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

Wise LE, Thorpe AJ, Lichtman AH - Neuropsychopharmacology (2009)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.

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.

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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.
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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.

Mentions: We next evaluated whether intrahippocampal administration of rimonabant (0.06 μg) would prevent radial arm maze performance deficits caused by either CP-55,940 (0.05 mg/kg) or Δ9-THC (5.6 mg/kg). Both cannabinoid receptor agonists significantly impaired radial arm maze choice accuracy in rats given intrahippocampal infusions of vehicle (see Figure 2A and 2C), as previously reported (Lichtman, et al 1995). Intrahippocampal rimonabant administration completely blocked the memory deficits elicited by systemically administered CP-55,940. A two-way ANOVA revealed a significant interaction between rimonabant and CP-55,940, F (1,54) = 15.24, p < 0.001. Treatment with vehicle + CP-55,940 resulted in significantly more errors than each of the other three drug combinations, indicating that rimonabant blocked the memory disruptive effects of this cannabinoid receptor agonist. In contrast, there were no main effects of rimonabant treatment (p = 0.79) and CP-55,940 (p = 0.25), as well as no interaction between rimonabant and CP-55,940 (p = 0.51) for the maze completion data (Figure 2B).


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

Wise LE, Thorpe AJ, Lichtman AH - Neuropsychopharmacology (2009)

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.
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Related In: Results  -  Collection

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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.
Mentions: We next evaluated whether intrahippocampal administration of rimonabant (0.06 μg) would prevent radial arm maze performance deficits caused by either CP-55,940 (0.05 mg/kg) or Δ9-THC (5.6 mg/kg). Both cannabinoid receptor agonists significantly impaired radial arm maze choice accuracy in rats given intrahippocampal infusions of vehicle (see Figure 2A and 2C), as previously reported (Lichtman, et al 1995). Intrahippocampal rimonabant administration completely blocked the memory deficits elicited by systemically administered CP-55,940. A two-way ANOVA revealed a significant interaction between rimonabant and CP-55,940, F (1,54) = 15.24, p < 0.001. Treatment with vehicle + CP-55,940 resulted in significantly more errors than each of the other three drug combinations, indicating that rimonabant blocked the memory disruptive effects of this cannabinoid receptor agonist. In contrast, there were no main effects of rimonabant treatment (p = 0.79) and CP-55,940 (p = 0.25), as well as no interaction between rimonabant and CP-55,940 (p = 0.51) for the maze completion data (Figure 2B).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.

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.

Show MeSH
Related in: MedlinePlus