Hippocampal CB(1) receptors mediate the memory impairing effects of Delta(9)-tetrahydrocannabinol

Abstract

It is firmly established that the hippocampus, a brain region implicated in spatial learning, episodic memory, and consolidation, contains a high concentration of CB(1) receptors. Moreover, systemic and intrahippocampal administration of cannabinoid agonists have been shown to impair hippocampal-dependent memory tasks. However, the degree to which CB(1) receptors in the hippocampus play a specific functional role in the memory disruptive effects of marijuana or its primary psychoactive constituent Delta(9)-tetrahydrocannabinol (Delta(9)-THC) is unknown. This study was designed to determine whether hippocampal CB(1) receptors play a functional role in the memory disruptive effects of systemically administered cannabinoids, using the radial arm maze, a well characterized rodent model of working memory. Male Sprague-Dawley rats were implanted with bilateral cannulae aimed at the CA1 region of the dorsal hippocampus. The CB(1) receptor antagonist, rimonabant, was delivered into the hippocampus before to a systemic injection of either Delta(9)-THC or the potent cannabinoid analog, CP-55,940. Strikingly, intrahippocampal administration of rimonabant completely attenuated the memory disruptive effects of both cannabinoids in the radial arm maze task, but did not affect other pharmacological properties of cannabinoids, as assessed in the tetrad assay (that is, hypomotility, analgesia, catalepsy, and hypothermia). Infusions of rimonabant just dorsal or ventral to the hippocampus did not prevent Delta(9)-THC-induced memory impairment, indicating that its effects on mnemonic function were regionally selective. These findings provide compelling evidence in support of the view that hippocampal CB(1) receptors play a necessary role in the memory disruptive effects of marijuana.

Figure 1

Establishing an effective dose of rimonabant for intrahippocampal administration. A. Intrahippocampal rimonabant (Rim; 0.06 μg/rat) blocked the memory disruptive effects of intrahippocampal CP-55,940 (CP; 10 μg/rat) in the eight arm radial maze task. B. Intrahippocampal injection of CP-55,940 and rimonabant given separately or in combination did not affect maze running speed. C. Location of intracerebral infusion sites. Drugs were tested in a counterbalanced order. ** p < 0.01 for each group vs. vehicle-vehicle (v-v) treated rats. Results are shown as mean ± SE. n = 9 rats/group.

Figure 2

Hippocampal CB₁ receptors mediate the memory disruptive effects of systemically administered cannabinoid receptor agonists in the radial arm maze task. A. Intracerebral administration of rimonabant (Rim; 0.06 μg/rat) into the dorsal hippocampal blocked re-entry errors caused by the potent cannabinoid CP-55,940 (CP; 0.05 mg/kg; i.p.). B. CP-55,940 and rimonabant given separately or in combination did not affect maze running speed. C. Intracerebral administration of rimonabant (0.06 μg/rat) into the dorsal hippocampal blocked re-entry errors caused by Δ⁹-THC (THC; 5.6 mg/kg; i.p.). D. Δ⁹-THC led to a significant decrease in the rate of entry into each arm, which was not affected by rimonabant. E. Location of intracerebral infusion sites. Closed and open circles respectively reflect injections sites properly placed within the hippocampus and outside the hippocampus. E. Photomicrograph of cannulae placement in dorsal hippocampus from a representative rat. ** p < 0.01 versus each other group. ## p < 0.01 for Δ⁹-THC vs. vehicle treatment. Results are shown as mean ± SE. n=7-17 rats/group.

Figure 3

Rimonabant (Rim) infused dorsal to the hippocampus does not reduce Δ⁹-THC-induced memory impairment. Systemic administration of Δ⁹-THC (5.6 mg/kg) produced significant increases in re-entry errors (A) and arm entry rates (B) that were not blocked by rimonabant (0.06 μg/rat) microinjected in sites dorsal to the hippocampus. C. Location of intracerebral infusion sites. Closed circles depict intracerebral infusion sites from cannulae implanted dorsal to the hippocampus. Results are shown as mean ± SE. n = 6-13 rats/group. # p < 0.05, ## p < 0.01 for Δ⁹-THC vs. vehicle treatment.

Figure 4

Rimonabant (Rim) infused ventral to the hippocampus does not reduce Δ⁹-THC-induced memory impairment. Systemic administration of Δ⁹-THC (5.6 mg/kg) produced significant increases in re-entry errors (A) and arm entry rates (B) that were not blocked by rimonabant (0.06 μg/rat) given ventral to the border of the hippocampus. C. Location of intracerebral infusion sites. Closed circles depict intracerebral infusion sites from cannulae implanted ventral to the hippocampus. Results are shown as mean ± SE. n = 8 rats/group. # p < 0.05, ## p < 0.01 for Δ⁹-THC vs. vehicle treatment.

Figure 5

Intracerebral administration of rimonabant (Rim; 0.06 μg/rat) into the dorsal hippocampal does not block the non-mnemonic effects of systemically administered CP-55,940 (CP; 0.15 mg/kg, i.p.), as assessed in the tetrad assay that includes hypomotility (A), antinociception (B), catalepsy (C), and hypothermia (D). * p < 0.05, ** p < 0.01 for each group vs. vehicle-vehicle (V-V) treatment. Results are shown as mean ± SE. n=4-9 rats/group.