Characteristics of abnormal behavior induced by delta 9-tetrahydrocannabinol in rats

delta 9-Tetrahydrocannabinol (THC), one of the active compounds of marihuana, is known to induce drug dependence and tolerance, and its action is weaker than those of other abused drugs in humans and animals. Acute effects of THC, "high", "irritable" and "cognitive deficits" are more important than the drug dependence and tolerance. For this reason, we examined characteristics of abnormal behavior such as catalepsy-like immobilization, aggressive behavior including irritable aggression and muricide, and spatial cognition impairment induced by acute and chronic treatments of THC in rats. The catalepsy-like immobilization is related to a decrease in catecholaminergic and serotonergic neurons in the nucleus accumbens and amygdaloid nucleus and thus serves as a useful model for amotivational syndrome, one of cannabis psychoses. In aggressive behavior, muricide was determined by the housing condition. Muricide was induced if the rat was placed under an isolated housing condition within the period of the effect of single injection of THC. The behavioral change resembles exacerbation and flashback in humans. Spatial cognition is impaired by the interaction between cannabinoid (CB1) and 5-HT2 receptor in the dorsal raphe-hippocampal serotonergic neurons. Thus the abnormal behavior induced by THC can be a useful model for investigating mental function in humans and new drugs for the treatment of mental disorders.     

Self-administration of delta 9-tetrahydrocannabinol by rats.

The present study examines the dose-response pattern of delta 9-tetrahydrocannabinol self-injection in naive rats at 80% reduced body weight and 100% body weight, both conditions with a fixed-time 1 min (FT-1) food delivery schedule. The results indicated that food deprived animals tested on a FT-1 min schedule self-injected low doses of delta 9-THC at a higher rate than those animals at 100% body weight and on a FT-1 min schedule. Animals at 80% reduced body weight without a schedule did not differ from rats self-injecting delta 9-THC at free feeding situation. These findings suggest that rats without previous history of drug dependence self-administer low doses of delta 9-THC and that the interaction between the food deprivation state and the environmental contingencies introduced by a FT-1 min schedule is a critical variable in the acquisition period.     

Noradrenergic involvement in catalepsy induced by delta 9-tetrahydrocannabinol

In order to elucidate the role of the catecholaminergic system in the cataleptogenic effect of delta 9-tetrahydrocannabinol (THC), the effect of pretreatment with 6-hydroxydopamine (6-OHDA) or with desipramine and 6-OHDA and lesions of the locus coeruleus were investigated in rats. The cataleptogenic effect of THC was significantly reduced in rats treated with 6-OHDA and in rats with lesions of the locus coeruleus but not in rats treated with desipramine and 6-OHDA, as compared with control rats. On the contrary, the cataleptogenic effect of haloperidol was significantly reduced in rats treated with desipramine and 6-OHDA but not in rats treated with 6-OHDA or in rats with lesions of the locus coeruleus. These results indicate that noradrenergic neurons have an important role in the manifestation of catalepsy induced by THC, whereas dopaminergic neurons are important in catalepsy induced by haloperidol.     

Irritable aggression induced by delta 9-tetrahydrocannabinol in rats pretreated with 6-hydroxydopamine

Administration of delta 9-tetrahydrocannabinol (THC) to grouped rats injected intraventricularly with 6-hydroxydopamine (6-OHDA) produced violent fighting accompanied by remarkable hyperirritability. This behavior was induced reproducibly from the 10th to 100th postoperative days. It was shown that this irritable aggression could be measured continuously and quantitatively in terms of degree of activity and/or vocalization using a newly designed analyzer. The effect of THC differed markedly from the action of apomorphine and methamphetamine in 6-OHDA pretreated rats. Apomorphine induced irritable aggression but not vigorous vocalization. On the other hand, methamphetamine induced much less irritable aggression than apomorphine-induced aggression. It is assumed that a THC-invoked imbalance in catecholamine agonistic and serotonin antagonistic action brought about by activation of supersensitized catecholaminergic receptor was operating to produce the aggression. Specifically, hypoactivity of serotonergic neurons might play a key role in the occurrence of THC-induced irritable aggression.     

