3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol and Marijuana-Abuse

In many species, adolescence is a critical phase in which the endocannabinoid system can regulate the maturation of important neuronal networks that underlie cognitive function. Therefore, adolescents may be more susceptible to the neural consequences of chronic cannabis abuse. We reported previously that chronically exposing adolescent rats to the synthetic cannabinoid agonist CP55,940 leads to impaired performances in adulthood i.e. long-lasting deficits in both visual and spatial short-term working memories. Here, we examined the synaptic structure and function in the prefrontal cortex (PFC) of adult rats that were chronically treated with CP55,940 during adolescence. We found that chronic cannabinoid exposure during adolescence induces long-lasting changes, including (1) significantly altered dendritic arborization of pyramidal neurons in layer II/III in the medial PFC (2) impaired hippocampal input-induced synaptic plasticity in the PFC and (3) significant changes in the expression of PSD95 (but not synaptophysin or VGLUT3) in the medial PFC. These changes in synaptic structure and function in the PFC provide key insight into the structural, functional and molecular underpinnings of long-term cognitive deficits induced by adolescent cannabinoid exposure. They suggest that cannabinoids may impede the structural maturation of neuronal circuits in the PFC, thus leading to impaired cognitive function in adulthood.

Topics: Animals; Blotting, Western; Cannabinoids; Chronic Disease; Cyclohexanols; Dendrites; Disease Models, Animal; Disks Large Homolog 4 Protein; Hippocampus; Intracellular Signaling Peptides and Proteins; Long-Term Potentiation; Male; Marijuana Abuse; Membrane Proteins; Microelectrodes; Prefrontal Cortex; Pyramidal Cells; Rats, Wistar; Synaptophysin; Vesicular Glutamate Transport Proteins

This study examined the actions of pregabalin and topiramate on behavioural and gene transcription alterations induced by spontaneous cannabinoid withdrawal in mice. Tolerance was induced in mice by administration of CP-55,940 (0.5 mg/kg/12 hours; i.p.; 7 days). Behavioural assessment of spontaneous cannabinoid withdrawal was performed by measuring motor activity, somatic signs and anxiety-like behaviour on days 1 and 3 after cessation of treatment with CP-55,940. On days 1-3 of cannabinoid withdrawal, mice received pregabalin (40 mg/kg/12 hours; p.o.) or topiramate (50 mg/kg/12 hours; p.o.) and their actions on signs of withdrawal and anxiety-like behaviour were evaluated. The administration of CP-55,940 decreased rectal temperature and motor activity on day 1. On day 1 after interruption of cannabinoid administration, motor activity and the number of rearings increased compared with control group. Anxiety-like behaviour induced by cessation of cannabinoid treatment increased significantly on days 1 and 3 of withdrawal. The administration of pregabalin or topiramate blocked the motor signs and reduced significantly anxiety-like behaviour. Cannabinoid withdrawal decreased tyrosine hydroxylase (TH) gene expression in the ventral tegmental area and µ-opioid receptor gene expression in the nucleus accumbens (NAcc) and increased CB1 receptor gene expression in the NAcc. Treatment with topiramate or pregabalin blocked the decrease of TH and the increase of CB1 gene expressions induced by cannabinoid withdrawal. Both drugs failed to alter µ-opioid receptor gene expression. These results suggest that pregabalin and topiramate may result useful for the treatment of anxiety-like behaviour and motor symptoms associated with spontaneous cannabinoid withdrawal.

Topics: Analysis of Variance; Animals; Anticonvulsants; Anxiety; Behavior, Animal; Body Temperature; Cannabinoids; Cyclohexanols; Dose-Response Relationship, Drug; Drug Tolerance; Fructose; gamma-Aminobutyric Acid; Male; Marijuana Abuse; Mice; Models, Animal; Motor Activity; Nucleus Accumbens; Pregabalin; Receptor, Cannabinoid, CB1; Receptors, Opioid, mu; Substance Withdrawal Syndrome; Topiramate; Transcription, Genetic; Tyrosine 3-Monooxygenase; Ventral Tegmental Area

