Strain-specific facilitation of dopamine efflux by Δ9-tetrahydrocannabinol in the nucleus accumbens of rat: An in vivo microdialysis study

doi:10.1016/0304-3940(91)90739-G

Neuroscience Letters

Volume 129, Issue 1, 5 August 1991, Pages 136-140

https://doi.org/10.1016/0304-3940(91)90739-G Get rights and content

Abstract

This study tests the hypothesis that Δ⁹-tetrahydrocannabinolΔ⁹-THC) has a strain-specific facilitatory effect on dopamine (DA) efflux in rat nucleus accumbens, a crucial forebrain convergence of reward-relevant DA neural fibers that has been implicated as a focal brain locus mediating the euphorigenic properties of drugs of abuse. The dependent variable is presynaptic DA efflux measured by in vivo microdialysis in the nucleus accumbens. The independent variables are: (1) intraperitoneal injections of Δ⁹-THC at 0.0 (vehicle), 0.5 and 1.0 mg/kg; (2) Sprague-Dawley vs Lewis strain rat. Results show that Δ⁹-THC produces a dose-dependent, strain-specific enhancement of basal DA efflux in Lewis strain rats. These results suggest that genetic variation influences drug abuse vulnerability.

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Δ⁹-tetrahydrocannabinol (THC) is the main phytocannabinoid present in the Cannabis sativa. It can produce dose-dependent anxiolytic or anxiogenic effects in males. THC effects on anxiety have scarcely been studied in females, despite their higher prevalence of anxiety disorders. Cannabidiol, another phytocannabinoid, has been reported to attenuate anxiety and some THC-induced effects. The present study aimed to investigate the behavioral and neurochemical effects of THC administered alone or combined with CBD in naturally cycling female rats tested in the elevated plus-maze. Systemically administered THC produced biphasic effects in females, anxiolytic at low doses (0.075 or 0.1 mg/kg) and anxiogenic at a higher dose (1.0 mg/kg). No anxiety changes were observed in males treated with the same THC dose range. The anxiogenic effect of THC was prevented by co-administration of CBD (1.0 or 3.0 mg/kg). CBD (3.0 mg/kg) caused an anxiolytic effect. At a lower dose (1.0 mg/kg), it facilitated the anxiolytic effect of the low THC dose. The anxiogenic effect of THC was accompanied by increased dopamine levels in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). In contrast, its anxiolytic effect was associated with increased mPFC serotonin concentrations. The anxiolytic effect of CBD was accompanied by increased mPFC serotonin turnover. Together, these results indicate that female rats are susceptible to the biphasic effects of low THC doses on anxiety. These effects could depend on mPFC and NAc dopaminergic and serotoninergic neurotransmissions. CBD could minimize potential THC high-dose side effects whereas enhancing the anxiolytic action of its low doses in females.
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Cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC) have been the most investigated cannabinoids at the human and preclinical levels, although the neurobiological mechanisms underlying their effects remain unclear. Human experimental evidence complemented by observational studies suggests that THC may have psychotogenic effects while CBD may have antipsychotic effects. However, whether their effects on brain function are consistent with their opposing behavioral effects remains unclear. To address this, here we synthesize neuroimaging evidence investigating the acute effects of THC and CBD on human brain function using a range of neuroimaging techniques, with an aim to identify the key brain substrates where THC and CBD have opposing effects. After a systematic search, a review of the available studies indicated marked heterogeneity. However, an overall pattern of opposite effect profiles of the two cannabinoids was evident with some degree of consistency, primarily attributed to the head-to-head challenge studies of THC and CBD. While head-to-head comparisons are relatively few, collectively the evidence suggests that opposite effects of THC and CBD may be present in the striatum, parahippocampus, anterior cingulate/medial prefrontal cortex, and amygdala, with opposite effects less consistently identified in other regions. Broadly, THC seems to increase brain activation and blood flow, whereas CBD seems to decrease brain activation and blood flow. Given the sparse evidence, there is a particular need to understand the mechanisms underlying their opposite behavioral effects because it may not only offer insights into the underlying pathophysiological mechanisms of psychotic disorders but also suggest potentially novel targets and biomarkers for drug discovery.
