum through the combined action of glutamate NMDA and D1-dopamine receptors. Significantly, they also showed that ERK activation was not achieved in mice lacking dopamine- and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32), a protein that has since been found to play a crucial role in regulating plasticity in striatal neurons.
DARPP32 (also known as 'protein phosphatase 1 regulatory subunit 1B' - PPP1R1B) is a protein found in medium spiny neurons that express dopamine (D1 and/or D2) receptors, the highest concentrations of which are found in the striatum (95%), the anatomical area that contains the Nac and VTA. It is thought to be important in integrating a variety of biochemical, electrophysiological, and behavioural responses which are controlled by dopamine and other neurotransmitters. The actions of DARPP32 depend on the state of phosphorylation of amino acids at 4 sites: Ser(97), Ser(130), Thr(34) and Thr(75). Phosphorylation (and dephosphorylation) of the 4 sites is achieved by a combination of intracellular regulators which include protein kinase A (PKA), cyclin-dependent kinase 5 (CDK5), CK1 and CK2. Levels of these regulators are in turn controlled by receptor stimulation in response to the neurotransmitters dopamine, glutamate, serotonin and adenosine, which are differentially released by recreational drugs (Tab. X).
For example, activation of D1 receptors results in cAMP formation which in turn causes PKA mediated phosphorylation of DARRP32 at Thr(34) and a subsequent decrease in phosphorylation at Thr(75). This creates a potent protein phosphatase-1 (PP-1) inhibitor. Activation of D2 receptors on the other hand stops Thr(34) phosphorylation by inhibiting adenylyl cyclase which blocks the cAMP-dependent pathway from activating PKA- which in itself is another significant role for DARPP32. The phosphorylation states of Ser(97) and Ser(130) also have an effect in the phosphorylation of Thr(34) and are determined by CK1 and CK2. Control of all 4 phosphorylation states, and therefore the role of DARPP32, is a balancing act dependent on the integration of numerous signals conveyed from cell surface receptors which ultimately depend on the neurotransmitter released by afferent neurons.
The high concentrations of DARPP32 (and therefore PP-1/PKA regulation) in the striatum are significant when thinking about long term addiction as PP-1 and PKA have been shown to be important regulators of synaptic plasticity. These proteins interact with several molecules that have been found to have key roles in plasticity- Ca21/calmodulin-dependent protein kinase II, the GluR1 unit of the AMPA receptor and the cAMP response element binding protein (CREB). Thus, DARPP32 may influence the induction and maintenance of LTP and LTD via several different mechanisms. Indeed, studies using DARPP32 knockout mice indicate that plasticity at corticostriatal synapses is under the control of DARPP32.
Given the current evidence for a role of the DARPP-32 in mediating synaptic plasticity, it presents an attractive target for possible therapeutic intervention but where to begin poses a particular problem. For a protein that has such a myriad of roles it is difficult to guess the effect of directly inhibiting its action. In their paper, xxxx , XXXX et al investigated just this. They used DARPP32 siRNA gene silencing to prevent the expression of DARPP32 in primary normal human astrocytes (NHA) cells in vitro. They then observed the effect that this had on the expression of PP-1, ERK, and CREB gene expression in the cells. They found that DARPP-32 silencing in the NHA cells resulted in significant modulation of the activity of these downstream effector molecules. However, taking place in vitro, this is more of a proof of concept than a serious therapeutic bit it does show that DARPP32 can be targeted and the effects are as predicted. What effect altered levels of the downstream molecules would then have on behaviour remains to be seen.
XXX et al targeted another aspect of the DARPP32 mediated pathway. Following cessation of repeated cocaine use, one of the most stable and persistent proteins expressed in striatal regions is ΔFosB. CDK5 serves as a downstream target gene of ΔFosB indicating that CDK5 may specifically play an important role in cocaine addiction. As a mediator of DARPP32 phosphorylation at Thr(34), CDK5 enhances DARPP32 inhibition of PKA, thus reducing dopamine stimulated signal transduction by PKA. XXXX et al infused CDK5 inhibitor roscovitine into the Nac of rats before giving injections of cocaine. They found that the inhibitor augmented the expression and stimulant effects of the cocaine when compared with control animals. The incentive-motivation of the animals was measured using a Pavlovian discriminative approach in which the animals received self-administered doses of cocaine. Repeating the experiment with another CDK5 inhibitor, olomoucine, yielded the same results. The enhancing effects of the CDK5 inhibitors on incentive motivation persisted for at least 2 weeks following the final roscovitine infusion further strengthening the link between CDK5 mediation of long term adaptations to cocaine.
XXXXX et al showed ERK that it could be an important target in chronic conditions. They showed that when mice previously conditioned for cocaine-place preference were re-exposed to cocaine in the drug-paired compartment after systemic administration of SL327 (an inhibitor of ERK activation) the conditioned place preference (CPP) response was abolished 24 h later. Interestingly, the authors found that this effect could only be achieved if SL327 was given in combination with cocaine in animals that had been previously conditioned to self-administer cocaine in the drug-paired compartment. The same effect was observed in in animals that had been conditioned with morphine, suggesting that it was not a drug specific effect. Systemic treatment of an inhibitor that prevents ERK activation during re-exposure erases the previously learned behavioural response.
Current research into the mechanisms of drug addiction is moving forward rapidly. Over the last few years, great advances have been made in eliciting the underlying molecular pathways and mediators of addictive behaviour and a steady picture is being formed. The papers in this review have demonstrated several of many potential targets for future drug therapy of addiction including the ERK pathway, CDK5 and DARPP32, however it remains to be seen which target the day when addiction can be cured with a single pill is long off and much work must be done.