The peripubertal period appears to be critical in relation to the abuse of cannabinoids and opioids in humans. However there is little information about the acute effects of cannabinoids and their interactions with opioids in young experimental animals. We have studied the effects of the cannabinoid agonist CP 55,940 (0.1, 0.2, 0.4 and 0.6 mg/kg) on the nociceptive responses (tail immersion test) and holeboard activity of 40-day-old rats, and the involvement of the CB(1) receptor (antagonism by SR 141716A, 3 mg/kg). The implication of the opioid system was evaluated using the opioid antagonist naloxone (1 mg/kg) and a combined treatment with subeffective doses of CP 55,940 (0.1 mg/kg) and morphine (1 mg/kg). The effects of CP 55,940 on the serum corticosterone levels (radioimmunoassay) and on the dopamine and DOPAC contents of discrete brain regions (high-performance liquid chromatography) were also assessed. The antinociceptive effect of CP 55,940 was of a similar magnitude at all the doses used. The results show the involvement of the CB(1) receptor. The cannabinoid agonist significantly depressed the holeboard activity in a dose-dependent manner. The results indicate that the CB(1) receptor is involved in the effects on motor activity but not in the effects on the exploratory activity. The behavioural effects of CP 55,940 were modulated by morphine. The cannabinoid agonist (0.6 mg/kg) induced a CB(1)-mediated increase in the serum corticosterone levels, but no effect on the dopaminergic systems of either the striatum or the limbic forebrain was found.

Topics: Analgesics; Animals; Behavior, Animal; Cannabinoids; Corticosterone; Cyclohexanols; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Female; Grooming; Male; Marijuana Abuse; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Neostriatum; Neurosecretory Systems; Nociceptors; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Sex Characteristics

Cannabinoids are known to impair motor function in humans and laboratory animals. We have demonstrated an accentuation of cannabinoid (CP55,940)-induced motor incoordination in mice by the adenosine A(1) receptor-selective agonist N(6)-cyclohexyladenosine (CHA) (4 ng) using an intracerebellar (ICB) microinjection method. This effect was mediated by the A(1) receptor because pre-treatment with ICB 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (100 ng), an adenosine A(1) receptor selective antagonist, completely abolished the accentuation. Furthermore, ICB pre-treatment with DPCPX (100 ng) before ICB CP55,940 (15 microg) attenuated the motor incoordination suggesting a modulation by an endogenous adenosine A(1) system. ICB microinjection of CHA or DPCPX prior to ICB vehicle had no effect on normal motor coordination. ICB microinjection of dipyridamole (25 microg), an adenosine transport inhibitor, significantly accentuated the motor incoordination by ICB CP55,940 (15 microg), providing further support for the involvement of endogenous adenosine in the action of CP55,940. Tolerance to the motor incoordinating effect of ICB CP55,940 was demonstrated following 3 days of i.p. CP55,940 (0.1, 1 or 2 mg/kg every 12 or 24 h; total of six or three injections, respectively). Interestingly, animals which exhibited tolerance to ICB CP55,940 also demonstrated tolerance to the accentuating effect of ICB CHA suggesting cross-tolerance between adenosine agonists and cannabinoids. Cross-tolerance was also demonstrated following 3 days of i.p. CHA (0.25 or 1 mg/kg every 24 h; total of three injections) as further evidence of the modulatory role of the cerebellar adenosine system in the acute manifestation of CP55,940-induced motor incoordination. The involvement of cerebellar adenosine and the A(1) receptor in cannabinoid actions is circumstantially supported by previous evidence that CB(1) receptors and A(1) receptors are both localized on cerebellar granule cell parallel fiber terminals and basket cell neurons where they serve to inhibit the release of neurotransmitters.

