Differential effects of the cannabinoid agonist WIN55,212–2 on delay and trace eyeblink conditioning.

Steinmetz, Adam B.; Freeman, John H.

doi:10.1037/a0034210

Cited by 6 publications

(11 citation statements)

References 39 publications

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“…Manipulations of cannabinoid receptors before training sessions, via agonist/inverse agonist action or removal of the receptors in knockout mice, result in impaired cerebellar learning (Kishimoto and Kano 2006; Steinmetz and Freeman, 2010; 2011; 2013). The current set of experiments show that manipulating cannabinoid activity within the cerebellar cortex by either a CB1R agonist (WIN55,212-2), increasing endocannabinoid levels (JZL), or decreasing endocannabinoid levels (THL) resulted in impaired learning if administered prior to each session.…”

Section: Discussionmentioning

confidence: 99%

“…CB1Rs within the cerebellar cortex have been demonstrated to be important for the induction of long-term depression (LTD) in parallel fiber synapses with Purkinje cells in vitro (Lévénés, et al, 1998; Safo and Regher, 2005; van Beugen, Nagaraja, and Hansel, 2006). In addition, systemic or genetic CB1R manipulations, which impair CB1R function throughout the brain, result in decrements in the rate of eyeblink conditioning, a type of associative learning that depends on the cerebellar cortical plasticity (Kishimoto and Kano, 2006; Skosnik et al, 2008; Edwards et al, 2008; Steinmetz and Freeman, 2010; 2011; 2013; Steinmetz et al, 2012). The hypothesis drawn from these studies is that the decrement in acquisition of eyeblink conditioning is the result of impaired synaptic plasticity mechanisms within Purkinje cells.…”

Section: Introductionmentioning

confidence: 99%

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Cannabinoid modulation of memory consolidation within the cerebellum

Steinmetz

Freeman

2016

Neurobiology of Learning and Memory

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Cannabinoid receptors contribute to learning and synaptic plasticity mechanisms. The cerebellum contains a high density of cannabinoid receptors and manipulations of cannabinoid receptors affect synaptic plasticity within the cerebellar cortex. In vivo studies have found that cannabinoid agonists impair learning of cerebellum-dependent eyeblink conditioning in rodents and humans. However, the role of cannabinoid receptors or endocannabinoids in memory consolidation within the cerebellum has not been examined. In the current study, we examined the role of cannabinoid receptors and endocannabinoids during learning and consolidation of eyeblink conditioning in rats. Administration of the cannabinoid receptor agonist WIN55,212-2 or drugs that increase/decrease endocannabinoid levels directly into the cerebellar cortex before each training session resulted in marked learning impairments. When administered 1 hr after each training session, during memory consolidation, the cannabinoid inverse agonist SR141716A or the endocannabinoid suppressor THL impaired memory. In contrast, increasing endocannabinoid levels with JZL-184 or infusion of WIN55,212-2 within the cerebellar cortex facilitated memory consolidation 1 hr post-training. Intracerebellar manipulations of cannabinoid receptors or endocannabinoid levels had no effect on memory consolidation when administered 3 or 6 hr after each training session. The results demonstrate that cannabinoids impair cerebellar learning, but facilitate memory consolidation mechanisms within the cerebellar cortex 1– 3 hr after training.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cannabinoid modulation of memory consolidation within the cerebellum

Steinmetz

Freeman

2016

Neurobiology of Learning and Memory

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“…These studies also demonstrated that cannabinoid-induced impairments in EBC occur through agonist action on CB1Rs [51]. Control conditions in these studies including assessments of spontaneous blinks, non-associative responses to the CS, non-associative responses to the US, and sensitivity to the US indicate that the cannabinoid-induced deficit in EBC is a learning impairment and not caused by sensory or motor deficits [49][50][51][52][53]. The results of these studies indicate that cannabinoid agonist cause a dose-dependent deficit in EBC and this impairment is due to alteration of plasticity mechanisms within the cerebellar cortex.…”

Section: Introductionmentioning

confidence: 79%

Intracerebellar cannabinoid administration impairs delay but not trace eyeblink conditioning

