THC-induced Catalepsy Research Articles

Role of vasopressin V1a receptor in ∆9-tetrahydrocannabinol-induced cataleptic immobilization in mice.

Cannabis is a widely used illicit substance. ∆9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, is known to cause catalepsy in rodents. Recent studies have shown that vasopressin V1a and V1b receptors are widely distributed in the central nervous system and are capable of influencing a wide variety of brain functions such as social behavior, emotionality, and learning and memory. The present study was designed to examine the possible involvement of V1a and V1b receptors in THC-induced catalepsy-like immobilization. The induction of catalepsy following treatment with THC (10mg/kg, i.p.) or haloperidol (1mg/kg, i.p.) was evaluated in wild-type (WT), V1a receptor knockout (V1aRKO), and V1b receptor knockout (V1bRKO) mice. The effect of treatment with the selective 5-hydroxytryptamine1A receptor antagonist WAY100635 (0.1mg/kg, i.p.) on THC-induced catalepsy was also evaluated in V1aRKO mice. Moreover, the effects of the V1a receptor antagonist VMAX-357 and the V1b receptor antagonist ORG-52186 on THC-induced catalepsy were evaluated in ddY mice. THC and haloperidol markedly caused catalepsy in V1bRKO mice as well as in WT mice. However, V1aRKO mice exhibited a reduction in catalepsy induced by THC but not by haloperidol. WAY100635 dramatically enhanced THC-induced catalepsy in V1aRKO mice. Although VMAX-357 (10mg/kg, p.o.) but not ORG-52186 significantly attenuated THC-induced catalepsy, it had no significant effect on the enhancement of THC-induced catalepsy by WAY100635 in ddY mice. These findings suggest that V1a receptor regulates THC-induced catalepsy-like immobilization.

Gonadal hormone modulation of ∆9-tetrahydrocannabinol-induced antinociception and metabolism in female versus male rats

The gonadal hormones testosterone (T) in adult males and estradiol (E2) in adult females have been reported to modulate behavioral effects of ∆9-tetrahydrocannabinol (THC). This study determined whether activational effects of T and E2 are sex-specific, and whether hormones modulate production of the active metabolite 11-hydroxy-THC (11-OH-THC) and the inactive metabolite 11-nor-9-carboxy-THC (THC-COOH). Adult male and female rats were gonadectomized (GDX) and treated with nothing (0), T (10-mm Silastic capsule/100g body weight), or E2 (1-mm Silastic capsule/rat). Three weeks later, saline or the cytochrome P450 inhibitor proadifen (25mg/kg; to block THC metabolism and boost THC's effects) was injected i.p.; 1h later, vehicle or THC (3mg/kg females, 5mg/kg males) was injected i.p., and rats were tested for antinociceptive and motoric effects 15–240min post-injection. T did not consistently alter THC-induced antinociception in males, but decreased it in females (tail withdrawal test). Conversely, T decreased THC-induced catalepsy in males, but had no effect in females. E2 did not alter THC-induced antinociception in females, but enhanced it in males. The discrepant effects of T and E2 on males' and females' behavioral responses to THC suggests that sexual differentiation of THC sensitivity is not simply due to activational effects of hormones, but also occurs via organizational hormone or sex chromosome effects. Analysis of serum showed that proadifen increased THC levels, E2 increased 11-OH-THC in GDX males, and T decreased 11-OH-THC (and to a lesser extent, THC) in GDX females. Thus, hormone modulation of THC's behavioral effects is caused in part by hormone modulation of THC oxidation to its active metabolite. However, the fact that hormone modulation of metabolism did not alter THC sensitivity similarly on all behavioral measures within each sex suggests that other mechanisms also play a role in gonadal hormone modulation of THC sensitivity in adult rats.

β-Arrestin2 Regulates Cannabinoid CB1 Receptor Signaling and Adaptation in a Central Nervous System Region–Dependent Manner