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Citation Excerpt :
In the present study, we did not restrict probe placement to the NAc shell or core due to the practical difficulty in separating these subregions in mice. It is important to note that in previous studies acute Δ9-THC injections increased extracellular DA in the NAc in rats (Chen et al., 1991, 1990; Malone and Taylor, 1999; Tanda et al., 1997). This work conflicts with our own findings in mice.
Cannabinoids produce both rewarding and aversive effects in humans and experimental animals. However, the mechanisms underlying these conflicting findings are unclear. Here we examined the potential involvement of CB₁ and CB₂ receptors in cannabinoid action using transgenic CB₁-knockout (CB₁-KO) and CB₂-knockout (CB₂-KO) mice. We found that Δ⁹-tetrahydrocannabinol (Δ⁹-THC) induced conditioned place preference at a low dose (1 mg/kg) in WT mice that was attenuated by deletion of the CB₁ receptor. At 5 mg/kg, no subjective effects of Δ⁹-THC were detected in WT mice, but CB₁-KO mice exhibited a trend towards place aversion and CB₂-KO mice developed significant place preferences. This data suggests that activation of the CB₁ receptor is rewarding, while CB₂R activation is aversive. We then examined the nucleus accumbens (NAc) dopamine (DA) response to Δ⁹-THC using in vivo microdialysis. Unexpectedly, Δ⁹-THC produced a dose-dependent decrease in extracellular DA in WT mice, that was potentiated in CB₁-KO mice. However, in CB₂-KO mice Δ⁹-THC produced a dose-dependent increase in extracellular DA, suggesting that activation of the CB₂R inhibits DA release in the NAc. In contrast, Δ⁹-THC, when administered systemically or locally into the NAc, failed to alter extracellular DA in rats. Lastly, we examined the locomotor response to Δ⁹-THC. Both CB₁ and CB₂ receptor mechanisms were shown to underlie Δ⁹-THC-induced hypolocomotion. These findings indicate that Δ⁹-THC's variable subjective effects reflect differential activation of cannabinoid receptors. Specifically, the opposing actions of CB₁ and CB₂ receptors regulate cannabis reward and aversion, with CB₂-mediated effects predominant in mice.
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Spontaneously hypertensive rats (SHR) are a well-established model to study neurodevelopment of schizophrenia since they exhibit behavioral alterations mimicking schizophrenia that can be improved with antipsychotic drugs. SHR mothers are hypertensive, and the SHR offspring develop in preeclampsia-like conditions.
Hypoxic conditions increase levels of adenosine, which play an important role in brain development. The enhanced levels of adenosine at birth could be related to the future development of schizophrenia. To investigate this hypothesis adenosine levels of brain neonatal Wistar rats and SHR were quantified. After that, caffeine, an antagonist of adenosinergic system, was administrated on PND (postnatal day) 7 (neurodevelopmental age similar to a human at delivery) and rats were observed at adolescent and adult ages. We also investigated the acute effects of caffeine at adolescent and adult ages.
SHR control adolescent and adult groups presented behavioral deficits like hyperlocomotion, deficit in social interaction (SI), and contextual fear conditioning (CFC). In SHR, neonatal caffeine treatment on PND 7 normalized hyperlocomotion, improved SI, and CFC observed at adolescent period and adult ages, showing a beneficial effect on schizophrenia-like behaviors. Wistar rats neonatally treated with caffeine exhibited hyperlocomotion, deficit in SI and CFC when observed at adolescent and adult ages.
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In conclusion, caffeine can be suggested as a useful drug to prevent behavioral deficits observed in this animal model of prenatal hypoxia-induced schizophrenia profile when specifically administered on PND 7.
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Strain-specific facilitation of dopamine efflux by Δ9-tetrahydrocannabinol in the nucleus accumbens of rat: An in vivo microdialysis study

Abstract

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Trends Pharmacol. Sci.

Life Sci.

Pharmacol. Biochem. Behav.

Neuroscience

Pharmacol. Biochem. Behav.

Prog. Neuro-Psychopharmacol.

Brain Res. Bull.

Injectable dispersion of Delta-9-tetrahydrocannabinol in saline using polyvinylpyrrolidone

J. Pharm. Pharmacol.

Facilitation of brain stimulation reward by Δ9-tetrahydrocannabinol

Psychopharmacology

Strain-specific facilitation of dopamine efflux by Δ⁹-tetrahydrocannabinol in the nucleus accumbens of rat: An in vivo microdialysis study

Facilitation of brain stimulation reward by Δ⁹-tetrahydrocannabinol