Drugs which stimulate or facilitate central cholinergic transmission interact synergistically with delta-9-tetrahydrocannabinol to produce marked catalepsy in mice

doi:10.1016/0028-3908(91)90044-C

Neuropharmacology

Volume 30, Issue 1, January 1991, Pages 67-71

https://doi.org/10.1016/0028-3908(91)90044-C Get rights and content

Abstract

In experiments in which mice were placed with their forepaws over a 4 cm high horizontal bar, delta-9-tetrahydrocannabinol (THC; 10 mg/kg i.p.) delayed descent from the bar. This effect on descent latency was markedly enhanced by physostigmine (0.05 or 0.25 mg/kg s.c.) and oxotremorine (0.04 or 0.08 mg/kg s.c.), administered immediately before THC. These interactions were attenuated by atropine (2.0 mg/kg s.c.) and (−)-scopolamine (1.9 mg/kg s.c.) but not by atropine methyl nitrate (2.11 mg/kg s.c.), which does not readily cross the blood-brain barrier. However, atropine methyl nitrate did prevent salivation induced by oxotremorine in the presence of THC. No synergism was detected between THC and neostigmine (0.047 mg/kg s.c.). Atropine and (−)-scopolamine also decreased the ability of chlordiazepoxide (10 mg/kg s.c.) to enhance the effect of THC on descent latency. The interaction was not antagonized by atropine methyl nitrate or mecamylamine (1.17 or 2.34 mg/kg s.c.). These results point to an involvement of central acetylcholine-releasing pathways in the cataleptic response of mice to THC.