Cannabinoid CB(1) receptors (CB(1)Rs) mediate the effects of ▵(9)-tetrahydrocannabinol (THC), the psychoactive component in marijuana. Repeated THC administration produces tolerance and dependence, which limit therapeutic development. Moreover, THC produces motor and psychoactive side effects. β-arrestin2 mediates receptor desensitization, internalization, and signaling, but its role in these CB(1)R effects and receptor regulation is unclear. CB(1)R signaling and behaviors (antinociception, hypothermia, catalepsy) were assessed in β-arrestin2-knockout (βarr2-KO) and wild-type mice after THC administration. Cannabinoid-stimulated [(35)S]GTPγS and [(3)H]ligand autoradiography were assessed by statistical parametric mapping and region-of-interest analysis. β-arrestin2 deletion increased CB(1)R-mediated G-protein activity in subregions of the cortex but did not affect CB(1)R binding, in vehicle-treated mice. βarr2-KO mice exhibited enhanced acute THC-mediated antinociception and hypothermia, with no difference in catalepsy. After repeated THC administration, βarr2-KO mice showed reduced CB(1)R desensitization and/or downregulation in cerebellum, caudal periaqueductal gray, and spinal cord and attenuated tolerance to THC-mediated antinociception. In contrast, greater desensitization was found in hypothalamus, cortex, globus pallidus, and substantia nigra of βarr2-KO compared with wild-type mice. Enhanced tolerance to THC-induced catalepsy was observed in βarr2-KO mice. β-arrestin2 regulation of CB(1)R signaling following acute and repeated THC administration was region-specific, and results suggest that multiple, overlapping mechanisms regulate CB(1)Rs. The observations that βarr2-KO mice display enhanced antinociceptive responses to acute THC and decreased tolerance to the antinociceptive effects of the drug, yet enhanced tolerance to catalepsy, suggest that development of cannabinoid drugs that minimize CB(1)R interactions with β-arrestin2 might produce improved cannabinoid analgesics with reduced motor suppression.

Inhibition of the cataleptic effect of tetrahydrocannabinol by other constituents of Cannabis sativa L.

Tetrahydrocannabinol (THC) induced catalepsy in mice, whereas a cannabis oil (6.68% w/w THC), four cannabinoids and a synthetic mixture did not. Cannabinol (CBN) and olivetol inhibited THC-induced catalepsy in the mornings and the evenings, but cannabidiol (CBD) exhibited this effect only in the evenings. A combination of CBN and CBD inhibited THC-induced catalepsy equal to that of CBN alone in the mornings, but this inhibition was greater than that produced by CBN alone in the evenings.

Δ 9-Tetrahydrocannabinol-induced catalepsy-like immobilization is mediated by decreased 5-HT neurotransmission in the nucleus accumbens due to the action of glutamate-containing neurons

Δ 9-Tetrahydrocannabinol (THC) has been reported to induce catalepsy-like immobilization, but the mechanism underlying this effect remains unclear. In the present study, in order to fully understand the neural circuits involved, we determined the brain sites involved in the immobilization effect in rats. THC dose-dependently induced catalepsy-like immobilization. THC-induced catalepsy-like immobilization is mechanistically different from that induced by haloperidol (HPD), because unlike HPD-induced catalepsy, animals with THC-induced catalepsy became normal again following sound and air-puff stimuli. THC-induced catalepsy was reversed by SR141716, a selective cannabinoid CB 1 receptor antagonist. Moreover, THC-induced catalepsy was abolished by lesions in the nucleus accumbens (NAc) and central amygdala (ACE) regions. On the other hand, HPD-induced catalepsy was suppressed by lesions in the caudate putamen (CP), substantia nigra (SN), globus pallidus (GP), ACE and lateral hypothalamus (LH) regions. Bilateral microinjection of THC into the NAc region induced catalepsy-like immobilization. This THC-induced catalepsy was inhibited by serotonergic drugs such as 5-hydroxy-L-tryptophan (5-HTP), a 5-HT precursor, and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), a 5-HT receptor agonist, as well as by anti-glutamatergic drugs such as MK-801 and amantadine, an N-methyl- d-aspartate (NMDA) receptor antagonist. THC significantly decreased 5-HT and glutamate release in the NAc, as shown by in vivo microdialysis. SR141716 reversed and MK-801 inhibited this decrease in 5-HT and glutamate release. These findings suggest that the THC-induced catalepsy is mechanistically different from HPD-induced catalepsy and that the catalepsy-like immobilization induced by THC is mediated by decreased 5-HT neurotransmission in the nucleus accumbens due to the action of glutamate-containing neurons.

IL-1β and TNFα modulate δ9-tetrahydrocannabinol-induced catalepsy in mice

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.

Effect of dizocilpine (MK-801) on the catalepsy induced by delta 9-tetrahydrocannabinol in mice.

Mice treated with delta 9-tetrahydrocannabinol (THC; 5 and 10 mg/kg i.v.) showed the catalepsy in high bar test, and median descent latencies of catalepsy were about 150 sec. Dizocilpine (MK-801, 0.05 and 0.1 mg/kg), non-competitive N-methyl-D-aspartate (NMDA) antagonist, significantly attenuated THC-induced catalepsy. Furthermore, the anticataleptic effect of MK-801 on THC-induced catalepsy was blocked by acetylcholine agonist oxotremorine (0.005 mg/kg) and dopamine antagonist haloperidol (0.01 mg/kg), but not by NMDA. Oxotremorine, haloperidol, and NMDA themselves did not affect THC-induced catalepsy at the doses used. These results suggest that the anticataleptic effect of MK-801 on THC-induced catalepsy may be developed through dopaminergic and acetylcholinergic neuronal systems.

