Impaired learning in adulthood following neonatal Δ9-THC exposure

Cannabis is one of the most commonly used illicit drugs during pregnancy, but little is known about the lasting effects of early-life exposure to this drug. In this study, male Wistar rat pups were treated daily with (-)-Δ9-tetrahydrocannabinol (THC; 5 mg/kg, s.c.) or its vehicle between postnatal days (PND) 4 and 14. Drug administration during this early postnatal period in rats is analogous to the third trimester of gestation in humans, which is a major period of synaptogenesis. Rats were subsequently tested drug-free during young adulthood (PND 56) using a two-component food-motivated double Y-maze test. Each trial included distinct spatial discrimination and delayed alternation components, which permitted the simultaneous assessment of reference memory and working memory. Rats were tested for 30 trials/day, 5 days/week for 5 weeks. Results revealed no significant differences between THC- and vehicle-treated rats in the spatial discrimination task. However, compared to vehicle-treated rats, THC-treated rats committed significantly more errors, and required significantly longer to obtain 80% correct over two consecutive days in the delayed alternation task. Results suggest that neonatal THC exposure leads to a specific and lasting deficit in learning in adulthood, which is likely due to impaired working memory function

Suppression of feeding, drinking, and locomotion by a putative cannabinoid receptor 'silent antagonist'

This study compared the effects of the putative cannabinoid receptor 'silent antagonist' O-2050 with the cannabinoid receptor inverse agonist SR 141716 on food and water consumption, and locomotor activity. Non-deprived male Wistar rats were habituated to the apparatus and testing procedures, then injected intraperitoneally with vehicle, O-2050 (0.03-3.0 mg/kg), or SR 141716 (3.0 mg/kg) prior to 4-h test sessions. Food consumption was significantly reduced by both drugs. Water intake and locomotor activity were significantly reduced only by O-2050. Results support the notion that cannabinoid receptor antagonists suppress feeding behaviour by blocking an endogenous cannabinoid orexigenic signal, rather than by inverse agonism at cannabinoid receptors. However, further studies are needed to confirm the status of O-2050 as a cannabinoid CB₁ receptor antagonist devoid of inverse agonist properties

Repeated cannabinoid exposure during perinatal, adolescent or early adult ages produces similar long-lasting deficits in object recognition and reduced social interaction in rats

There is mounting evidence that chronic cannabis use might result in lasting neurobehavioural changes, although it remains unclear whether vulnerability diminishes with age. The current study compared the effects of cannabinoid exposure at three developmental periods on subsequent measures of memory and anxiety. Male rats aged 4 days (perinatal), 30 days (adolescent) and 56 days (young adult) were injected with vehicle or incremental doses of the cannabinoid receptor agonist CP 55940, daily for 21 consecutive days (0.15, 0.20 or 0.30mg/kg for 7 days per dose, respectively). Following a 28-day drug-free period, working memory was assessed in an object recognition task. One week later, social anxiety was assessed in a social interaction test. Two days later, generalized anxiety was assessed in an emergence test. Results revealed that CP 55940 impaired working memory and social interaction similarly at all three ages. CP 55940 had no effects in five of six emergence test measures, but a modest but significant reduction in anxiety was noted in one measure following adolescent exposure. We conclude that chronic cannabinoid exposure leads to long-term memory impairments and increased anxiety, irrespective of the age at which drug exposure occurs

Co-administration of THC and MDMA ('Ecstasy') Synergistically Disrupts Memory in Rats

3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy') and cannabis are two of the most commonly used illicit drugs in the western world, and are often used in combination. Very little research has examined their effect on cognitive function or behavior when combined. The present study used a double Y-maze task to examine the acute effect of MDMA and Δ9-tetrahydrocannabinol (THC, the principal psychoactive ingredient of cannabis) on mnemonic function in rats, at a range of doses representative of common human use. Experiment 1 (low doses) examined the effect of 0.25 mg/kg THC and 1.25 mg/kg MDMA alone and together. At these doses MDMA or THC given alone had no effect on working memory, but the co-administered drugs significantly disrupted working memory. Experiment 2 (medium doses) examined the effect of 0.5 mg/kg THC and 2.5 mg/kg MDMA given alone or together. At these doses THC, but not MDMA, impaired working memory. Although MDMA alone had no effect, it exacerbated the impairment due to THC when the drugs were co-administered. Experiment 3 (high doses) examined the effects of 1 mg/kg THC and 5 mg/kg MDMA alone and together. Both drugs significantly impaired memory when given alone, although the impairment due to MDMA was less than that caused by THC. When co-administered at these doses, the drugs caused a major disruption of behavior and this precluded ascribing a mnemonic cause to poor performance on the double Y-maze task. Taken together, these experiments demonstrate a synergistic disruption of working memory by acute co-administration of THC and MDMA

