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Chronic ??-tetrahydrocannabinol exposure induces a sensitization of dopamine D?/? receptors in the mesoaccumbens and nigrostriatal systems.

ABSTRACT: ??-tetrahydrocannabinol (THC), through its action on cannabinoid type-1 receptor (CB?R), is known to activate dopamine (DA) neurotransmission. Functional evidence of a direct antagonistic interaction between CB?R and DA D?-receptors (D?R) suggests that D?R may be an important target for the modulation of DA neurotransmission by THC. The current study evaluated, in rodents, the effects of chronic exposure to THC (1?mg/kg/day; 21 days) on D?R and D?R availabilities using the D?R-prefering antagonist and the D?R-preferring agonist radiotracers [¹?F]fallypride and [³H]-(+)-PHNO, respectively. At 24?h after the last THC dose, D?R and D?R densities were significantly increased in midbrain. In caudate/putamen (CPu), THC exposure was associated with increased densities of D?R with no change in D?R mRNA expression, whereas in nucleus accumbens (NAcc) both D?R binding and mRNA levels were upregulated. These receptor changes, which were completely reversed in CPu but only partially reversed in NAcc and midbrain at 1 week after THC cessation, correlated with an increased functionality of D?/?R in vivo, based on findings of increased locomotor suppressive effect of a presynaptic dose and enhanced locomotor activation produced by a postsynaptic dose of quinpirole. Concomitantly, the observations of a decreased gene expression of tyrosine hydroxylase in midbrain together with a blunted psychomotor response to amphetamine concurred to indicate a diminished presynaptic DA function following THC. These findings indicate that the early period following THC treatment cessation is associated with altered presynaptic D?/?R controlling DA synthesis and release in midbrain, with the concurrent development of postsynaptic D?/?R supersensitivity in NAcc and CPu. Such D?/?R neuroadaptations may contribute to the reinforcing and habit-forming properties of THC.

SUBMITTER: Ginovart N

PROVIDER: S-EPMC3442351 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Chronic Δ⁹-tetrahydrocannabinol exposure induces a sensitization of dopamine D₂/₃ receptors in the mesoaccumbens and nigrostriatal systems.

Ginovart Nathalie N Tournier Benjamin B BB Moulin-Sallanon Marcelle M Steimer Thierry T Ibanez Vicente V Millet Philippe P

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20120613 11

Δ⁹-tetrahydrocannabinol (THC), through its action on cannabinoid type-1 receptor (CB₁R), is known to activate dopamine (DA) neurotransmission. Functional evidence of a direct antagonistic interaction between CB₁R and DA D₂-receptors (D₂R) suggests that D₂R may be an important target for the modulation of DA neurotransmission by THC. The current study evaluated, in rodents, the effects of chronic exposure to THC (1 mg/kg/day; 21 days) on D₂R and D₃R availabilities using the D₂R-prefering antagoni ...[more]

PMID: 22692568

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Project description:Mouse models of food allergy have contributed to our understanding of various aspects of the disease, including susceptibilities, symptom spectra, cellular mechanisms, and therapeutic approaches. Previously, we used a mouse model of non-anaphylactic cow's milk allergy (CMA) and investigated sex- and strain-dependent differences in immunological, neurological, and behavioral sequelae. We showed that male C57BL/6J mice sensitized to a bovine whey protein, β-lactoglobulin (BLG; Bos d 5), exhibited anxiety- and depression-like behavior upon acute allergen challenge. Systemic levels of BLG-specific immunoglobulins, cytokines and chemokines were also elevated in the sensitized mice. Furthermore, neuroinflammation and intestinal dysbiosis were evident as the possible causes of the altered behavior. To assess whether frequent allergen exposure influences CMA-associated pathologies over an extended period in this subclinical model, we placed BLG-sensitized mice on a whey protein (WP)-containing or whey-free control (CTL) diet for 3 months. As expected, allergen-specific IgE was significantly elevated in the plasma after completing the 5-week sensitization phase. However, the IgE levels declined in both diet groups after 3 months. In contrast, allergen-specific IgG1 stayed elevated in sensitized mice with the CTL diet, and the WP diet to a lesser extent. Interestingly, BLG-sensitized mice on the WP diet exhibited anxiety-like behavior and a trend toward spatial memory decline compared to the sham or the sensitized mice on the CTL diet. Moreover, increased immunoreactivities for GFAP and Iba1 and elevated levels of CXCL13 and CCL12, the chemokines involved in central leukocyte recruitment and other neurological diseases, were also observed in the brain. We demonstrated that sensitization to the whey protein, particularly with continuous allergen exposure, resulted in persistent neuroinflammation and associated behavioral changes despite lowered allergen-specific immunoglobulin levels. These results suggested that continuous consumption of the offending allergen may lead to adverse consequences in the brain even after desensitization.

Dataset Information

Chronic ??-tetrahydrocannabinol exposure induces a sensitization of dopamine D?/? receptors in the mesoaccumbens and nigrostriatal systems.

Publications

Chronic Δ⁹-tetrahydrocannabinol exposure induces a sensitization of dopamine D₂/₃ receptors in the mesoaccumbens and nigrostriatal systems.

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