Cannabis use disrupts eyeblink conditioning: evidence for cannabinoid modulation of cerebellar-dependent learning

Abstract

While the cerebellum contains the highest density of cannabinoid receptor (CB1) in the brain, no studies have assessed the effect of exogenous cannabinoids on cerebellar-dependent learning in humans. The current study, therefore, examined the effect of chronic cannabis use on classical eyeblink conditioning (EBC), a cerebellar-mediated task which has been shown to be disrupted in CB1 knockout mice. Chronic cannabis users (24 h abstinence before study; positive THC urine drug test) free of DSM-IV Axis-I or -II disorders, were evaluated. A delay EBC task was utilized, in which a conditioned stimulus (CS; 400 ms tone) co-terminated with a corneal air puff unconditioned stimulus (US; 50 ms), thus eliciting a conditioned blink response (CR). The cannabis group exhibited markedly fewer, and more poorly timed CRs as compared to drug-naive controls. There were no differences between the groups in either the unconditioned response (UR) or an EEG measure of selective attention to the CS (N100 auditory ERP), indicating that the disruption observed in the cannabis group was specific to CR acquisition. These results suggest that cannabis use is associated with functional deficits in the cerebellar circuitry underlying EBC, a finding which corroborates the recent work in CB1 knockout mice.

Figure 1

Experimental setup. Visual overview of the experimental setup showing method and timing of US and CS presentation, and EEG/EMG recording.

Figure 2

Grand averaged trial-by-trial EMG data from all paired CS–US trials. The 400-ms tone CS (1 kHz, 80 dB) co-terminates with a 50 ms (10 psi) airpuff. The outlined sections and panels display the time window where conditioned responses (CRs) occurred (approximately 220 – 350 ms). At around block 3, the control participants (top) begin to show robust CRs, as evidenced by the increased amplitude in the period shortly before US onset. Conversely, cannabis users (bottom) are impaired in the acquisition and timing of the CR. Both groups show decreased unconditioned response (UR) amplitudes as the experiment progresses due to habituation.

Figure 3

Mean % conditioned responses (CRs) across blocks (1 block = 9 CS-US paired trials) for cannabis users versus controls. Both groups displayed approximately equal % CRs in the first block of the learning phase, with controls showing greater learning across time. Both groups show similar declines in the percentage of CRs across the extinction blocks, indicating similar rates of extinction of the CR. Error bars indicate ± SEM.

Figure 4

Grand averaged transient ERPs elicited by tone CS onset for both cannabis users and control participants at electrode FCz. The similar N100 component in the cannabis users and controls provide evidence of intact acoustic stimulus processing and CS encoding in both groups.