Δ9-THC reinstates beer- and sucrose-seeking behaviour in abstinent rats: comparison with midazolam, food deprivation and predator odour

Aims: Recent studies suggest that cannabinoid receptor agonists may promote relapse to drug-seeking behaviour after a period of abstinence. In this study, the ability of Δ9-tetrahydrocannabinol (THC) to reinstate previously reinforced responding for alcoholic and non-alcoholic beverages was assessed in rats using a novel lick-based paradigm. Methods: Rats were initially given free access to beer (containing 4.5% ethanol v/v), near-beer (a beverage that looks and tastes like beer but contain

Pre-exposure to the cannabinoid receptor agonist CP 55,940 enhances morphine behavioral sensitization and alters morphine self-administration in Lewis rats

Three experiments examined the influence of pre-exposure to the cannabinoid receptor agonist CP 55940 ((-)-cis-3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-trans-4-(3-hydroxypropyl)cyclohexanol) on the sensitization of morphine-induced locomotor hyperactivity and self-administration in Lewis rats. In Experiment 1, rats received daily injections of vehicle or CP 55940 (0.1 mg/kg for 7 days then 0.2 mg/kg for a further 7 days). Four weeks later, the locomotor response to morphine (10 mg/kg s.c.) was tested once per day over a 3-h period for 14 consecutive days. Rats given morphine showed hypoactivity during the first hour following morphine but hyperactivity during the second and third hours. A progressive increase in hyperactivity to morphine was seen over the 14 days of administration, which was significantly greater in rats pre-treated with CP 55940. In Experiment 2, rats were given morphine (10 mg/kg) once a day for 14 days in combination with either vehicle, CP 55940 (0.1 mg/kg) or the cannabinoid CB(1) receptor antagonist SR 141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride) (3 mg/kg). Both CP 55940 and SR 141716 initially inhibited the hyperactive response to morphine, but these effects gradually wore off and by the end of 14 days, hyperactivity was similar in all morphine-treated groups. When tested 3 weeks later for their response to morphine (10 mg/kg) given alone, rats previously given the morphine/CP 55940 combination, but not the SR 141716/morphine combination, showed a greater locomotor stimulation than those previously exposed to morphine only. In Experiment 3, rats were pre-exposed to CP 55940 or vehicle for 14 days and were subsequently trained to self-administer morphine intravenously (1 mg/kg per lever press) for 14 days. Rats pre-exposed to CP 55940 self-administered a significantly greater number of morphine infusions than vehicle pre-exposed rats. However, both active and inactive ('dummy') lever presses were increased by cannabinoid pre-treatment. Overall, these results suggest that cannabinoid pre-exposure can lead to an exaggeration of morphine-induced hyperactivity and may alter the reinforcing effects of morphine in Lewis rats. The implications for 'gateway' theories of cannabinoid effects in humans are discussed

Paraventricular hypothalamic CB₁ cannabinoid receptors are involved in the feeding stimulatory effects of Δ⁹-tetrahydrocannabinol

Background/Aims: The paraventricular nucleus of the hypothalamus (PVN) is the target of converging orexigenic and anorexigenic pathways originating from various hypothalamic sites and is, therefore, considered to be the chief site mediating hypothalamic regulation of energy homeostasis. Although a large body of evidence suggests that central CB₁ cannabinoid receptors mediate food intake, it is not clear whether PVN CB₁ receptors are involved in the control of feeding behaviour. The present study therefore examined the effects of intra-PVN administration of Δ⁹-tetrahydrocannabinol (THC) and the cannabinoid receptor antagonist SR 141716 on feeding. Methods: After being habituated to the test environment and injection procedure, sated rats were injected with SR 141716 (0.03-3.0 μg, Experiment 1) alone or in combination with THC (5.0μg, Experiment 2) into the PVN. Food intake and locomotor activity then were recorded for 120 min. Results: Intra-PVN administration of THC produced a significant increases in food intake that was attenuated by SR 141716. Administration of SR 141716 alone did not affect feeding. Locomotor activity was not significantly affected by any drug treatments, suggesting that effects on feeding were not due to a non-specific reduction in motivated behaviour. These findings suggest an important role for PVN cannabinoid signalling in mediating THC-induced feeding behaviour. These results also demonstrate that the blockade of PVN CB₁ receptors alone is insufficient to reduce baseline feeding behaviour under these conditions

Perinatal Exposure to Δ9-Tetrahydrocannabinol Alters Heroin-Induced Place Conditioning and Fos-Immunoreactivity