Competitive NMDA antagonists enhance the catalepsy induced by delta 9-tetrahydrocannabinol in mice.

Competitive N-methyl-D-aspartate (NMDA) receptor antagonists, such as CPP and AP-7, dose-dependently enhanced the catalepsy induced by delta 9-tetrahydrocannabinol (THC; 5 mg/kg) in mice, but CPP failed to enhance haloperidol-induced catalepsy. The enhancing effect of CPP on THC-induced catalepsy was dose-dependently blocked by a muscarinic receptor antagonist, scopolamine, and by dopamine D1 and D2 receptor agonists such as apomorphine, SKF 38393 and quinpirole. The effect of CPP was quite opposite to that of the noncompetitive NMDA receptor antagonist MK-801. Therefore, the THC-induced catalepsy model may be useful for distinguishing between both classes of NMDA receptor antagonists.

An investigation of the involvement of GABA in certain pharmacological effects of delta-9-tetrahydrocannabinol

Experiments were performed with mice to determine whether doses of the benzodiazepine, flurazepam, or the GABA uptake inhibitor, NO-328, known to potentiate catalepsy induced by delta-9-tetrahydrocannabinol (THC), would also interact synergistically with THC in the production of certain other effects. No synergism was detected either in the production of antinociception (tail flick test) or in a test in which the ability of flurazepam to delay onset of clonic convulsions induced by intravenous infusion of pentylenetetrazole was compared in the presence and absence of THC or cannabidiol. The hypothermic effect of THC was unaffected by NO-328 but enhanced by flurazepam, albeit only at doses higher than those needed to potentiate THC-induced catalepsy. In vitro experiments with guinea pig ileum showed that the ability of THC to inhibit electrically evoked contractions was unaffected by delta-amino-n-valeric acid, a GABA B receptor antagonist, and that preparations rendered tolerant to GABA responded normally to THC. Contractions induced by GABA in unstimulated ileal longitudinal muscle were attenuated by THC. We conclude that there is little evidence from our data that any of the THC effects studied were GABA mediated.

選択的セロトニン取り込み阻害作用を有する新しい抗うつ薬Ｐａｒｏｘｅｔｉｎｅの行動薬理学的研究

The behavioral effects of paroxetine were investigated in mice and rats in comparison with imipramine and amitriptyline. 1) Locomotor activities were decreased by imipramine and amitriptyline but not by paroxetine in both animal species. 2) Paroxetine antagonized methamphetamine-induced hyperactivity in mice as did imipramine and amitriptyline. 3) Paroxetine showed a more potent antimuricidal effect in raphe-lesioned rats than imipramine and amitriptyline, and it also inhibited muricide in olfactory bulbectomized rats. 4) The immobility of rats in the forced swimming test was markedly decreased by imipramine and amitriptyline, but only slightly by paroxetine. 5) Like imipramine and amitriptyline, paroxetine potentiated the methamphetamine- or L-DOPA-induced stereotyped sniffing, and it inhibited oxotremorine-induced tremor. 6) Paroxetine antagonized reserpine-induced hypothermia, tetrabenazine-induced ptosis, and enhanced ether-induced anesthesia, all less potently than imipramine and amitriptyline. 7) The analgesic action of paroxetine was stronger than that of imipramine and amitriptyline. 8) Paroxetine did not antagonize maximal electroshock- or pentetrazol-induced convulsions and haloperidol- or THC-induced catalepsy in rats. In addition, paroxetine neither exerted muscle relaxation nor affected the shuttle-box type conditioned avoidance in rats. From these results, the behavioral effects of paroxetine, as compared with imipramine and amitriptyline, were characterized by its potent antimuricidal action in raphe-lesioned rats and its weak effect in the forced swimming test and by its less potent muscle relaxant, anticonvulsant, anticataleptic and anesthesia-potentiating actions.

A major metabolite of delta 1-tetrahydrocannabinol reduces its cataleptic effect in mice.

The results described here demonstrate that THC-induced catalepsy in mice can be substantially inhibited by the prior administration of delta 1-THC-7-oic acid, the major metabolite of THC in most species including humans. This raises the possibility that the intensity and duration of action of THC may depend to a large degree on the levels of this metabolite at the sites of action.