Memory impairment following combined exposure to delta(9)-tetrahydrocannabinol and ethanol in rats

Cannabis derivatives and alcohol are widely co-abused, particularly among adolescents. Since both ethanol and cannabinoids are known to impair learning and memory, the present study investigated in rats the effects of combined exposure to ethanol and delta(9)-tetrahydrocannabinol (THC) in a memory task, the object recognition test. The results of the present study provide evidence that ethanol, voluntarily ingested in alcohol-preferring rats, and THC, given by intraperitoneal injection, have a synergic action to impair object recognition, when a 15-min interval was adopted between the sample phase and the choice phase of the test. Neither voluntary ethanol ingestion nor 2 or 5 mg/kg of THC were able per se to modify object recognition in these experimental conditions, but when voluntary ethanol ingestion was combined with administration of these doses of THC object recognition was markedly impaired. THC impaired object recognition only at the dose of 10 mg/kg, when its administration was not combined with that of ethanol. The selective cannabinoid CB(1) receptor antagonist SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1(2, 4-dichloro-phenyl)-4-methyl-1H-pyrazole carboxamide.HCl) at the dose of 1 mg/kg reversed the amnesic effect of THC, 10 mg/kg, suggesting that the effect is mediated by this receptor subtype. The synergism of ethanol and THC was not detected when an inter-trial interval of 1 min was adopted. The present findings are in keeping with the notion that Cannabis derivatives impair memory processes and provide evidence for a synergic action of THC and ethanol, thus emphasizing the risks consequent to their co-administration.     

D(2) dopamine receptors enable delta(9)-tetrahydrocannabinol induced memory impairment and reduction of hippocampal extracellular acetylcholine concentration

1. The systemic administration of Delta(9)-tetrahydrocannabinol (2.5 - 7.5 mg kg(-1)) reduced hippocampal extracellular acetylcholine concentration and impaired working memory in rats. 2. Both effects were antagonized not only by the CB(1) cannabinoid receptor antagonist SR141716A (0.5 mg kg(-1), i.p.) but also unexpectedly by the D(2) dopamine receptor antagonist S(-)-sulpiride (5, 10 and 25 mg kg(-1), i.p.). Conversely, Delta(9)-tetrahydrocannabinol-induced memory impairment and inhibition of hippocampal extracellular acetylcholine concentration were potentiated by the subcutaneous administration of the D(2) dopamine receptor agonist (-)-quinpirole (25 and 500 microg kg(-1)). The inhibition of hippocampal extracellular acetylcholine concentration and working memory produced by the combination of (-)-quinpirole and Delta(9)-tetrahydrocannabinol was suppressed by either SR141716A or S(-)-sulpiride. 3. Our findings suggest that impairment of working memory and inhibition of hippocampal extracellular acetylcholine concentration are mediated by the concomitant activation of D(2) dopamine and CB(1) cannabinoid receptors, and that D(2) dopamine receptor antagonists may be useful in the treatment of the cognitive deficits induced by marijuana.     

Antagonism by chlornaltrexamine of some effects of delta 9-tetrahydrocannabinol in rats

Chlornaltrexamine (beta-CNA) a selective, long-acting irreversible opiate antagonist inhibited the analgesia, hypothermia, hypothermia tolerance and physical dependence produced by delta 9-tetrahydrocannabinol (THC) in rats. The results suggest that there are some common features between cannabis and opiates and some actions of THC may be mediated by opioid related mechanisms in the central nervous system.     

Sex differences in the effects of delta9-tetrahydrocannabinol on spatial learning in adolescent and adult rats

