Integrating synaptic plasticity and striatal circuit function in addiction
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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