Δ9-Tetrahydrocannabinol, but not the endogenous cannabinoid receptor ligand anandamide, produces conditioned place avoidance

Mallet, Paul E.; Beninger, Richard J.

doi:10.1016/s0024-3205(98)00226-4

Cited by 101 publications

(77 citation statements)

References 34 publications

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“…This work confirms previous findings that cannabinoid agonists are aversive to rats, as shown by the formation of a conditioned place aversion (McGregor et al, 1996;SanudoPena et al, 1997;Mallet and Beninger, 1998;Cheer et al, 2000). D 9 -THC-treated adult rats avoided the drug-paired side after both four and eight contextual pairings, while adolescent rats only showed a trend toward place aversion, and only after eight pairings.…”

Section: Acute Aversive Effects Of Thcsupporting

confidence: 91%

“…This hypothesis has not to our knowledge been tested using animal models. Rats generally find cannabinoids aversive, with D-9-tetrahydrocannabinol (D 9 -THC) and synthetic cannabinoids producing conditioned place aversion (Parker and Gillies, 1995;McGregor et al, 1996;Sanudo-Pena et al, 1997;Mallet and Beninger, 1998;Cheer et al, 2000) and conditioned taste avoidance (Parker and Gillies, 1995;McGregor et al, 1996). Reports of dysphoria and panic by human cannabis users (Hall et al, 1994) suggest these aversive effects may sometimes have a human correlate.…”

Section: Introductionmentioning

confidence: 99%

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Adolescent Rats Find Repeated Δ9-THC Less Aversive Than Adult Rats but Display Greater Residual Cognitive Deficits and Changes in Hippocampal Protein Expression Following Exposure

Quinn

Matsumoto

Callaghan

et al. 2007

Neuropsychopharmacol

272

225

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The current study examined whether adolescent rats are more vulnerable than adult rats to the lasting adverse effects of cannabinoid exposure on brain and behavior. Male Wistar rats were repeatedly exposed to D-9-tetrahydrocannabinol (D 9 -THC, 5 mg/kg i.p.) in a place-conditioning paradigm during either the adolescent (post-natal day 28 + ) or adult (post-natal day 60 + ) developmental stages. Adult rats avoided a D 9 -THC-paired environment after either four or eight pairings and this avoidance persisted for at least 16 days following the final D 9 -THC injection. In contrast, adolescent rats showed no significant place aversion. Adult D 9 -THC-treated rats produced more vocalizations than adolescent rats when handled during the intoxicated state, also suggesting greater drug-induced aversion. After a 10-15 day washout, both adult and adolescent D 9 -THC pretreated rats showed decreased social interaction, while only D 9 -THC pretreated adolescent rats showed significantly impaired object recognition memory. Seventeen days following their last D 9 -THC injection, rats were euthanased and hippocampal tissue processed using two-dimensional gel electrophoresis proteomics. There was no evidence of residual D 9 -THC being present in blood at this time. Proteomic analysis uncovered 27 proteins, many involved in regulating oxidative stress/mitochondrial functioning and cytoarchitecture, which were differentially expressed in adolescent D 9 -THC pretreated rats relative to adolescent controls. In adults, only 10 hippocampal proteins were differentially expressed in D 9 -THC compared to vehicle-pretreated controls. Overall these findings suggest that adolescent rats find repeated D 9 -THC exposure less aversive than adults, but that cannabinoid exposure causes greater lasting memory deficits and hippocampal alterations in adolescent than adult rats.

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Section: Acute Aversive Effects Of Thcsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Adolescent Rats Find Repeated Δ9-THC Less Aversive Than Adult Rats but Display Greater Residual Cognitive Deficits and Changes in Hippocampal Protein Expression Following Exposure

Quinn

Matsumoto

Callaghan

et al. 2007

Neuropsychopharmacol

272

225

View full text Add to dashboard Cite

show abstract

“…These effects, which may be associated with contextual cues, are better modeled in animals by place conditioning procedures (see review, Tzschentke, 1998). Previous reports have found that lower doses of THC are not effective as conditioning stimuli in place conditioning procedures (Mallet and Beninger, 1998;Parker and Gillies, 1995;Robinson et al, 2003). In contrast, higher doses of cannabinoids such as CP 55,940 (McGregor et al, 1996), WIN 55212-2 (Chaperon et al, 1998), THC (Sanudo-Pena et al, 1997); (Cheer et al, 2000); (Hutcheson et al, 1998); (Parker and Gillies, 1995), and HU210 (Cheer et al, 2000) produced aversion in place conditioning procedures in both rats and mice.…”