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This study employed the same elevated plus maze testing procedure described above. Directly after elevated plus maze testing, all rats were tested for catalepsy using the bar test [52,53]. Forepaws were placed on a stainless steel bar (suspended 9 cm above a flat platform) when hindpaws remained in contact with a table, as described previously [54].
Dysregulation in signaling of the endocannabinoid 2-arachidonoylglycerol (2-AG) is implicated in hyperresponsiveness to stress. We hypothesized that blockade of monoacylglycerol lipase (MGL), the primary enzyme responsible for 2-AG deactivation in vivo, would produce context-dependent anxiolytic effects in rats. Environmental aversiveness was manipulated by varying illumination of an elevated plus maze. Percentage open arm time and numbers of open and closed arm entries were measured in rats receiving a single intraperitoneal (i.p.) injection of either vehicle, the MGL inhibitor JZL184 (1–8 mg/kg), the benzodiazepine diazepam (1 mg/kg), the cannabinoid CB₁ receptor antagonist rimonabant (1 mg/kg), or JZL184 (8 mg/kg) coadministered with rimonabant (1 mg/kg). JZL184 (8 mg/kg) produced anxiolytic-like effects (i.e., increased percentage open arm time and number of open arm entries) under high, but not low, levels of environmental aversiveness. Diazepam produced anxiolytic effects in either context. Rimonabant blocked the anxiolytic-like effects of JZL184, consistent with mediation by CB₁. Anxiolytic effects of JZL184 were preserved following chronic (8 mg/kg per day × 6 days) administration. Chronic and acute JZL184 treatment similarly enhanced behavioral sensitivity to an exogenous cannabinoid (WIN55,212-2; 2.5 mg/kg i.p.) 24 or 72 h following the terminal injection, suggesting a pervasive effect of MGL inhibition on the endocannabinoid system. We attribute our results to alterations in emotion rather than locomotor activity as JZL184 did not alter the number of closed arm entries in the plus maze or produce motor ataxia in the bar test. Our results demonstrate that JZL184 has beneficial, context-dependent effects on anxiety in rats, presumably via inhibition of MGL-mediated hydrolysis of 2-AG. These data warrant further testing of MGL inhibitors to elucidate the functional role of 2-AG in controlling anxiety and stress responsiveness. Our data further implicate a role for 2-AG in the regulation of emotion and validate MGL as a therapeutic target.
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Effects of AV3V lesion on pilocarpine-induced pressor response and salivary gland vasodilation
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In the present study, the effects of the pre-treatment with the cholinergic muscarinic receptor antagonist atropine methyl bromide injected iv in sham and AV3V-lesioned rats were used to distinguish between central and peripheral actions of pilocarpine ip. Quaternary ammonium compounds, such as atropine methyl bromide, are known to diffuse only poorly through the blood–brain barrier [12,27,30], and the action of a low dose of atropine methyl bromide injected iv is probably restricted to the periphery. Atropine methyl bromide iv blocking the peripheral muscarinic receptors abolished the hypotension to ip pilocarpine in AV3V-lesioned rats, while the pressor response to pilocarpine in sham rats that depends on central muscarinic receptor activation was not affected suggesting that different mechanisms are involved in cardiovascular responses to ip pilocarpine in sham and AV3V-lesioned rats.
The cholinergic agonist pilocarpine injected intraperitoneally (ip) increases mean arterial pressure (MAP) and superior mesenteric (SM) vascular resistance and reduces submandibular/sublingual gland (SSG) vascular resistance. In the present study, we investigated the effects of electrolytic lesions of the anteroventral third ventricle (AV3V) region on the changes in MAP, SM, and SSG vascular resistances induced by ip pilocarpine. Male Holtzman rats anesthetized with urethane (1.0 g/kg) and chloralose (60 mg/kg) were submitted to sham or electrolytic AV3V lesions and had pulsed Doppler flow probes implanted around the arteries. Contrary to sham rats, in 1-h and 2-day AV3V-lesioned rats, pilocarpine (4 μmol/kg) ip decreased MAP (−41 ± 4 and −26 ± 4 mm Hg, respectively, vs. sham: 19 ± 4 mm Hg) and SM (−48 ± 11 and −45 ± 10%, respectively, vs. sham: 41 ± 10%) and hindlimb vascular resistances (−65 ± 32 and −113 ± 29%, respectively, vs. sham: 19 ± 29%). In 7-day AV3V-lesioned rats, pilocarpine produced no changes on MAP and SM and hindlimb vascular resistances. Similar to sham rats, pilocarpine reduced SSG vascular resistance 1 h after AV3V lesions (−46 ± 6%, vs. sham: −40 ± 6%), but it produced no effect 2 days after AV3V lesions and increased SSG vascular resistance (37 ± 6%) in 7-day AV3V-lesioned rats. The responses to ip pilocarpine were similar in 15-day sham and AV3V-lesioned rats. The cholinergic antagonist atropine methyl bromide (10 nmol) iv slightly increased the pressor response to ip pilocarpine in sham rats and abolished for 40 min the fall in MAP induced by ip pilocarpine in 1-h AV3V-lesioned rats. The results suggest that central mechanisms dependent on the AV3V region are involved in the pressor responses to ip pilocarpine. Although it was impaired 2 and 7 days after AV3V lesions, pilocarpine-induced salivary gland vasodilation was not altered 1 h after AV3V lesions which suggests that this vasodilation is not directly dependent on the AV3V region.