In the present study, the effects of perinatal exposure to Δ9-tetrahydrocannabinol (THC) on heroin-induced place conditioning and Fos-immunoreactivity (Fos-IR) were examined. Male albino Wistar rats (N=104) were pretreated with vehicle (n=52) or 5 mg/kg THC (n=52) from postnatal days 4 through 14. At approximately 8 weeks of age, 72 rats were divided into six equal groups (n=12 per group) and injected subcutaneously (s.c.) with vehicle, 0.5, or 2.0 mg/kg heroin and tested in an unbiased two-compartment place conditioning task. In vehicle-pretreated rats, 2.0 mg/kg but not 0.5 mg/kg heroin produced a significant place preference. Perinatal THC exposure significantly enhanced the rewarding properties of both doses of heroin. In the second experiment, 32 rats were divided into four equal groups (n=8 per group) and injected with vehicle or 0.5 mg/kg heroin s.c. and perfused 2-h later. Fos-IR was examined in several brain regions directly or indirectly involved in reward. Acute administration of heroin in vehicle pretreated rats increased Fos-IR in the central, medial, and dorsomedial caudate putamen (CPu), nucleus accumbens (NAC, core and shell regions), lateral septum, islands of Calleja-major (ICjM), bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CEA), dorsolateral and dorsomedial periaqueductal gray (PAG), ventral tegmental area (VTA), Edinger-Westphal nucleus (EW). Perinatal THC exposure significantly increased heroin-induced Fos-IR in the dorsomedial CPu. Conversely, perinatal THC exposure reduced heroin-induced Fos-IR in the NAC (shell), BNST, CEA, dorsolateral and lateral PAG, VTA, and EW. The present study demonstrates an increase in the rewarding properties of heroin following exposure to THC at an early age and provides new evidence regarding possible neural correlates underlying this behavioral alteration

Repeated exposure to Δ⁹: tetrahydrocannabinol alters heroin-induced locomotor sensitisation and Fos-immunoreactivity

The present study examined the effect of chronic exposure to Δ⁹-tetrahydrocannabinol (THC) on heroin-induced locomotor sensitisation and Fos-immunoreactivity (Fos-IR). Adult male albino Wistar rats (n = 60) were injected intraperitoneally (i.p.) 21 times with vehicle, 0.05, 0.5, or 5.0 mg/kg THC (once every 48 h for 41 days). Locomotor activity was assessed for 180 min on pre-exposure days 1, 21, and 41. Following a 2-week washout period, rats were divided into five equal groups (n = 12) and injected subcutaneously (s.c.) with vehicle or heroin (0.5 mg/kg). Locomotor activity was recorded for 240 min. In drug-naïve rats, heroin significantly increased locomotor activity. THC pre-exposure further increased heroin-induced locomotion. After an interval of 2 weeks, rats pre-exposed to vehicle and 5.0 mg/kg THC in the first part of the experiment were randomly assigned to one of four treatment groups (n = 6) and injected s.c. with vehicle or 0.5 mg/kg heroin and perfused 2 h later. Fos-IR was examined in several brain regions. Acute heroin increased Fos-IR in drug-naive rats in the caudate-putamen (CPu; central, medial and dorsomedial regions), nucleus accumbens (NAC; core and shell regions), bed nucleus of the stria terminalis (BNST), lateral septum, central nucleus of the amygdala (CEA), periaqueductal grey (PAG; dorsolateral, dorsomedial, and lateral), and the Edinger–Westphal nucleus. Pre-exposure to THC significantly increased heroin-induced Fos-IR in the dorsomedial CPu and the NAC (core). Conversely, THC pre-exposure reduced heroin-induced Fos-IR in the BNST, CEA, and the PAG (dorsolateral and lateral). The present study demonstrates that THC pre-exposure increases the locomotor stimulating effects of heroin and provides new evidence for the neural correlates that may underlie cannabinoid and opioid cross-sensitisation

Consumption of high carbohydrate, high fat, and normal chow is equally suppressed by a cannabinoid receptor antagonist in non-deprived rats

Administration of the CB₁ receptor antagonist SR 141716 [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] suppresses intake of highly palatable (high carbohydrate) food. However, the effects of SR 141716 on intake of foods with varying macronutrient compositions, and in non-deprived animals have not been well studied. In the present study, non-deprived rats were injected intraperitoneally with SR 141716 (0.03-3.0 mg/kg) and presented with a high carbohydrate, high fat, or normal chow diet. Food intake and locomotor activity were recorded for 120 min. Results showed that SR 141716 significantly suppressed food intake irrespective of the composition of the test food without affecting locomotor activity. These data suggest that food deprivation or high palatability of the ingesta are not necessary to observe the suppressive effects of SR 141716 on food intake