Topics: Adenosine; Analgesics; Animals; Cannabinoids; Cerebellar Ataxia; Cerebellum; Cyclohexanols; Dipyridamole; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance; Male; Marijuana Abuse; Mice; Neurons; Phosphodiesterase Inhibitors; Psychomotor Performance; Receptors, Cannabinoid; Receptors, Drug; Receptors, Purinergic P1; Signal Transduction; Tritium; Xanthines

Previous studies have suggested that cannabis-like drugs produce mainly aversive and anxiogenic effects in Wistar strain rats, but rewarding effects in Lewis strain rats. In the present study we compared Fos expression, body temperature effects and behavioral effects elicited by the cannabinoid CB(1) receptor agonist CP 55,940 in Lewis and Wistar rats. Both a moderate (50 microg/kg) and a high (250 microg/kg) dose level were used. The 250 microg/kg dose caused locomotor suppression, hypothermia and catalepsy in both strains, but with a significantly greater effect in Wistar rats. The 50 microg/kg dose provoked moderate hypothermia and locomotor suppression but in Wistar rats only. CP 55,940 caused significant Fos immunoreactivity in 24 out of 33 brain regions examined. The most dense expression was seen in the paraventricular nucleus of the hypothalamus, the islands of Calleja, the lateral septum (ventral), the central nucleus of the amygdala, the bed nucleus of the stria terminalis (lateral division) and the ventrolateral periaqueductal gray. Despite having a similar distribution of CP 55,940-induced Fos expression, Lewis rats showed less overall Fos expression than Wistars in nearly every brain region counted. This held equally true for anxiety-related brain structures (e.g. central nucleus of the amygdala, periaqueductal gray and the paraventricular nucleus of the hypothalamus) and reward-related sites (nucleus accumbens and pedunculopontine tegmental nucleus). In a further experiment, Wistar rats and Lewis rats did not differ in the amount of Fos immunoreactivity produced by cocaine (15 mg/kg). These results indicate that Lewis rats are less sensitive to the behavioral, physiological and neural effects of cannabinoids. The exact mechanism underlying this subsensitivity requires further investigation.

Topics: Analgesics; Animals; Behavior, Animal; Body Temperature; Brain; Cannabinoids; Catalepsy; Cell Count; Cyclohexanols; Dose-Response Relationship, Drug; Immunohistochemistry; Marijuana Abuse; Motor Activity; Neurons; Proto-Oncogene Proteins c-fos; Rats; Rats, Inbred Lew; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug

Chronic exposure to CP55,940 produced a significant down-regulation of cannabinoid receptors in the striatum, cortex, hippocampus, and cerebellum of rat brain. At 24 h after SR141716-precipitated withdrawal, we observed a tendency to return to basal levels in the striatum and cortex, whereas the specific binding remained lower in the hippocampus and cerebellum. When we surveyed cannabinoid receptor-activated G proteins, in chronic CP55,940-treated rats the guanosine 5'-O:-(3-[(35)S]thiotriphosphate) ([(35)S]GTPgammaS) binding assay revealed a decrease of activated G proteins in the striatum, cortex, and hippocampus, whereas no significant changes were seen in the cerebellum. At 24 h after the SR141716-precipitated withdrawal, [(35)S]GTPgammaS binding increased compared with that of rats chronically exposed to CP55,940, attaining the control level except for cerebellum, where we observed a trend to overcome the control amounts. Concerning the cyclic AMP (cAMP) cascade, which represents the major intracellular signaling pathway activated by cannabinoid receptors, in the cerebral areas from rats chronically exposed to CP55,940 we found alteration in neither cAMP levels nor protein kinase A activity. In the brain regions taken from CP55, 940-withdrawn rats, we only observed a significant up-regulation in the cerebellum. Our findings suggest that receptor desensitization and down-regulation are strictly involved in the development of cannabinoid tolerance, whereas alterations in the cAMP cascade in the cerebellum could be relevant in the mediation of the motor component of cannabinoid abstinence.

Topics: Animals; Behavior, Animal; Brain; Cannabinoids; Cerebellum; Cerebral Cortex; Corpus Striatum; Cyclic AMP; Cyclohexanols; Disease Models, Animal; Down-Regulation; Drug Administration Schedule; Drug Tolerance; GTP-Binding Proteins; Hippocampus; Injections, Intraperitoneal; Male; Marijuana Abuse; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Signal Transduction