Integrating synaptic plasticity and striatal circuit function in addiction

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Exposure to addictive drugs causes changes in synaptic function within the striatal complex, which can either mimic or interfere with the induction of synaptic plasticity. These synaptic adaptations include changes in the nucleus accumbens (NAc), a ventral striatal subregion important for drug reward and reinforcement, as well as the dorsal striatum, which may promote habitual drug use. As the behavioral effects of drugs of abuse are long-lasting, identifying persistent changes in striatal circuits induced by in vivo drug experience is of considerable importance. Within the striatum, drugs of abuse have been shown to induce modifications in dendritic morphology, ionotropic glutamate receptors (iGluR) and the induction of synaptic plasticity. Understanding the detailed molecular mechanisms underlying these changes in striatal circuit function will provide insight into how drugs of abuse usurp normal learning mechanisms to produce pathological behavior.

Highlights

► Modifications in MSN excitatory synapses occur in response to drugs of abuse. ► MSN modifications depend on amount of drug experience and time since last exposure. ► MSN subtypes have distinct properties and may adapt differently to drug experience. ► The two different MSNs subtypes exert opposing influences on behavioral responses. ► Circuit specific manipulations will be vital for elucidating mechanisms of addiction.

Introduction

The development, progression, and persistence of drug addiction are thought to involve dynamic alterations in synaptic transmission within the striatum and related basal ganglia circuits. Synapses in these regions exhibit various forms of long-term synaptic plasticity, which appear to be aberrantly engaged by exposure to addictive drugs [1, 2]. These forms of plasticity include strengthening of synaptic connectivity, or long-term potentiation (LTP), as well as its weakening, or long-term depression (LTD). These synaptic changes often manifest themselves as changes in the number and function of iGluRs, including AMPA receptors (AMPARs) and NMDA receptors (NMDARs). Thus, it is of great interest to elucidate the mechanisms of synaptic plasticity in the striatal circuitry that underlie important aspects of addiction related behaviors.

While our understanding of drug-evoked synaptic plasticity has expanded greatly over the past decade, the intrinsic complexity of the striatal circuitry has hampered our ability to place these synaptic adaptations in the context of the neural circuits that mediate behavioral responses relevant to addiction. Recent work has begun to focus on defining the specific neuronal populations that are modified by drug experience, as well as delineating the temporal dynamics and mechanisms of the circuit adaptations that occur during repeated drug exposure, withdrawal or extinction, and events associated with relapse.

Section snippets

Striatal circuitry

The striatal circuitry functions to integrate a complex mix of excitatory, inhibitory and modulatory inputs to optimize adaptive motivated behaviors. At a macroscopic level, subregions of the striatum can be differentiated on the basis of their anatomical connections and behavioral functions. Ventral portions of the striatum, which include the nucleus accumbens (NAc) core and shell, are commonly differentiated from dorsal striatal regions, which include both dorsomedial and dorsolateral

Synaptic properties of MSNs

Recent studies have compared the synaptic properties of direct and indirect pathway MSNs by using fluorescent protein expression in BAC transgenic mice [7, 8] to guide targeted whole-cell recordings from acute brain slices. These studies have revealed that MSN populations exhibit different basal electrophysiological membrane and synaptic properties in both NAc core [9] and dorsal striatum [4, 5, 10, 11•]. On average, indirect pathway MSNs have a higher synaptic release probability and greater

Single cocaine exposure

A single cocaine exposure alters the induction of LTD by mGluR5 in indirect pathway MSNs of the NAc core [9]. Possible mechanisms for this cocaine induced ablation of mGluR5 LTD will be discussed below. By contrast, a single exposure to cocaine does not detectably alter the function or number of iGluRs in the NAc [12, 13, 14, 15•, 16, 17]. However, acute drug administration often occurs in a novel environment, and environmental novelty can directly affect NAc synapses [16], so care must be

Behavioral ramifications of NAc synaptic plasticity

A major challenge in this field is to provide experimental evidence that strongly supports causal links between plastic changes at NAc synapses and behavioral responses to abused drugs. For instance, a decade ago, the decrease in NAc synaptic strength following cocaine re-exposure was shown to occlude induction of NMDAR-dependent LTD at these synapses [17], suggesting these two phenomena share a common mechanistic basis. Based on these findings, subsequent experiments demonstrated that loading

Dorsal striatum: a home for bad habits?

The various subregions of the striatum are organized in an ascending spiral, with ventral areas projecting to midbrain dopamine neurons that subsequently project to more dorsal striatal regions [3]. Based on this anatomical organization, it has been proposed that initial adaptations in ventral striatal regions come to control more dorsal striatal regions over the course of chronic drug exposure, transforming drug-seeking into a compulsive habit [59]. Recent evidence to support this theory has

Conclusion and future directions

By outlining recent developments in the area of striatal synaptic plasticity and addiction, we have highlighted several emerging trends. A number of studies using a variety of approaches have provided convergent evidence regarding the time course of synaptic adaptations in the NAc, following both acute and repeated cocaine exposure, withdrawal/extinction, and re-exposure/reinstatement (Figure 1). However, we are just beginning to understand synaptic adaptations in dorsal striatal subregions,

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

Work on our laboratory is supported by the National Institutes of Health.

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