The effects of cannabinoids on the brain
1999, Progress in Neurobiology
Cannabinoids have a long history of consumption for recreational and medical reasons. The primary active constituent of the hemp plant Cannabis sativa is Δ⁹-tetrahydrocannabinol (Δ⁹-THC).
In humans, psychoactive cannabinoids produce euphoria, enhancement of sensory perception, tachycardia, antinociception, difficulties in concentration and impairment of memory. The cognitive deficiencies seem to persist after withdrawal. The toxicity of marijuana has been underestimated for a long time, since recent findings revealed Δ⁹-THC-induced cell death with shrinkage of neurons and DNA fragmentation in the hippocampus.
The acute effects of cannabinoids as well as the development of tolerance are mediated by G protein-coupled cannabinoid receptors. The CB1 receptor and its splice variant CB1A, are found predominantly in the brain with highest densitities in the hippocampus, cerebellum and striatum.
The CB2 receptor is found predominantly in the spleen and in haemopoietic cells and has only 44% overall nucleotide sequence identity with the CB1 receptor. The existence of this receptor provided the molecular basis for the immunosuppressive actions of marijuana. The CB1 receptor mediates inhibition of adenylate cyclase, inhibition of N- and P/Q-type calcium channels, stimulation of potassium channels, and activation of mitogen-activated protein kinase. The CB2 receptor mediates inhibition of adenylate cyclase and activation of mitogen-activated protein kinase.
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The psychoactive cannabinoids increase the activity of dopaminergic neurons in the ventral tegmental area-mesolimbic pathway. Since these dopaminergic circuits are known to play a pivotal role in mediating the reinforcing (rewarding) effects of the most drugs of abuse, the enhanced dopaminergic drive elicited by the cannabinoids is thought to underlie the reinforcing and abuse properties of marijuana.
Thus, cannabinoids share a final common neuronal action with other major drugs of abuse such as morphine, ethanol and nicotine in producing facilitation of the mesolimibic dopamine system.
Neurobehavioral effects of Δ<sup>9</sup>-THC and cannabinoid (CB1) receptor gene expression in mice
1995, Behavioural Brain Research
The differential sensitivity following the administration of Δ⁹-THC to 3 mouse strains, C57BL/6, DBA/2 and ICR mice, indicated that some of the neurobehavioral changes may be attributable to genetic differences. The objective of this study was to determine the extent to which the cannabinoid (CB1) receptor is involved in the observed behavioral changes following Δ⁹-THC administration. This objective was addressed by experiments using: (1) DNA-PCR and reverse PCR; (2) systemic administration of Δ⁹-THC, and; (3) intracerebral microinjection of Δ⁹-THC. The site specificity of action of Δ⁹-THC in the brain was determined using stereotaxic surgical approaches. The intracerebral microinjection of Δ⁹-THC into the nucleus accumbens was found to induce catalepsy, while injection of Δ⁹-THC into the central nucleus of amygdala resulted in the production of an anxiogenic-like response. Although the DNA-PCR data indicated that the CB1 gene appeared to be identical and intronless in all 3 mouse strains, the reverse PCR data showed two additional distinct CB1 mRNAs in the C57BL/6 mouse which also differed in pain sensitivity and rectal temperature changes following the administration of Δ⁹-THC. It is suggested that the diverse neurobehavioral alterations induced by Δ⁹-THC may not be mediated solely by the CB1 receptors in the brain and that the CB1 genes may not be uniform in the mouse strains.
IL-1β and TNFα modulate δ<sup>9</sup>-tetrahydrocannabinol-induced catalepsy in mice
1995, Pharmacology, Biochemistry and Behavior
The role of the proinflammatory cytokines interleukin-lα (IL-lα), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα) in THC-induced catalepsy in mice was examined. Recombinant IL-1β (400 ng/mouse, IV) and TNFα (500 ng/mouse, IV) were effective in potentiating the cataleptic effect of low-dose THC (10 μg/mouse, IV). Recombinant IL-1α and IL-6 did not potentiate catalepsy at any dose tested. Anti-IL-1β and anti-TNFα antibodies were effective in attenuating high-dose (75 μg/ mouse) THC-induced catalepsy. Antibodies to IL-1α and IL-6 had no effect on catalepsy. Early onset catalepsy (10 min postinjection) was potentiated by exogenous recombinant IL-1β and TNFα but only later catalepsy (2 h postinjection) was attenuated by antibodies to endogenous IL-1β or TNFα. This divergence of the cytokine effect suggests that these substances regulate, by different mechanisms, the early and late THC-induced cataleptic response.

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Drugs which stimulate or facilitate central cholinergic transmission interact synergistically with delta-9-tetrahydrocannabinol to produce marked catalepsy in mice

Abstract

Neuropharmacology

Neuropharmacology

Neuropharmacology

Neuropharmacology

Int. J. Neuropharmac.

Neuropharmacology

Cannabis-induced neurotoxicity in mice: effect on cholinergic (muscarinic) receptors and blood brain barrier permeability

Res. Commun. Subst. Abuse