[Drugs of abuse share the ability to enhance dopaminergic neurotransmission in the dorsal and ventral striatum.3] [They target the brain's reward system by flooding the circuit with dopamine. 0][ This diagram represents a sagittal section of the rat brain. Highlighted are the nuclei representing the limbic structures of the basal forebrain including the amygdala, hippocampus, prefrontal cortex (PFC), nucleus accumbens (N. Acc.), ventral pallidum (VP) and ventral tegmental area (VTA). Dopaminergic neurons in the VTA modulate information flow through the limbic circuit via projections to the nucleus accumbens, amygdala, hippocampus, PFC and VP. Increased dopaminergic transmission in limbic nuclei, particularly the nucleus accumbens, underlies the reinforcing effect of virtually every abused drug. Note that psychostimulants increase dopaminergic transmission in areas receiving projections from the VTA via interactions with dopamine transporters.0.1]
[As a person continues to overstimulate the "reward circuit", the brain adapts to the overwhelming surges in dopamine by producing less of the hormones or by reducing the number of receptors in the reward circuit. As a result, the chemical's impact on the reward circuit is lessened, reducing the abuser's ability to enjoy the things that previously brought pleasure. This decrease compels those addicted to dopamine to increase the drug consumption in order to attempt to bring their "feel-good" hormone level back to normal -an effect known as tolerance.0]
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However this tolerance effect, while characteristic of many addictive states, does not account for psychological changes defining [addiction, such as craving, withdrawal and, perhaps most importantly, relapse. 7][Indeed, an influential hypothesis is that addiction represents a pathological, yet powerful, form of learning and memory5-10 7]
WHAT IS LTP/LTD LEARNING
[Work to date suggests an essential role for synaptic plasticity in the VTA in the early behavioural responses following initial drug exposures, as well as in triggering long-term adaptations in regions innervated by dopamine (DA) neurons of the VTA9 7]
Dopamine, DARPP and plasticity
[One well-studied target for the actions of dopamine is DARPP32. In the densely dopamine- and glutamate-innervated rat caudate-putamen, DARPP32 is expressed in medium-sized spiny neurons that also express dopamine D1 receptors. The function of DARPP32 seems to be regulated by receptor stimulation. Both dopaminergic and glutamatergic (NMDA) receptor stimulation regulate the extent of DARPP32 phosphorylation, but in opposite directions. Dopamine D1 receptor stimulation enhances cAMP formation, resulting in the phosphorylation of DARPP32; phosphorylated DARPP32 is a potent protein phosphatase-1 (PPP1CA) inhibitor. NMDA receptor stimulation elevates intracellular calcium, which leads to activation of calcineurin and dephosphorylation of phospho-DARPP32, thereby reducing the phosphatase-1 inhibitory activity of DARPP32. 0]
Add in short (5 words or so) reminder that drugs affect dopamine receptors and can affect other receptors (e.g. 5ht)
[The action of dopamine is modulated by additional neurotransmitters, including glutamate, serotonin and adenosine. All these neurotransmitters regulate the phosphorylation state of Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32). Phosphorylation at Thr(34) by protein kinase A converts DARPP-32 into a potent inhibitor of the multifunctional serine/threonine protein phosphatase, PP-1. Phosphorylation at Thr(75) by Cdk5 converts DARPP-32 into an inhibitor of protein kinase A. The state of phosphorylation of DARPP-32 at Thr(34) also depends on the phosphorylation state of Ser(97) and Ser(130), which are phosphorylated by CK2 and CK1, respectively. By virtue of regulation of these 4 phosphorylation sites, and through its ability to modulate the activity of PP-1 and protein kinase A, DARPP-32 plays a key role in integrating a variety of biochemical, electrophysiological, and behavioral responses controlled by dopamine and other neurotransmitters. Importantly, there is now a large body of evidence that supports a key role for DARPP-32-dependent signaling in mediating the actions of multiple drugs of abuse including cocaine, amphetamine, nicotine, caffeine, LSD, PCP, ethanol and morphine.3]
[Valjent et al. (4) provide an important link, implicating dopamine, cAMP-regulated phosphoprotein of 32,000 kDa (DARPP-32) glutamate as mediators of drug-related changes in the activity of the extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase pathway. Activation of the ERK cascade represents an exciting nexus for drug-induced changes in neural plasticity-it is known to be important for long-term synaptic plasticity, and its activation has been shown to depend on both dopamine and glutamate receptors. 9]
[Substrates for PP-1 that are likely to be involved in regulation of synaptic plasticity include Ca21/calmodulin-dependent protein kinase II (Silva et al., 1992; Lledo et al., 1995; Mayford et al., 1996; Rotenberg et al., 1996), the GluR1 subunit of the AMPA receptor (Barria et al., 1997), and the cAMP response element binding protein (CREB) (Bourtchuladze et al., 1994; Bito et al., 1996). Thus, PP-1 may influence the induction and maintenance of LTP and LTDvia several differentmechanisms. Studies using DARPP-32 knockout mice indicate that plasticity at cor- ticostriatal synapses is under the control of DARPP- 32 (P. Calabresi, personal communication).8]
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Given the current evidence for a role of the DARPP-32/X signalling pathway as a dopamine mediated modulator of synaptic plasticity in the (and subsequently implicated in memory and associated changes that occur during addiction), it seems to present an obvious target for possible therapeutic intervention of addiction.
