Marijuana Addiction

Molecular characteristics of cannabinoid receptors Cnrs

Marijuana, Cnr gene had been elusive to clone but evidence for the existence of the receptor had been demonstrated since the 1980s (Howlett et al., 1988 Devane et al., 1988). It has now been shown and recognized that cannabinoids have specific receptors with endogenous ligands and inhibit adenylate cyclase. The CB1 receptors also modulate the activities of calcium and potassium channels. Although a number of approaches are now available for the cloning of genes encoding different receptors, the...

Changes effected through cannabinoid receptors

Cannabinoid Membrane Interactions

THC at lower concentrations, and at sites distal to the lung, may affect immune cell functions by signaling through cannabinoid receptors. Cannabinoid receptors have been identified both within the brain and cells of the immune system (Figure 9.5). Two cannabinoid receptors, CBX and CB2, have been identified. The CBX has been localized to neuronal tissues (Matsuda et al., 1990) and testis (Gali gue et al., 1995), and to a lesser extent to immune cells. In contrast, the CB2 has been observed...

Mechanisms of vasorelaxation for endocannabinoids

The original findings suggested that anandamide might act via a hyperpolarizing mechanism (Randall et al., 1996). This proposal was confirmed electrophysiologi-cally by the demonstration that anandamide causes hyperpolarization or repolar-ization of vascular smooth muscle, but in both cases this effect was independent of cannabinoid CBX receptors (Plane et al., 1997, Chataigneau et al., 1998). The hyperpolarization was also found to be endothelium-dependent (Chataigneau et al., 1998 Zygmunt et...

Spasticity Animal studies

The cannabinoid agonist WIN 55,212-2 relieves symptoms of dystonia in mutant dystonic hamsters (Richter and Losher, 1994). Cannabidiol attenuates dystonia and torticollus in mutant rats (Consroe et al., 1988), apomorphine induced turning Table 23 Selected well controlled studies on the antiemetic effects of THC in patients on cancer chemotherapy Chang et al. (1979) Frytak et al. (1979) 22 patients on cancer chemotherapy, resistant to standard drugs 15 patients on high dose methotrexate 116...

The hippocampal slice

Marijuanna Effect Hippocampus

The high CBX density observed in hippocampus combined with its important role in cognitive processes designate this structure as a prime target to investigate. Numerous studies aimed at understanding learning and memory have been conducted in hippocampus Shen et al., 1994 . Hippocampal neurophysiology has been extensively studied and a wealth of data is available on its network organization, neuronal population, and neuronal properties. Thus, cannabinoid studies can be largely focused on a...

Effects Of Perinatal Exposure To Cannabinoids

The major psychoactive component of marijuana, A9-THC, has been shown to cross the placenta in humans (Blackard and Tennes, 1984) and in rodents (Vardaris et al., 1976). Moreover, during pregnancy, CBX receptors have been detected in uterus (Das et al., 1995), blastocytes (Paria et al., 1995) and in fetal tissue from the earliest day studied (day 11, Buckley et al., 1998), thus exposing the developing organism to potential teratogenic effects of cannabinoids throughout gestation. Hence,...

References

Achiron, A., Miron, S., Lavie, V., Margalit, R. and Biegon, A. (2000) Dexanabinol (HU-211) effect on experimental autoimmune encephalomyelitis implications for the treatment of acute relapses of multiple sclerosis, Journal of Neuroimmunology 102(1) 26-31. Arata, S., Newton, C., Klein, T. and Friedman, H. (1992) Enhanced growth of Legionella pneumophila in tetrahydrocannabinol-treated macrophages, Proceedings of the Society for Experimental Biology and Medicine 199 65-67. Baczynsky, W. O. T. and...