Like other recreational drugs, cannabinoids may produce different effects in men and women. In this study we measured the effects of delta9-tetrahydrocannabinol (THC) on spatial learning in two groups that are underrepresented in drug research--females and adolescents. In the first experiment, adolescent (postnatal day 30) and adult (postnatal day 70) rats of both sexes were treated subchronically with 5.0 mg/kg THC or vehicle for five consecutive days. Thirty minutes after each daily injection, they were tested on the spatial version of the Morris water maze task. In the second experiment, a separate group of adolescent and adult rats of both sexes was treated with 5.0 mg/kg THC or vehicle daily for 21 days and tested, 4 weeks later, on the spatial version of the water maze. Subchronic THC impaired spatial learning, and this effect was dependent upon both the age and sex of the animals tested. Prior exposure to chronic THC, however, did not cause any long-lasting spatial learning deficits. On the basis of our previous studies in male rats the third experiment assessed the dose-response relationship for the effects of THC on spatial learning and memory in female animals. We found that subchronic THC treatment (2.5, 5.0, or 10.0 mg/kg, intraperitoneally) disrupted learning in both adolescents and adults, but with greater effects at higher doses in adolescents compared with adults. The developmental sensitivity to subchronic THC confirms previous work carried out in our laboratory, and the sex-dependent effects highlight the importance of including females in drug abuse and addiction research.     

尼莫地平对铝致大鼠学习记忆障碍的影响

观察了尼莫地平对铝引起的大鼠学习记忆障碍的影响. ip AlCl₃ 49.4 mg·kg^-1·d^-1,每3 d停1 d,连续60 d可引起大鼠自发活动减少,穿梭箱实验中主动回避反应能力下降. 若同时每天ig给予0.05 mg·kg^-1尼莫地平60 d,可显著改善铝引起的大鼠学习记忆和运动行为障碍,并可降低铝所致的脑细胞数减少程度. 本结果为尼莫地平用于预防与铝有关的神经退行性疾病的发生或减轻痴呆症状提供了动物实验依据.     

柚皮苷改善CCL2所致大鼠学习记忆障碍及其机制

目的探究柚皮苷改善CCL2诱导大鼠学习记忆障碍及其机制。方法56只SD大鼠随机分为空白组、假手术组、模型组(CCL2)、阳性药(CCL2+memantine)组、柚皮苷低(CCL2+25 mg·kg^-1柚皮苷)、中(CCL2+50 mg·kg^-1柚皮苷)、高(CCL2+100 mg·kg^-1柚皮苷)剂量组。除空白、假手术组外,各组均通过脑部定位将CCL2注射至大鼠海马制作学习记忆障碍模型。Morris水迷宫检测各组大鼠的学习和记忆水平;HE染色观察大鼠海马CA1区神经元形态;试剂盒检测海马SOD、GSH-PX活力和MDA含量;qRT-PCR检测凋亡基因caspase-3、caspase-8、Bax、Bcl-2 mRNA的相对表达。结果与模型组相比,各柚皮苷给药组大鼠逃避潜伏期及游泳路程均明显减少,平台穿越次数增加;海马CA1区神经元排列紧密且形态良好;SOD、GSH-PX活力升高,MDA含量降低;凋亡基因caspase-8、caspase-3、Bax mRNA相对表达量减少;Bcl-2表达量增加。结论柚皮苷能明显改善CCL2所致大鼠学习记忆功能障碍,其机制与柚皮苷的抗氧化和抗凋亡效应有关。     

Acquisition and extinction of variable interval schedule behavior by rats under delta9-tetrahydrocannabinol

Twenty eight rats were given 10 acquisition sessions under a variable interval 30 sec schedule of water reinforcement for lever-press responding. This training was followed by one extinction session in which no responses were reinforced. The rats were divided into 4 groups and were administered either 0, 0.5, 2.0 or 8.0 mg Δ⁹-THC per kg of body weight throughout both variable interval schedule acquisition and extinction. The presence of Δ⁹-THC during acquisition suppressed variable interval response rates and decreased the number of reinforcements obtained in a dose-related manner. Likewise, a dose dependent decrease in extinction responding was obtained as compared to nondrug control extinction responding.     

