Karen Brebner, Anthony G. Phillips, Yu Tian Wang, and Tak Pan Wong*
Synaptic plasticity at excitatory synapses has been proposed as the cellular substrate of information processing and memory formation in the brain under both physiological and pathological conditions, including addiction. There is a growing body of evidence that implicates long-term depression (LTD), particularly in the nucleus accumbens (NAc), as a potential mediator of drug-induced neural plasticity. In animals, behavioral sensitization is used to model enduring changes in neuronal activity and behavior that result from repeated exposure to drugs of abuse. Given the links between behavioral sensitization and enduring drug-induced neuroplasticity, it is possible that compounds that can disrupt LTD may form the basis for a rational drug development strategy for repairing abnormal synaptic functions that are related to exposure to addictive substances. The data reviewed here provide evidence that facilitated AMPAR endocytosis and LTD in the NAc is critically involved in behavioral sensitization associated with drug addiction, indicating that both the expression and possibly the induction phases of LTD may represent promising targets for developing novel therapeutics for the clinical management of drug addicts.
Signaling and communication between cells is a pervasive and core issue in the biological sciences. Neurons in the mammalian brain accomplish these functions through a process known as synaptic transmission. The strength of
'Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 2A1; [email protected]
synaptic transmission at individual synapses and the number of synapses are not static, but rather are subject to dynamic regulation, and these changes in turn are believed to be intimately associated with development of neuronal circuitry, and behavioral adaptation manifested as learning and memory1-3. Many of these adaptive "plastic" changes in synaptic function occur in the region of the postsynaptic density4. This is a complex region involving specific neurotransmitter-gated ionic and G-protein-coupled receptors and second messenger cascades involving specific kinase and phosphatase activity, all of which are potential targets for the development of new drugs. Despite this complexity, remarkable progress has been achieved in recent years in identifying molecules essential for prolonged changes in the efficacy of synaptic transmissions (functional alterations), and consequent rewiring of synaptic connections (structural alterations).
A growing body of evidence implicates abnormal synaptic function in a broad spectrum of neurological and neuropsychiatric disorders, including Alzheimer's disease, autism, mental retardation, schizophrenia, and addiction.5-8 Traditional pharmacotherapies for these disorders have been based primarily on enhancing or reducing extracellular levels of specific neurotransmitters or blocking specific receptors with small molecules. While this approach has alleviated some symptoms of various forms of mental illness, the effects are often nonspecific, and limited by side effects due to interference with the normal function in unaffected regions of the brain and body9. Thus, novel approaches with greater specificity in targeting only affected synaptic processes are urgently needed.
Alterations in synaptic connections in certain brain regions may result, at least in part, from prolonged functional and structural alterations arising from abnormal interplay in certain protein-protein interactions within the synapses. This raises the possibility that the therapeutic use of "interference peptides" that can be delivered systemically to block specific protein-protein interactions involved in synaptic dysfunctions may represent a novel pharmacotherapeutic strategy in the clinical management of psychiatric illnesses where synaptic alterations are at the root of the pathogenesis. The successful development of effective interference peptides with therapeutic efficacy could spark the development of similar treatments for many neurological and neuropsychiatric illnesses.
Drug addiction is a complex neuropsychiatric disorder in which repeated self-administration of specific drugs, including amphetamines, cocaine, nicotine, heroin, and alcohol, induces long-lasting changes in neural function and behavior10. Addictive behavior is characterized by compulsion centered on the procurement and use of a drug of choice (i.e., craving). Drug addiction is also defined as a chronic relapsing disorder, as individuals who have successfully abstained from drug use for extended periods are still susceptible to renewed episodes of drug seeking and abuse, following a single exposure to environmental stimuli associated with prior drug use, or a small quantity of the drug itself11,12. Studies that have been conducted to investigate the neural adaptation underlying the development and recurrence of addictive behaviors suggest that addiction may involve mechanisms of neural plasticity implicated in learning and memory, and in particular with associative mechanisms which serve to link environmental stimuli with drug reward12-14.
3. LTD AND BEHAVIORAL SENSITIZATION: A MODEL FOR THE ROLE OF SYNAPTIC PLASTICITY IN ADDICTION
Craving is a key feature of relapse to drug-seeking behavior and is modeled in preclinical studies as increased motor activity (i.e., behavioral sensitization) induced by repeated intermittent administration of many drugs of abuse, including amphetamine, cocaine, heroin, and nicotine. Behavioral sensitization in turn is linked to neural adaptations in the mesocorticolimbic regions of the brain, including a terminal region in the NAc that receives dopaminergic projections from the ventral tegmental area (VTA) and excitatory glutamatergic inputs from the prefrontal cortex. Brain-imaging studies with human drug addicts report that craving induced by drug-associated stimuli is accompanied by activation of the prefrontal cortex, anterior cingulate, amygdala, and ventral striatum15,16. These brain regions are innervated by the mesocorticolimbic dopamine (DA) system, which subserves the primary reinforcing effects of many drugs of abuse, including psychostimulants and opiates15-17. Recent findings also implicate DA in synaptic plasticity and memory18-20. Given the importance of DA systems in drug addiction, there have been intensive efforts seeking DA-based therapeutics for the clinical management of patients suffering from drug addictions. However, this approach has met with only limited success, characterized by short periods of efficacy with unacceptable side effects due to interference with the normal function of DA and its receptor systems in unaffected brain regions9.
Neural adaptations in the VTA play an essential role in the induction of behavioral sensitization, whereas synaptic modifications in the NAc are involved in its long-term maintenance (expression). Initial work on behavioral sensitization focused on pre- and postsynaptic changes in DA systems. However, evidence accumulated recently supports a critical role of synaptic plastic changes in glutamatergic transmission at both the VTA and NAc levels13. Consistent with differential roles of the VTA and NAc in mediating sensitization, repeated stimulation of glutamatergic cortical inputs to the VTA triggers sensitization, while the maintenance (expression) of this behavioral adaptation is blocked by inhibition of glutamatergic synapses in the NAc21-23.
The evidence supporting the importance of the VTA and the NAc in experience-dependent neural plasticity has been accumulating for several years. It was only recently, however, that changes in excitatory synaptic transmission after repeated drug exposure were examined directly. Thomas and colleagues24 examined excitatory synaptic responses in NAc brain slices from animals that had been sensitized to cocaine. They reported a long-lasting enhancement of LTD of glutamatergic transmission in the shell region of the NAc in sensitized mice. This demonstration of LTD in the NAc following repeated cocaine applications provided the first correlation between acquired LTD and the development of behavioral changes associated with drug addiction, and supports the hypothesis that the neural adaptations that lead to addiction involve the same glutamate-dependent cellular mechanisms that underlie learning and memory.
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