Balentino Rossi

Ackner, B. (1954) Depersonalization 1. Etiology and phenomenology 2. Clinical syndromes, Journal of Mental Science 100 836-872. Agarwal, A. K., Sethi, B. B. and Gupta, S. C. (1975) Physical and cognitive effects of chronic bhang (cannabis) intake, Indian Journal of Psychiatry 17 1-7. Alavi, A., Dann, R., Chawluk, J., Alavi, J., Kushner, N. and Reivich, M. (1986) Positron emission tomography of regional cerebral glucose metabolism, Seminars in Nuclear Medicine 16 2. American Psychiatric...

Cannabinoid receptor gene expression

The expression of CBX Cnr in the CNS has been extensively studied (Onaivi et al., 1996). The CB2 receptor gene has been detected particularly in the immune system and the expression of its transcripts found in spleen, tonsils, thymus, mast cells and blood cells. CBX and CB2 Cnrs can be co-expressed in some of the same cells, in which cannabimimetic effects can be mediated by their combination. The relative abundance of the endocannabinoids and the relatively large numbers of expressed...

Feeding And Appetite

Marijuana or its major psychotropic constituent A9-THC is used clinically to enhance appetite in acquired immunodeficiency syndrome (AIDS) (Beal et al., 1997 Mattes et al., 1994 Plasse et al., 1991 Struwe et al., 1993 Mechoulam et al., 1998a). The rationale for such use is based both on anecdotal and scientific evidence. Thus cannabis, A9-THC as well as endocannabinoids enhance appetite (Mechoulam et al., 1998b Gallate et al, 1999 Williams et al, 1998 Williams and Kirkham, 1999), although no...

Developmental Aspects Of Cannabinoids The cannabinoid system in development

Initial reports studying the first weeks of postnatal life in the rat described a gradual increase in brain CBX receptor mRNA (McLaughlin and Abood, 1993) and in the density of CB1 receptors (Belue et al., 1995 Rodriguez de Fonseca et al., 1993). In later studies, investigating the gestational period, CB1 receptor mRNA was detected from gestational day 11 in the rat (Buckley et al., 1998). Additional studies have uncovered more complex developmental patterns. Thus, whereas the highest levels of...

Time sense after tetrahydrocannabinol administration

Marijuana intoxication is known to cause changes in the perception of time (Clark et al, 1970 Mathew and Wilson, 1996 McNair et al, 1971 Melges et al., 1970a Melges I I Placebo I I 0.15 mg min I I 0.25 mg min Figure 8.9 Plasma levels after THC infusion. Figure 8.9 Plasma levels after THC infusion. et al., 1970b Melges et al., 1971 Spielberger et al, 1970 Tinklenberg et al., 1972 Tinklenberg et al., 1976). An association between time perception and cerebellar function has been reported (Keele...

Chronic effects related to marijuana use

Drug induced phenomena may be subsumed under acute effects, withdrawal, chronic residual (possibly reversible) effects and permanent effects that may be associated with morphological changes. Demarcation among these categories is clearer with certain drugs but less so with others. For example, in the case of ethyl alcohol, phenomena related to intoxication (acute effect), withdrawal (delirium tremens in extreme cases), reversible functional changes (cognitive changes including memory defects)...

Human Research

There is no evidence from human studies of any structural brain damage following prolonged exposure to cannabinoids. The most recent study using sophisticated technology and measurement techniques showed that frequent but relatively short-term use of marijuana does not produce any structural brain abnormalities or global or regional changes in brain tissue volume or composition assessable by magnetic resonance imaging (MRI) (Block et al., 2000a). Existing methods of brain imaging may not be...

Cannabis Markianos

E., Sauss, C., Fan, F., Tilton, C. L. and Martin, B. R. 1993 Development of behavioral tolerance to A9-THC without alteration of cannabinoid receptor binding or mRNA levels in whole brain, Pharmacology Biochemistry and Behavior 46 575-579. Adams, I. B. and Martin, B. R. 1996 Cannabis Pharmacology and toxicology in animals and humans, Addiction 91 1585-1614. Amen, D. G. and Waugh, M. 1998 High resolution brain SPECT imaging of marijuana smokers with AD HD, Journal of Psychoactive Drugs...