In vivo metabolism of the n-butyl-homologues of delta 9-tetrahydrocannabinol and delta 8-tetrahydrocannabinol by the mouse

1. n-Butyl-homologues of delta 8-tetrahydrocannabinol (delta 8-THC) and delta 9-THC were synthesized from 5-butyl-1,3-dihydroxybenzene and (1S)-cis-verbenol, and the delta 9-isomer was shown to have the same g.l.c.-mass spectral characteristics as the natural product. 2. Metabolism of these cannabinoids was studied in mice following i.p. injection. Metabolites were extracted from the livers, separated from endogenous lipids by chromatography on Sephadex LH-20 and examined by g.l.c.-mass spectrometry. 3. Thirteen metabolites were identified from both n-butyl-delta 8-THC and n-butyl-delta 9-THC. 4. Major metabolic routes were hydroxylations in the 2', 3', 8 and 11 positions and oxidation of the resulting 11-hydroxy-metabolites to carboxylic acids. 5. Metabolism was very similar to that of the pentyl homologues, the major constituents of cannabis, but with the production of a greater proportion of acidic metabolites at the expense of alcohols.     

The triple effect induced by delta 9-tetrahydrocannabinol on the rat blood pressure

The intravenous injection of delta 9-tetrahydrocannabinol (2-10 mg/kg) produced dose-related changes in the rat blood pressure. Three effects were detected: (1) an immediate and short-lasting hypotension related to bradycardia, blocked after atropine, vagotomy hexamethonium and pithing; (2) A rise in blood pressure 30 seconds after injection, insensitive to yohimbine, hexamethonium, pithing and reserpine treatment; (3) a slow and persistent hypotension, 5 min later, insensitive to atropine and vagotomy but inhibited by hexamethonium, pithing and reserpine treatment. It was concluded that intravenous injection of THC in rats may induce vagal stimulation and hypotension. This effect was reversed and followed by hypertension due to direct vasoconstriction not dependent on sympathetic activity. After this action a central decrease in sympathetic tonus led to a persistent hypotension an effect which is commonly reported for mammals.     

Assessment of tolerance to immunosuppressive activity of delta 9-tetrahydrocannabinol in rats

Immunosuppression evoked by delta 9-tetrahydrocannabinol (delta 9-THC) has been a consistent finding in rats but the development of tolerance to this phenomenon has not been explored. Therefore, Fischer rats of both sexes were orally given delta 9-THC at 6 or 12 mg/kg or sesame oil as vehicle control for 5-26 days before and after I.P. antigenic stimulation with sheep red blood cells (SRBC). delta 9-THC doses were relevant to those of man and produced mild CNS-inhibition followed by CNS-stimulation, tolerance developing to both behavioral phases. The primary immune response was evaluated by determining splenic antibody-forming cells (AFC), hemagglutinin (HT) and/or hemolysin (HS) titers. Simultaneous administration of delta 9-THC and SE induced dose-related splenic atrophy and reduced AFC proliferation as well as HT and HS responses. These changes were not elicited by sesame oil. Tolerance did not develop to immunosuppression during 26 days of cannabinoid treatment. delta 9-THC given 3 days post SRBC inoculation induced immunosuppression at 12 but not 6 mg/kg. Immunosuppression was directly related to delta 9-THC rather than to non-specific debilitating factors since body weights are stable. The inductive phase of the primary immune response was most sensitive to impairment although the reproductive phase was also affected at the high dose level.     

Behavioral and neurochemical effects of repeated administration of delta 9-tetrahydrocannabinol in rats

The effects of repeated administrations of Δ⁹-tetrahydrocannabinol (THC, 10 mg/kg i.p. twice daily at 8-hr interval) were investigated on spontaneous motor activity (SMA) in 2.5 hr daily sessions and on the levels of various neurotransmitters (e.g. norepinephrine, NE; dopamine, DA; serotonin, 5-HT) in different brain areas such as caudate nucleus (CN), pons-medulla (PM) and diencephalon-midbrain (DM) in rats. After a single dose of the drug, the SMA of rats decreased during the first hour postdrug along with a decrease of DA levels in the CN and DM and NE levels in the DM and PM, and increase of 5-HT levels in the DM and PM. Following repeated daily administration, the SMA gradually decreased during the first hour postdrug to a minimum on day 5, and then increased beyond the normal level on day 8 reaching its peak on day 10. The SMA then decreased again and remained close to the normal level on day 15 onwards. Concomitantly, DA and NE levels decreased to their minimum, and 5-HT levels increased to their maximum in the respective brain areas on day 5; the levels of neurotransmitters then gradually approached their normal up to day 15. Thus, during the first hour after repeated administration of THC, the changes in behavioral depression can be correlated to the changes in the brain neurotransmitter levels. During the second hour of THC action, SMA was enhanced. On its repeated administration, this increase was gradually reduced up to day 6 after which SMA was again increased to its peak between day 8 and day 10 and then decreased. These behavioral changes could also be correlated with the changes in DA and 5-HT levels in the brain areas during the second hour postdrug after repeated administration.     