Steinmetz

Freeman

2020

Behavioural Brain Research

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Intracerebellar administration of cannabinoid agonists impairs cerebellum-dependent delay eyeblink conditioning (EBC) in rats. It is not known whether the cannabinoid-induced impairment in EBC is found with shorter interstimulus intervals (ISI), longer ISIs, or with trace EBC. Moreover, systemic administration of cannabinoid agonists does not impair trace EBC, suggesting that cannabinoid receptors within the cerebellum are not involved in trace EBC. To more precisely assess the effects of cannabinoids on cerebellar learning mechanisms the current study examined the effects of the cannabinoid agonist WIN55,212-2 (WIN) infusion into the area of the cerebellar cortex necessary for EBC (the eyeblink microzone) in rats during short delay (250 ms CS), long delay (750 ms CS), and trace (250 ms CS, 500 ms trace interval) EBC. WIN was infused into the eyeblink microzone 30 min before pretraining sessions and five EBC training sessions, followed by five EBC training sessions without infusions to assess recovery from drug effects and savings. WIN had no effect on spontaneous blinks or non-associative responses to the CS or US during the pretraining sessions. Short and long delay EBC were impaired by WIN but trace EBC was unaffected. The results indicate that trace EBC is mediated by mechanisms that are resistant to cannabinoid agonists.

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“…), indicating that parallel fibre plasticity is Cb1 receptor‐dependent. Furthermore, knocking out Cb1 receptors or systemic injection of Cb1 receptor agonists or antagonists impairs acquisition of delay eyeblink conditioned responses, a cerebellum‐dependent form of learning (Kishimoto & Kano, ; Steinmetz & Freeman, , ). This suggest that a reduction in Cb1 receptor expression, as observed following 4 Hz stimulation in the present study, may prevent or raise the threshold for induction of LTD and LTP at parallel fibre synapses.…”

Section: Discussionmentioning

confidence: 99%

Long‐term depression of presynaptic cannabinoid receptor function at parallel fibre synapses

Yang

Kreko‐Pierce

Howell

et al. 2019

The Journal of Physiology

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Key points Inhibition of synaptic responses by activation of presynaptic cannabinoid type‐1 (Cb1) receptors is reduced at parallel fibre synapses in the cerebellum following 4 Hz stimulation. Activation of adenylyl cyclase is necessary and sufficient for down‐regulation of Cb1 receptors induced by 4 Hz stimulation. 4 Hz stimulation reduces Cb1 receptor function by (i) increasing the rate of endocannabinoid clearance from the synapse and (ii) decreasing expression of Cb1 receptors. Abstract Cannabinoid type‐1 receptors (Cb1R) are expressed in the presynaptic membrane of many synapses, including parallel fibre‐Purkinje cell synapses in the cerebellum, where they are involved in short‐ and long‐term plasticity of synaptic responses. We show that Cb1R expression itself is a plastic property of the synapse regulated by physiological activity patterns. We made patch clamp recordings from Purkinje cells in cerebellar slices and assessed Cb1R activity by measuring depolarization‐induced suppression of excitation (DSE). We find that DSE is normally stable at parallel fibre synapses but, following 4 Hz stimulation, DSE is persistently reduced and recovers more rapidly. Using a combination of electrophysiology, pharmacology and biochemistry, we show that changes in DSE are a result of the reduced expression of Cb1Rs and increased degradation of endocannabinoids by monoacylglycerol lipase. Long‐term changes in presynaptic Cb1R expression may alter other forms of Cb1R‐dependent plasticity at parallel fibre synapses, priming or inhibiting the circuit for associative learning.

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Differential effects of the cannabinoid agonist WIN55,212–2 on delay and trace eyeblink conditioning.

Cited by 6 publications

References 39 publications

Cannabinoid modulation of memory consolidation within the cerebellum

Cannabinoid modulation of memory consolidation within the cerebellum

Intracerebellar cannabinoid administration impairs delay but not trace eyeblink conditioning

Long‐term depression of presynaptic cannabinoid receptor function at parallel fibre synapses

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