Section: Place Conditioning Effects Of Thc and Cbdmentioning

confidence: 99%

Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Δ9-tetrahydrocannabinol

Vann

Gamage

Warner

et al. 2008

Drug and Alcohol Dependence

110

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Cannabis sativa (marijuana plant) contains myriad cannabinoid compounds; yet, investigative attention has focused almost exclusively on Δ 9 -tetrahydrocannabinol (THC), its primary psychoactive substituent. Interest in modulation of THC's effects by these other cannabinoids [e.g., cannabidiol (CBD)] has been stimulated anew by recent approval by Canada of Sativex (a 1:1 dose ratio combination of CBD:THC) for the treatment of multiple sclerosis. The goal of this study was to determine the degree to which THC's abuse-related effects were altered by co-administration of CBD. To this end, CBD and THC were assessed alone and in combination in a two-lever THC discrimination procedure in Long-Evans rats and in a conditioned place preference/aversion (CPP/ A) model in ICR mice. CBD did not alter the discriminative stimulus effects of THC at any CBD:THC dose ratio tested. In contrast, CBD, at CBD:THC dose ratios of 1:1 and 1:10, reversed CPA produced by acute injection with 10 mg/kg THC. When administered alone, CBD did not produce effects in either procedure. These results suggest that CBD, when administered with THC at therapeutically relevant ratios, may ameliorate aversive effects (e.g., dysphoria) often associated with initial use of THC alone. While this effect may be beneficial for therapeutic usage of a CBD:THC combination medication, our discrimination results showing that CBD did not alter THC's discriminative stimulus effects suggest that CBD:THC combination medications may also produce THC-like subjective effects at these dose ratios.

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“…One study using the potent synthetic CB1 receptor agonist CP 55, 940 and Wistar rats found conditioned place preferences at a dose of 20 μg/kg but there were no effects at lower or higher doses (61); another study using Sprague-Dawley rats and THC found conditioned place preferences at a dose of 0.1 mg/kg but no effect at lower or higher doses (62); a third study using Wistar rats and WIN55,212-2 found conditioned place preferences at a dose of 1 mg/kg in rats housed in enriched conditions but not in rats housed in standard conditions (63). A number of studies have found that cannabinoid agonists produce conditioned place aversions and not place preferences (61,(64)(65)(66)(67)(68). These studies used the same compounds, the same rat strains, similar conditioning procedures, and similar dose range as the studies that demonstrated conditioned place preferences.…”

Section: Conditioned Place Preference and Aversion With Cannabinoidsmentioning

confidence: 99%

Endocannabinoid system involvement in brain reward processes related to drug abuse

Solinas

Yaşar

Goldberg

2007

Pharmacological Research

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Cannabis is the most commonly abused illegal drug in the world and its main psychoactive ingredient, delta-9-tetrahydrocannabinol (THC), produces rewarding effects in humans and non-human primates. Over the last several decades, an endogenous system comprised of cannabinoid receptors, endogenous ligands for these receptors and enzymes responsible for the synthesis and degradation of these endogenous cannabinoid ligands has been discovered and partly characterized. Experimental findings strongly suggest a major involvement of the endocannabinoid system in general brain reward functions and drug abuse. First, natural and synthetic cannabinoids and endocannabinoids can produce rewarding effects in humans and laboratory animals. Second, activation or blockade of the endogenous cannabinoid system has been shown to modulate the rewarding effects of noncannabinoid psychoactive drugs. Third, most abused drugs alter brain levels of endocannabinoids in the brain. In addition to reward functions, the endocannabinoid cannabinoid system appears to be involved in the ability of drugs and drug-related cues to reinstate drug-seeking behavior in animal models of relapse. Altogether, evidence points to the endocannadinoid system as a promising target for the development of medications for the treatment of drug abuse.

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Δ9-Tetrahydrocannabinol, but not the endogenous cannabinoid receptor ligand anandamide, produces conditioned place avoidance

Cited by 101 publications

References 34 publications

Adolescent Rats Find Repeated Δ9-THC Less Aversive Than Adult Rats but Display Greater Residual Cognitive Deficits and Changes in Hippocampal Protein Expression Following Exposure

Adolescent Rats Find Repeated Δ9-THC Less Aversive Than Adult Rats but Display Greater Residual Cognitive Deficits and Changes in Hippocampal Protein Expression Following Exposure

Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Δ9-tetrahydrocannabinol

Endocannabinoid system involvement in brain reward processes related to drug abuse

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