1. Proposed mechanism for nicotinic modulation of striatal synaptic plasticity following amphetamine self-administration.
Proposed mechanism for nicotinic modulation of striatal synaptic plasticity following amphetamine self-administration. A, The simplified striatal circuit is composed of MSNs, ChIs, and glia. Glutamate released from cortical and thalamic afferents excites MSNs through ionotropic glutamate receptors (iGluRs). In the drug naive condition, ACh efflux from ChIs binds to excitatory α4β2*- and α7*-type nicotinic receptors and modulates ChI firing and glutamate release from corticostriatal terminals (Bamford et al., 2008; Wang et al., 2013a). The glial glutamate transporter (GLT1) limits the access of synaptic glutamate to the extracellular space (Kalivas, 2009). B, Synaptic depression develops during abstinence from repeated amphetamine. Repeated DA release by amphetamine stimulates inhibitory D2-class receptors on ChIs (Yan et al., 1997; Wang et al., 2013a). The reduction in tonic excitation at α4β2*- and α7*-type nicotinic receptors depresses corticostriatal activity. Low tonic levels of ACh are supported during drug withdrawal by nicotinic autoreceptors that lower the set point of ChI firing (Wang et al., 2013a). C, A drug cue promotes transient synaptic potentiation. Because of the lowered set point of ChI activity, DA released by a drug cue stimulates ACh efflux via excitatory D1-class receptors on ChIs (Yan and Surmeier, 1997; Wang et al., 2013a). The increase in ACh boosts glutamate release, causing PPP. D, Nicotine prevents PPP. The concentration of nicotine achieved in smokers (100 nm) desensitizes excitatory α4β2*-type nicotinic receptors (Dani and Harris, 2005). The lack of nicotinic receptor excitation reduces ChI spiking and corticostriatal activity in the drug naive condition and during abstinence. The drug cue enhances ACh tone but desensitization prevents PPP in response to drug reinstatement. Activation of α7*-type nicotinic receptors expressed on astrocytes (Pirttimaki et al., 2013) recruit AMPA receptors to glutamatergic terminals (Wang et al., 2013b), have a protective effect on oxidative stress (Liu et al., 2015), and increase activity of GLT1 to clear glutamate from the extracellular space (Kalivas, 2009).
Granville P. Storey et al. eneuro 2016;3:ENEURO
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