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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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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.
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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.

Mentions: In a preliminary experiment, we sought to determine an effective intrahippocampal dose of rimonabant that antagonizes the memory disruptive effects of the potent cannabinoid analog CP-55,940 (10 μg/rat) given in the same injection site. CP-55,950 produced a significant increase in the number of re-entry errors (Figure 1A), but did not affect the rate of entry into each arm (Figure 1B). A dose of 0.06 μg rimonabant completely blocked the memory disruptive effects of CP-55,940, as indicated by a significant interaction between rimonabant and CP-55,940 treatment, F (1,32) = 13.59, p < 0.01. Post hoc comparisons showed that microinjections of vehicle + CP-55,940 into the hippocampus elicited significantly more errors than each of the other three treatment conditions. Virtually no re-entry errors were committed by rats in the other three treatment conditions. Neither drug given alone nor in combination affected rate of arm entry, as indicated by no significant interaction between the two drugs (p = 0.51), as well as no significant main effect for either rimonabant treatment (p = 0.79) or CP-55,940 treatment (p = 0.25). The data include rats whose cannulae were correctly aimed at the hippocampus (see Figure 1C for cannulae placements). Thus, 0.06 μg was selected as the dose of rimonabant for intracerebral injections in subsequent experiments.


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

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

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2822461&req=5

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.
Mentions: In a preliminary experiment, we sought to determine an effective intrahippocampal dose of rimonabant that antagonizes the memory disruptive effects of the potent cannabinoid analog CP-55,940 (10 μg/rat) given in the same injection site. CP-55,950 produced a significant increase in the number of re-entry errors (Figure 1A), but did not affect the rate of entry into each arm (Figure 1B). A dose of 0.06 μg rimonabant completely blocked the memory disruptive effects of CP-55,940, as indicated by a significant interaction between rimonabant and CP-55,940 treatment, F (1,32) = 13.59, p < 0.01. Post hoc comparisons showed that microinjections of vehicle + CP-55,940 into the hippocampus elicited significantly more errors than each of the other three treatment conditions. Virtually no re-entry errors were committed by rats in the other three treatment conditions. Neither drug given alone nor in combination affected rate of arm entry, as indicated by no significant interaction between the two drugs (p = 0.51), as well as no significant main effect for either rimonabant treatment (p = 0.79) or CP-55,940 treatment (p = 0.25). The data include rats whose cannulae were correctly aimed at the hippocampus (see Figure 1C for cannulae placements). Thus, 0.06 μg was selected as the dose of rimonabant for intracerebral injections in subsequent experiments.

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