Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation
819—Cannabinoids: Neural Mechanisms, Addiction, Reinforcement, Seeking, Reinstatement, and Development
Wednesday, November 13, 2013, 1:00 pm - 5:00 pm
819.07: The effect of tetrahydrocannabinol on cerebellum-dependent learning in humans
Location: Halls B-H
*J. D. CAHILL, J. A. CORTES, C. LUDDY, M. RANGANATHAN, R. A. SEWELL, D. C. D'SOUZA, P. D. SKOSNIK; Yale Dept of Psychiatry, Yale Univ., New Haven, CT
Abstract Body: Central cannabinoid receptors (CB1Rs) are among the most abundant G-Protein coupled receptors in the central nervous system and are known to mediate the psychotropic effects of the drug Cannabis. The cerebellar cortex arguably contains the highest density of CB1Rs in the brain, and previous work has shown that CB1R knockout mice, rats administered CB1R agonists, and chronic cannabis users demonstrate deficits in cerebellum-dependent, delay eye blink conditioning (EBC). This ongoing study tests the acute, dose-dependent effects of intravenous delta-9-tetrahydrocannabinol (THC), the major active constituent of cannabis, on cerebellum-dependent delay EBC in healthy humans. Healthy male and female subjects completed three test days during which they received intravenous THC (placebo, low dose (0.015 mg/kg) and high dose (0.03 mg/kg)), in a double-blind, randomized, cross-over, and counterbalanced design. A standard 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). Eye blinks were detected with infrared reflectance. The primary outcome measure was percentage of trials showing a CR (%CRs) during acquisition and extinction phases. CR latency (in milliseconds) was additionally measured in light of a hypothetical model for the role of cerebellar CB1Rs in the timing of conditioned blinks. In keeping with our primary hypothesis, we observed a linear, dose-dependent disruption of %CRs by the end of acquisition. Secondarily, we found an interaction between THC dose and task block, which is in keeping with a differential effect of THC on acquisition versus extinction. These results corroborate previous animal studies and provide direct evidence of the role of CB1Rs in synaptic plasticity and learning within the human cerebellum.
Lay Language Summary: Our study suggests for the first time in humans that delta-9-tetrahydrocannabinol (THC), the main active component of cannabis, disrupts classical conditioning, a fundamental learning process. The medicinal and recreational use of cannabis is garnering growing legislative support in the USA. Cannabis in its various forms is already the most widely recreationally-used illicit substance in the world, and has been shown to disrupt some forms of memory (for example, one’s ability to learn lists of items). However, it is important to note that our brains also rely on even more fundamental forms of learning for our everyday functioning. One such form is termed Pavlovian, or classical conditioning. This type of learning allows us to automatically link stimuli in our environment with certain feelings and reflexive actions: we are alerted when the brake lights illuminate suddenly in the car in front or we crave ice cream when we hear the jingles associated with ice cream trucks. Classical conditioning keeps us safe, guides our decisions and helps us adapt to our environment. Specific circuits of our brain rewire to make this connection; but if our environment changes, these circuits can also unwire. This is known as neural plasticity. In this ongoing study we investigate one particular type of classical conditioning, Eye Blink Conditioning (EBC). Healthy volunteers are administered benign puffs of air to the eye which cause them to blink reflexively. A tone is played, starting just before and ending with, the air puffs (like an early warning signal). When this is repeated over and over again, the blinking occurs in response to the tone indicating that an association between the tone and puff has formed so that one’s eye is protectively closed when the puff occurs (the acquisition phase). When tones are repeatedly presented without air puffs the association between the tone and puff gets broken and the reflexive blinking stops (the extinction phase). Using an infrared sensor we can detect blinking and hence measure how effectively acquisition and extinction occur. In this experiment, each volunteer receives a high or low dose of THC or a saline placebo by injection, in randomized order, on three separate days. Performance (in both acquisition and extinction phases) across the three test days is compared. We find that the higher the dose of THC, the fewer adaptive blinks occur and the worse acquisition is. This may represent a disruption in the timing of the blinks - occurring too early or late to protect the eye from the air puff. This could result from THC’s effect on the brain’s ability to make and break connections in the cerebellum, an area responsible for the control and timing of movements. We also observe that THC’s relative effect on acquisition and extinction may change at different doses. This study is the first of its kind demonstrating the immediate effects of THC on EBC in humans. It also extends previous work examining the effects of long-term, heavy cannabis use on EBC, which found similar results. EBC tests one of many mechanisms by which classical conditioning helps us adapt to our environment. Our findings, by demonstrating a disruption of this fundamental brain process, call for future research to rule out a range of related, subtle yet significant, immediate adverse effects of cannabis use.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit