Acetylcholine Encodes Long-Lasting Presynaptic Plasticity at Glutamatergic Synapses in the Dorsal Striatum after Repeated Amphetamine Exposure

Abstract

Locomotion and cue-dependent behaviors are modified through corticostriatal signaling whereby short-term increases in dopamine availability can provoke persistent changes in glutamate release that contribute to neuropsychiatric disorders, including Parkinson's disease and drug dependence. We found that withdrawal of mice from repeated amphetamine treatment caused a chronic presynaptic depression (CPD) in glutamate release that was most pronounced in corticostriatal terminals with a low probability of release and lasted Ͼ50 d in treated mice. An amphetamine challenge reversed CPD via a dopamine D1-receptor-dependent paradoxical presynaptic potentiation (PPP) that increased corticostriatal activity in direct pathway medium spiny neurons. This PPP was correlated with locomotor responses after a drug challenge, suggesting that it may underlie the sensitization process. Experiments in brain slices and in vivo indicated that dopamine regulation of acetylcholine release from tonically active interneurons contributes to CPD, PPP, locomotor sensitization, and cognitive ability. Therefore, a chronic decrease in corticostriatal activity during withdrawal is regulated around a new physiological range by tonically active interneurons and returns to normal upon reexposure to amphetamine, suggesting that this paradoxical return of striatal activity to a more stable, normalized state may represent an additional source of drug motivation during abstinence. IntroductionThe neocortex refines volitional movements and goal-directed behaviors through the corticostriatal-basal ganglia-thalamocortical feedback loop (Albin et al., 1989;Jog et al., 1999). The input of this neural network consists of glutamatergic cortical afferents that excite D1-class (D1R) and D2-class dopamine receptor (D2R)-expressing striatal medium-sized spiny neurons (MSNs), which form distinct direct and indirect pathways that promote and suppress competing motor movements, respectively (Pennartz et al., 1994; Nicola et al., 2000). Modulation of these excitatory corticostriatal synapses is determined by the availability of dopamine and acetylcholine, which are necessary for the establishment of reward, attention, and motor learning (Kalivas and Volkow, 2005;Cepeda et al., 2010). Emerging evidence suggests that abnormalities in the availability of these neuromodulators may promote an imbalance between direct and indirect striatal pathways (Beutler et al., 2011;Kozorovitskiy et al., 2012; to produce the motor and neuropsychological symptoms of Parkinsonism and drug dependence Bamford and Cepeda, 2009).Addiction is considered a chronic, allostatic condition (Ahmed and Koob, 2005) characterized by drug seeking behaviors and relapse after withdrawal (Kalivas and Volkow, 2005). Psychostimulants have a high potential for abuse because they acutely increase brain dopamine levels (Sulzer, 2011) and their repeated use can trigger long-lasting changes in striatal glutamate (Pierce et al., 1996; Cornish et al., 1999; and acetylcholine (Abercrombie and DeBoer, 1997;Bamford...

Contributions of signaling by dopamine neurons in dorsal striatum to cognitive behaviors corresponding to those observed in Parkinson's disease

“…Traditionally, executive function has been seen primarily as a domain of the prefrontal cortex (Birrell and Brown, 2000; Brown and Bowman, 2002; Buckner, 2004; Simpson et al, 2010; Stefani et al, 2003), but several reports have also implicated striatal circuits in mediating cognitive flexibility in animal models (Floresco et al, 2006a; Ragozzino et al, 2009; Ragozzino et al, 2002; Wang et al, 2013). Our finding of mildly impaired cognitive flexibility after striatal DA depletion agrees with these previous studies and, more importantly, by demonstrating isolated contributions of nigro-striatal DA our data illustrate how one neural circuit that is affected in early-stage PD can cause impaired cognitive flexibility observed in patients (Leverenz et al, 2009; Lima et al, 2008).…”

Dopamine-dependent corticostriatal synaptic filtering regulates sensorimotor behavior

“…This “synaptic microcircuit” modulates corticostriatal activity of striatonigral direct pathway MSNs that express D1 receptors (D1-Rs) and initiate specific motor signals by pausing tonic activity of substantia nigra reticulata output neurons (“go” signals) and striatopallidal indirect pathway MSNs that express D2-Rs and are thought to suppress competing motor networks (“no-go” signals) (Cui et al, 2013; Kravitz et al, 2010). DA depresses the corticostriatal excitation to D2-R expressing indirect pathway neurons, and has little or no direct effect on corticostriatal inputs to D1-R direct pathway neurons (Wang et al, 2013), but rather can exert a postsynaptic response (Yagishita et al, 2014) that appears to be due in part to activation of a circuit involving cholinergic receptors (Wang et al, 2013). D2-Rs on corticostriatal presynaptic terminals (Wang and Pickel, 2002) may also inhibit synaptic vesicle fusion (Bamford et al, 2008; Bamford et al, 2004b), although ascribing actions clearly to D2-R at particular sites within the striatum has been challenging.…”

Specific contributions of N-methyl-d-aspartate receptors in the dorsal striatum to cognitive flexibility

“…The relatively moderate loss of NR1 expression in the dorsal striatum did, however, impair cognitive flexibility in our strategy-shifting paradigm. Similar to animals with either reduced cholinergic or dopaminergic signaling in the dorsal striatum or with pharmacologically inactivated MSNs in the dorsal striatum (Ragozzino et al, 2002, Darvas and Palmiter, 2011, Wang et al, 2013, Darvas et al, 2014), partial loss of NR1 expression caused a strategy-shifting impairment that was overcome with additional training sessions. Interestingly, reduction of NR1 expression did not alter reversal learning, a behavior that has been shown to be impaired, in a dose-dependent manner, by infusion of NMDA-receptor antagonists into the dorsal striatum (Palencia and Ragozzino, 2004).…”

“…Our current findings together with previous findings from our lab and others, suggest that cognitive flexibility requires integration of signaling that involves several brain regions, including the prefrontal cortex (Robbins, 2005, Floresco and Magyar, 2006) as well as ventral and dorsal striatum (Floresco et al, 2006). Cognitive flexibility depends on several neurotransmitter and neuromodulator systems, including glutamatergic, cholinergic (Ragozzino et al, 2009, Wang et al, 2013), serotonergic (Clarke et al, 2005), and dopaminergic signaling (De Steno and Schmauss, 2009, Darvas et al, 2014). We believe that our results suggest that NMDR-mediated plasticity contributes to strategy shifting.…”

“…One important cognitive behavior that is adversely affected by PD, HD and some of the psychiatric conditions is cognitive flexibility—the ability to disengage from previously learned behavior and adopt a new behavioral response (Lawrence et al, 1999, Buckner, 2004, Lima et al, 2008). Additional experimental support for an involvement of the striatum in mediating cognitive flexibility is provided by animal studies using either MSN lesions, transient pharmacological blockade of MSN activity, or inactivation of dopaminergic and cholinergic signaling in the striatum (Ragozzino et al, 2002, Floresco et al, 2006, Braun and Hauber, 2011, Darvas and Palmiter, 2011, Wang et al, 2013, Darvas et al, 2014). While it has been shown that acute pharmacological blockade of NMDA glutamate receptors in the dorsal striatum impairs one form of cognitive flexibility, i.e., response reversal learning (Palencia and Ragozzino, 2004), it remains unclear whether the effects of transient NMDA receptor blockade also extend to conditions of chronic NMDA receptor signaling loss and whether strategy-shifting, which is another form of cognitive flexibility, also requires NMDA-receptor signaling in the dorsal striatum.…”