Central cannabinoid receptors modulate acquisition of eyeblink conditioning

Abstract

Delay eyeblink conditioning is established by paired presentations of a conditioned stimulus (CS) such as a tone or light, and an unconditioned stimulus (US) that elicits the blink reflex. Conditioned stimulus information is projected from the basilar pontine nuclei to the cerebellar interpositus nucleus and cortex. The cerebellar cortex, particularly the molecular layer, contains a high density of cannabinoid receptors (CB1R). The CB1Rs are located on the axon terminals of parallel fibers, stellate cells, and basket cells where they inhibit neurotransmitter release. The present study examined the effects of a CB1R agonist WIN55,212-2 and antagonist SR141716A on the acquisition of delay eyeblink conditioning in rats. Rats were given subcutaneous administration of 1, 2, or 3 mg/kg of WIN55,212-2 or 1, 3, or 5 mg/kg of SR141716A before each day of acquisition training (10 sessions). Dose-dependent impairments in acquisition were found for WIN55,212-2 and SR141716A, with no effects on spontaneous or nonassociative blinking. However, the magnitude of impairment was greater for WIN55,212-2 than SR141716A. Dose-dependent impairments in conditioned blink response (CR) amplitude and timing were found with WIN55,212-2 but not with SR141716A. The findings support the hypothesis that CB1Rs in the cerebellar cortex play an important role in plasticity mechanisms underlying eyeblink conditioning.

Retention and extinction of delay eyeblink conditioning are modulated by central cannabinoids

“…Previous studies have examined CB1R function during acquisition of delay eyeblink conditioning (dEBC), which depends on synaptic plasticity mechanisms within the cerebellar cortex (Lavond and Steinmetz 1989;Chen et al 1996Chen et al , 1999Garcia et al 1999;Attwell et al 2001;Nolan and Freeman 2006;Thompson and Steinmetz 2009). Rats administered the CB1R agonist WIN55,212-2 or the antagonist SR141716A during acquisition of dEBC showed a dose-dependent impairment (Steinmetz and Freeman 2010). However, administration of WIN55,212-2 produced a larger impairment than that of SR141716A.…”

“…It was previously hypothesized that CB1Rs play a role in induction of synaptic plasticity within the cerebellar cortex (Steinmetz and Freeman 2010), suggesting that manipulating these receptors should not affect retention but will impair extinction, a type of inhibitory learning. Both the CB1R knockout mouse and human studies examined extinction and found no significant differences.…”

“…They were then administered WIN55,212-2, SR141716A, or vehicle during two sessions of CS-alone extinction. The doses of the agonist and antagonist were chosen because both produced impairments in acquisition of dEBC in a previous study (Steinmetz and Freeman 2010). The 3 mg/kg dose of WIN55,212-2 produced significant impairments compared to smaller dose of WIN55,212-2 (1 and 2 mg/kg).…”

Evaluation of bidirectional interstimulus interval (ISI) shift in auditory delay eye-blink conditioning in healthy humans

“…Manipulations of the cerebellar cortex by ablation, chemical inactivation, elimination of Purkinje cells genetically or chemically, or disrupting long-term depression (LTD) mechanisms that occur in the cortex have caused a severe impairment in acquisition of delay EBC (Attwell, Rahman, & Yeo, 2001;Chen, Bao, S., Lockard, Kim, & Thompson, 1996;Chen, Bao, & Thompson, 1999;Garcia, Steele, & Mauk, 1999;Nolan & Freeman, 2006;Steinmetz & Freeman, 2010;Thompson & Steinmetz, 2009). For example, Perrett et al (1993) demonstrated that cerebellar cortical lesions in rabbits resulted in maladaptive short-latency CRs in a discrimination delay EBC paradigm.…”

Cannabinoids and Tremor Induced by Motor-related Disorders: Friend or Foe?

“…Moreover, it has been shown that CB 1 R knockout mice, as well as chronic marijuana users or animals administered CB 1 R agonists, have clear impairment of eyeblink conditioning, an epitome of cerebellar cortex function [47][48][49][50][51]. 2-Arachidonoylglycerol (2-AG) and Narachidonoylethanolamine (AEA), 2 arachidonic acid derivatives, are the chief endocannabinoids in the brain; cerebellum CB 1 R are predominantly activated by 2-AG.…”