DARPP32 as target?
[In this study, we investigated the effect of the opiate (heroin) on D1 receptor (D1R) and DARPP-32 expression and additionally, evaluated the effects of DARPP-32-siRNA gene silencing on protein phosphatase-1 (PP-1), ERK, and cAMP response element-binding (CREB) gene expression in primary normal human astrocytes (NHA) cells in vitro. Our results indicate that heroin significantly upregulated both D1R and DARPP-32 gene expression, and that DARPP-32 silencing in the NHA cells resulted in the significant modulation of the activity of downstream effector molecules such as PP-1, ERK, and CREB which are known to play an important role in opiate abuse-induced changes in long-term neural plasticity. These findings have the potential to facilitate the development of DARPP32 siRNA-based therapeutics against drug addiction.6]
Interestingly, Bonoiu et al have also been studying the effects of DARPP-32-siRNA gene silencing but using gold nanorods as a delivery mechanism. XXXX?
CDK5 as target?
[Repeated infusions of the Cdk5 inhibitor roscovitine into the NAc before cocaine injections augmented both the development and expression of cocaine sensitization without having any intrinsic stimulant actions of its own. Additionally, repeated intra-NAc infusions of roscovitine to saline-injected rats enhanced locomotor responses to a subsequent cocaine challenge. Similar effects were found after infusions of another Cdk5 inhibitor, olomoucine, but not its inactive congener, iso-olomoucine. Repeated inhibition of Cdk5 within the NAc also robustly enhanced the incentive-motivational effects of cocaine, similar to the effect of prior repeated cocaine exposure. The enhanced responding with conditioned reinforcement induced by cocaine persisted at least 2 weeks after the final roscovitine infusion. NAc infusions of olomoucine also produced acute and enduring increases in "breakpoints" achieved on a progressive ratio schedule for cocaine reinforcement. These results demonstrate profound and persistent effects of NAc Cdk5 inhibition on locomotor sensitization and incentive-motivational processes and provide direct evidence for a role for striatal Cdk5-induced alterations in the brain's long-term adaptations to cocaine.11]
[When mice previously conditioned for cocaine-place preference were reexposed to cocaine in the drug-paired compartment after systemic administration of SL327, an inhibitor of ERK activation, CPP response was abolished 24 h later. This procedure also abolished the phosphorylation of ERK and glutamate receptor-1 observed in the ventral and dorsal striatum, 24 h later, during CPP test. Erasure of CPP by SL327 required the combination of cocaine administration and drug-paired context and did not result from enhanced extinction. Similarly, reexposure to morphine in the presence of SL327 long-lastingly abolished response of previously learned morphine-CPP. The effects of SL327 on cocaine- or morphine-CPP were reproduced by protein synthesis inhibition. In contrast, protein synthesis inhibition did not alter previously acquired locomotor sensitization to cocaine. Our findings show that an established CPP can be disrupted when reactivation associates both the conditioned context and drug administration. This process involves ERK, and systemic treatment preventing ERK activation during reexposure erases the previously learned behavioral response. These results suggest potential therapeutic strategies to explore in the context of addiction.13]
Discuss/Reflect on Link to CP