Synaptic mechanisms underlying persistent cocaine craving

Abstract

Although it is challenging for individuals with cocaine addiction to achieve abstinence, the greatest difficulty is avoiding relapse to drug taking, which is often triggered by cues associated with prior cocaine use. This vulnerability to relapse persists for long periods (months to years) after abstinence is achieved. Here, I discuss rodent studies of cue-induced cocaine craving during abstinence, with a focus on neuronal plasticity in the reward circuitry that maintains high levels of craving. Such work has the potential to identify new therapeutic targets and to further our understanding of experience-dependent plasticity in the adult brain under normal circumstances and in the context of addiction.

Figure 1. Reward pathways and their roles in incubation of cue-induced cocaine craving

Glutamate inputs to medium spiny neurons (MSNs) of the nucleus accumbens (NAc) influence the behavioural response to rewards and the cues that predict them. MSNs receive convergent inputs from multiple brain regions, and these inputs interact synaptically^, . Inputs from the medial prefrontal cortex (mPFC) provide executive control (important for behavioural flexibility, response inhibition and salience attribution), basolateral amygdala (BLA) inputs relay conditioned associations and affective drive, the hippocampus (Hipp) supplies spatial and contextual information, and the thalamic inputs presumably convey input about arousal and direct attention to behaviourally significant events. The central nucleus of the amygdala (CeA) does not project directly to the NAc, but CeA (and BLA) can influence NAc and other regions indirectly through connections with the midbrain (not shown) as well as other routes (see Box 4). Note that different anatomical substrates underlie incubation of cue-induced cocaine craving versus reinstatement of drug seeking after extinction or even cocaine seeking upon return to the drug self-administration context^, . Furthermore, differences exist between the neuronal pathways implicated in incubation of craving for cocaine versus other drugs of abuse^, . DLS, dorsolateral striatum; IL, infralimbic; PL, prelimbic; Sub Nigra, substantia nigra. Red lines, dopamine pathways. Blue lines, glutamate pathways. Grey boxes, adaptations associated with incubation.

Figure 2. Ca²⁺-permeable AMPARs in NAc core synapses are required for expression of incubated cocaine craving

a| In the nucleus accumbens (NAc) core of rats that undergo extended-access cocaine self-administration and prolonged withdrawal (>35 days), CP-AMPAR levels increase markedly and activation of these receptors is required for the expression of incubated cocaine seeking^, . We propose that this reflects the ability of high-conductance CP-AMPARs to augment MSN responsiveness to glutamate drive, enabling MSNs to respond more robustly when a cocaine cue is presented. Some CP-AMPARs are inserted into previously silent synapses^, b| Group I mGluR-mediated synaptic depression is altered in the NAc core of rats that show incubation of cocaine craving. In control rats, this synaptic depression depends upon mGluR5 stimulation, endocannabinoid formation, and activation of presynaptic CB1Rs. After prolonged withdrawal and incubation of craving, this mechanism is disabled and an mGluR1-mediated synaptic depression is observed that is expressed postsynaptically via CP-AMPAR removal^, . By eliciting this mGluR1-mediated synaptic depression, systemic or intra-NAc administration of mGluR1 positive allosteric modulators (PAMs) can reduce incubated cue-induced cocaine seeking. Similarly, mGluR1 activation removes CP-AMPARs from VTA synapses of cocaine-exposed animals^, . Although mGluR1-mediated synaptic depression is most obvious when CP-AMPAR levels are high, we speculate that it operates at a low level under normal conditions and that loss of mGluR1 tone during abstinence helps account for CP-AMPAR accumulation. Supporting this notion, decreased mGluR1 surface expression in the NAc core precedes and enables CP-AMPAR accumulation and incubation of craving.