Retardation of discrimination reversal by delta9-tetrahydrocannabinol in monkeys

Adult monkeys acquired a simultaneous 2-choice color discrimination after which they were given a series of ten successive discrimination reversals. Half of the monkeys received all of this discrimination training under the influence of a synthetic Δ⁹-trans-tetrahydrocannabinol (Δ⁹-THC), the major psychoactive constituent of marihuana, while the other monkeys served as nondrug controls. The drug states for the two groups were interchanged during the eleventh reversal. Although acquisition of the initial discrimination did not differ between the drug and control groups, subsequent discrimination reversals were markedly retarded for the drug group. Performance of the drug group on the initial reversals was characterized by perseveration to the previously reinforced stimulus. Introduction of the drug to the control group during the final reversal also produced an impairment of discrimination reversal performance.     

Specific inhibition of an acyltransferase by delta9-tetrahydrocannabinol

Increased phospholipid turnover in mouse lymphocytes during mitogen-induced blastogenesis can be prevented by low levels of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) invitro. Acyl CoA: lysophosphati-dylcholine acyltransferase, a lymphocyte plasma membrane enzyme, is inhibited by Δ⁹-THC with a K_i of 0.35 μM. Other cannabinoids with much lower psychoactivity inhibit the enzyme similarly only if present at more than 100 times the concentration needed for Δ⁹-THC inhibition. For cannabinoids other than Δ⁹-THC and for a variety of membrane-active lipids, the enzyme inhibition at higher concentrations of lipid correlates well with their anesthetic activity as measured by their ability to protect erythrocytes against hemolysis. However, the inhibition by Δ⁹-THC is much greater than that predicted by its anti-hemolytic activity, which indicates stereospecific requirements for inhibition of the enzyme. The inhibition of acyltransferase by Δ⁹-THC is not restricted to the lymphocyte enzyme and can also be demonstrated in mouse brain synaptosomes, suggesting a possible mechanism for psychoactive specificity.     

Permissive role of dopamine D(2) receptors in the hypothermia induced by delta(9)-tetrahydrocannabinol in rats

Cannabinoids produce analgesia, hypomotility, catalepsy, cognitive deficits and positive reinforcement. Moreover, Delta(9)-tetrahydrocannabinol (9-THC) and synthetic cannabinoids stimulate dopaminergic neurons and increase dopamine release in different brain areas. In order to clarify the role of endogenously released dopamine in the hypothermic response to cannabinoids, the effect of D(1) and D(2) dopamine receptor agonists and antagonists on Delta(9)-THC-induced hypothermia was studied in rats. Delta(9)-THC (2.5 and 5 mg/kg intraperitoneally [IP]) decreased body temperature in a dose-related manner. This effect was antagonized not only as expected by the CB(1) cannabinoid receptor antagonist SR 141716A (0.5 mg/kg, IP) but also, unexpectedly, by the dopaminergic D(2) receptor antagonists S(-)-sulpiride (5 and 10 mg/kg, IP) and S(-)-raclopride (1 and 3 mg/kg, IP). Conversely, the hypothermic effect of Delta(9)-tetrahydrocannabinol was potentiated by the D(2) dopamine receptor agonists (-)-quinpirole (0.025 and 0.500 mg/kg, SC) and (+)-bromocriptine (0.5 and 1 mg/kg, IP). In contrast, the Delta(9)-THC-induced hypothermic effect was not modified by either by the D(1) dopamine agonist SKF 38393 (10 mg/kg SC) or by the D(1) dopamine antagonist SCH 23390 (0.5 mg/kg SC). These results suggest that the D(2) dopamine receptors have a permissive role in the hypothermic action of cannabinoids.