An animal model of female adolescent cannabinoid exposure elicits a long-lasting deficit in presynaptic long-term plasticity

Abstract

Cannabis continues to be the most accessible and popular illicit recreational drug. Whereas current data link adolescence cannabinoid exposure to increased risk for dependence on other drugs, depression, anxiety disorders and psychosis, the mechanism(s) underlying these adverse effects remains controversial. Here we show in a mouse model of female adolescent cannabinoid exposure a deficient endocannabinoid (eCB)-mediated signaling and presynaptic forms of long-term depression at adult central glutamatergic synapses in the prefrontal cortex. Increasing endocannabinoid levels by blockade of monoacylglycerol lipase, the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG), with the specific inhibitor JZL184 ameliorates these deficits. The observed deficit in cortical eCB-dependent signaling may represent a neural maladaptation underlying network instability and abnormal cognitive functioning. Our study suggests that adolescent cannabinoid exposure may permanently impair brain functions, including the brain’s intrinsic ability to appropriately adapt to external influences.

Synaptic functions of endocannabinoid signaling in health and disease

“…While adults seem resistant to most protracted effects of cannabis exposure (Realini et al, 2011; Schneider and Koch, 2003), adolescent exposure precipitates the development of such aberrant behaviors as addiction and psychosis (for reviews see: Hurd et al, 2014). In animal models, PFC-dependent cognitive functions are impaired in adulthood following cannabis exposure during development (Lovelace et al, 2015; Raver et al, 2013). Enhanced deficits resulting from cannabis use in schizophrenic subjects provide further evidence supporting a role for dysfunction in the eCB system.…”

Closing the gap: long-term presynaptic plasticity in brain function and disease

“…eCB-LTD in the hippocampus and nucleus accumbens (NAc) following Δ 9 -THC [116], and MOR- and eCB-mediated LTD following the opioid painkiller, oxycodone [71]. Adolescent mice exposed daily to a CB 1 R agonist show impaired presynaptic eCB-LTD and mGluR2/3-mediated LTD in the prefrontal cortex (PFC) lasting into adulthood [72]. Repeated exposure to cocaine in rodents disinhibits dopamine neurons of the ventral tegmental area (VTA) in two ways: by facilitating the induction of presynaptic eCB-LTD of inhibitory inputs to dopamine VTA neurons [73] and indirectly by promoting LTP of GABA release from medium spiny neurons of the NAc projecting onto local interneurons that inhibit VTA dopamine neurons [74].…”

Chronic, intermittent treatment with a cannabinoid receptor agonist impairs recognition memory and brain network functional connectivity

“…In addition, cannabis-based medicines are increasingly being used to treat several diseases such as epilepsy (Maa and Figi 2014), chronic pain (Carter et al, 2015), multiple sclerosis (Fitzpatrick and Downer 2017) and neurodegenerative diseases (Fagan and Campbell 2014), but the potential for negative side effects has not been well characterized. Understanding the effects of chronic cannabinoid exposure upon brain and synaptic function opens a window into the development of therapeutic tools that could counteract the 'on target' side effects associated with chronic use of cannabis and cannabinoid-based medicines (Copeland et al 2013;Lovelace et al 2015).…”