Anandamide-induced behavioral disruption through a vanilloid-dependent mechanism in rats

Abstract

Rationale: Endocannabinoids are involved in a variety of behavioral and physiological processes that are just beginning to be understood. In the five-choice serial reaction-time task, exogenous cannabinoids have been found to alter attention, but endocannabinoids such as anandamide have not been studied.

Objectives: We used this task to evaluate the effects of anandamide in rats. Since anandamide is a ligand for not only cannabinoid receptors but also transient receptor potential vanilloid 1 (TRPV1) receptors, and as recently suggested, peroxisome proliferator-activated nuclear receptor-alpha (PPARalpha), we also determined whether anandamide's effects in this task were mediated by each of these receptors.

Materials and methods: Whenever one of five holes was illuminated for 2 s, a food pellet was delivered if a response occurred in that hole during the light or within 2 s after the light.

Results: Anandamide increased omission errors and decreased responding during inter-trial intervals. These effects were blocked by the TRPV1 antagonist capsazepine, but not by the cannabinoid-receptor antagonist rimonabant or the PPARalpha antagonist MK886. Testing with open-field activity and food-consumption procedures in the same rats suggested that the disruption of operant responding observed in the attention task was not due to motor depression, anxiety, decreased appetite, or an inability to find and consume food pellets.

Conclusions: The vanilloid-dependent behavioral disruption induced by anandamide was specific to the operant attention task. These effects of anandamide resemble effects of systemically administered dopamine antagonists and might reflect changes in vanilloid-mediated dopamine transmission.

Figure 1

Effects of anandamide (0, 1, 3, and 10 mg/kg, ip) on behavior in the attention task. a: Omission errors (percentage of trials on which no response was made). b: Anticipatory responses (number of responses during the inter-trial interval). c: Accuracy (number of trials with a correct response, as a percentage of all trials with a response). d: Latency on correct trials (number of seconds to respond on trials with a correct response). e: Latency on incorrect trials (number of seconds to respond on trials with an incorrect response). “*” indicates bars that differ significantly (p<.05) from vehicle (0 mg/kg anandamide). Error bars in all figures indicate s.e.m.

Figure 2

Effects of treatments that failed to alter anandamide’s effects on behavior in the attention task. Results are shown only for omission errors, since the treatments also failed to alter the effects of anandamide on the other measures shown in Figure 1. a: Effects of vehicle-only injections. b: Effects of treatment drugs (i.e., treatment drug plus the vehicle for anandamide). c: Effects of anandamide (i.e., vehicle for the treatment drug plus 10 mg/kg anandamide). d: Effects of treatment drugs plus anandamide. E: Effects of THC alone. “AEA”=anandamide. “URB”=URB597 (FAAH inhibitor). “SR”=SR141716 (rimonabant, cannabinoid-receptor antagonist). “MK”=MK886 (PPARα antagonist). Number after drug abbreviation=dose (mg/kg), with “0” dose indicating vehicle. “*” indicates bars that differ significantly (p<.05) from appropriate vehicle-only condition (0 mg/kg anandamide plus 0 mg/kg treatment).

Figure 3

Reversal by capsazepine (10 mg/kg) of the effects of anandamide (10 mg/kg) in the attention task. a: Omission errors. b: Anticipatory responses. c: Accuracy. d: Latency on correct trials. E: Latency on incorrect trials. “AEA”=anandamide. “0” indicates vehicle. “10” indicates 10 mg/kg dose. “*” indicates bars that differ significantly (p<.05) from anandamide vehicle plus capsazepine vehicle condition. “^” indicates bars that differ from anandamide plus capsazepine vehicle.

Figure 4

Effects of anandamide (10 mg/kg) and capsazepine (10 mg/kg), alone and in combination, on open-field behavior in the same rats tested previously in the attention task. Measures of general activity: Distance traveled, stereotypy counts, ambulatory episodes, average velocity, vertical counts (rearing), jump counts. Anxiety-related measures: center zone entries, thigmotaxis (time spent within 5 cm of a wall). “Veh”=anandamide vehicle plus capsazepine vehicle. “AEA”=anandamide 10 mg/kg plus capsazepine vehicle. “Cap”=capsazepine 10 mg/kg plus anandamide vehicle. “A+C”=anandamide 10 mg/kg plus capsazepine 10 mg/kg. “*” indicates significant (p<.05) difference from anandamide vehicle plus capsazepine vehicle condition.

Figure 5

Effects of anandamide (10 mg/kg) and capsazepine (10 mg/kg), alone and in combination, on open-field behavior in experimentally-naive rats. Details are the same as in Figure 4.

Figure 6

Consumption of food pellets after treatment with 0 or 10 mg/kg anandamide in the same rats tested previously in the attention task. Solid portion of bar represents number of seconds before the first pellet was picked up. Grey portion of bar represents number of seconds between picking up the first pellet and last pellet. Sum of black and grey portions stacked together represents total number of seconds to pick up all pellets. There were no significant differences between the conditions.