SK channel modulation rescues striatal plasticity and control over habit in cannabinoid tolerance

Abstract

Endocannabinoids (eCBs) regulate neuronal activity in the dorso-lateral striatum (DLS), a brain region that is involved in habitual behaviors. How synaptic eCB signaling contributes to habitual behaviors under physiological and pathological conditions remains unclear. Using a mouse model of cannabinoid tolerance, we found that persistent activation of the eCB pathway impaired eCB-mediated long-term depression (LTD) and synaptic depotentiation in the DLS. The loss of eCB LTD, occurring preferentially at cortical connections to striatopallidal neurons, was associated with a shift in behavioral control from goal-directed action to habitual responding. eCB LTD and behavioral alterations were rescued by in vivo modulation of small-conductance calcium activated potassium channel (SK channel) activity in the DLS, which potentiates eCB signaling. Our results reveal a direct relationship between drug tolerance and changes in control of instrumental performance by establishing a central role for eCB LTD in habit expression. In addition, SK channels emerge as molecular targets to fine tune the eCB pathway under pathological conditions.

Agent-causal libertarianism, statistical neural laws and wild coincidences

“…The ability of nervous systems, and their states, to be changed in this way is called plasticity; and plasticity generalizes across functioning nervous systems (e.g., Fu et al 2002;Jacob et al 2007;Cassenaer & Laurent 2007;Yin et al 2009;Nazzaro et al 2012;Smith & Graybiel 2013;Arce--McShane et al 2014). Nervous systems, and their subsystems, are 'plastic' in the sense that their proper functioning throughout daily life involves changes in the probability subsequent activities will occur (e.g., Dan & Poo 2006;McMahon & Leopold 2012;Veniero et al 2013).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…This correlates with drug-induced changes in synaptic functions (LTP, LTD) in the dorsal striatum (Gerdeman et al, 2003) and possibly agrees with chronic stimulant treatment-induced changes in the sensitization of behavioral stereotypy and striosomal early gene activation in the lateral striatum (Canales and Graybiel, 2000;. In THCdependent mice that show no difference in responding to valued versus devalued rewards, bilateral infusion of apamin (a SK Ca channel blocker) into the dorsolateral striatum rescued the eCB-dependent LTD (lost during tolerance development) for up to 5 days and changed the behavior from habitual responding to goal-directed responding with a significantly greater responding for valued than devalued rewards (Nazzaro et al, 2012). D 1 R activation (D 1 R-like) has been linked to LTP and D 2 R activation (D 2 R-like) to LTD in MSN glutamate synapses (Calabresi et al, 2007).…”

Synaptic Targets of 9-Tetrahydrocannabinol in the Central Nervous System

“…Also, similar to the NAc (ventral striatum), LTD of cortical glutamatergic inputs to the dorsal www.perspectivesinmedicine.org striatum is dependent on endocannabinoid activation of presynaptic CB1 receptors (Gerdeman et al 2002;Ronesi et al 2004), which may be involved in the establishment of striatal-dependent learning and habit formation (Kano et al 2009). Because of the importance of the endogenous cannabinoid system in mediating motor behavior, instrumental learning, and habit formation and its potential involvement in compulsive drug seeking, the role of THC in regulating endogenous cannabinoid function has been studied (Nazzaro et al 2012). This study found that, similar to previous work in other brain areas, treatment of mice with THC (10 mg/kg, i.p., 5 d) eliminated endogenous cannabinoid-dependent LTD of cortical inputs to MSNs in the dorsolateral striatum that was associated with behavioral tolerance to THC (Nazzaro et al 2012).…”

“…Because of the importance of the endogenous cannabinoid system in mediating motor behavior, instrumental learning, and habit formation and its potential involvement in compulsive drug seeking, the role of THC in regulating endogenous cannabinoid function has been studied (Nazzaro et al 2012). This study found that, similar to previous work in other brain areas, treatment of mice with THC (10 mg/kg, i.p., 5 d) eliminated endogenous cannabinoid-dependent LTD of cortical inputs to MSNs in the dorsolateral striatum that was associated with behavioral tolerance to THC (Nazzaro et al 2012). Striatal MSNs send their GABAergic output to downstream targets via two pathways known as indirect and direct, which are defined by various postsynaptically expressed receptors and neuropeptides (Kreitzer 2009).…”

“…Striatal MSNs send their GABAergic output to downstream targets via two pathways known as indirect and direct, which are defined by various postsynaptically expressed receptors and neuropeptides (Kreitzer 2009). When electrophysiologically recorded dorsolateral striatal MSNs were segregated according to indirect and direct pathways, using post-hoc identification with single-cell reverse transcriptase polymerase chain reaction (RT-PCR) or immunohistochemistry, it was found that only the DA D2 receptor expressing MSNs associated with the indirect pathway showed endogenous cannabinoid-dependent LTD (Nazzaro et al 2012). Furthermore, chronic THC treatment blocked LTD only at synapses onto these indirect pathway MSNs.…”