Inhibitory synaptic transmission

Inhibitory synaptic transmission is principally mediated by the release of 7-amino-butyric acid (GABA) which activates GABAa and GABAb receptors to transiently hyperpolarize neurons. Cannabinoids have been shown to affect inhibitory GABA transmission, but the effects of THC appear to differ from those of WIN-2, a feature reminiscent of the alteration of excitatory glutamatergic transmission by partial and full CBX agonists. Thus, THC increases the GABA response in CAX hippocampus and GABA...

Transduction mechanisms

Multiple second messenger pathways have been associated with CBX (Pertwee, 1997). The inhibition of cyclic AMP production by CB1 activation has been widely reported and implicates the coupling of CB1 with an inhibitory G-protein (Gi o) to inhibit adenylate cyclase. The modulation of IA and ID by cannabinoids occurs via a Gi o-protein and inhibition of adenylate cyclase, with subsequent modulation of cyclic AMP and protein kinase (Deadwyler et al., 1995 Mu et al, 1999). Cannabinoids also alter...

Effects of cannabinoids on DNMS performance

As reported previously, delay-dependent performance in the delayed-match-to-sample task was impaired following exposure to A9-THC Heyser et al., 1993 . The same is true for animals performing the delayed-nonmatch-to-sample task Figure 23.1a . Administration of A9-THC 1.5 mg kg, i.p. produced a highly significant decrease in performance F 5,257 18.11, p lt 0.001 at all delays gt 5 sec. This delay-dependent deficit was blocked when the animals were injected with the competitive cannabinoid...

Role of hippocampus in short term memory DNMS

Recent reports from this laboratory described the results of population statistical analyses applied to ensembles of simultaneously-recorded hippocampal CAX and CA3 pyramidal cells (Deadwyler et al., 1996 Hampson and Deadwyler, 1996a, 1998a, 1999b Deadwyler and Hampson, 1997). Ensemble neural activity was analyzed by canonical discriminant analysis (CDA) which indicated that the major sources of variance in ensemble activity corresponded to encoding of task phase, lever position, and trial...

Chronic Exposure To Cannabinoids Attenuates Effects On Shortterm Memory

A striking paradox uncovered in our initial investigation of chronic cannabinoid treatment on short-term memory was the marked attenuation in the acute disruptive effects that occurred over a 20-30 day period of daily exposure to high doses (10mg kg) of A9-THC (Deadwyler et al, 1995b). It is well known that the half-life of A9-THC in rats is quite long (10-100 days), and that repeated daily dosing leads to accumulation of the drug in fatty tissue and re-release of active metabolites as well as...

Summary

The effect of cannabinoids on short-term memory in rats performing the DNMS task is quite similar to the effects of complete hippocampal removal (1) behavioral deficits are produced at long delays (2) proactive influences between trials are no longer protected by hippocampus and (3) hippocampal neurons fail to strongly encode Sample phase information. The result of these deficits is a behavioral cascade in which the hippocampus is rarely engaged in strongly encoding information critical to the...

Effects of cannabinoids on prostaglandin levels in the CNS

In rats, THC at 2 mg kg caused a specific 33 reduction of PGE2 when measured in a bioassay procedure (Coupar and Taylor, 1982). This was accompanied by the induction of hypothermia and catatonia followed by sedation. Two points need to be made on these observations. First, is the non-specific nature of the measurements and second, is the possible involvement of THC metabolites in the inhibitory effect on PG levels. By contrast, in a study using radioimmunoassay, similar doses of THC in the rat...

Anandamide And Oleamide

Drowsiness and sleepiness are commonly observed in the later stages of marijuana intoxication. Increased sleeping time and slow wave sleep have been recorded upon acute administration of A9-THC, the major psychoactive ingredient of marijuana (Paton and Pertwee, 1973 Pivik et al., 1972). Anandamide was shown later to increase slow-wave and REM sleep in rats at the expense of wakefulness (Murillo- Rodriguez et al., 1998), while, conversely, the CBX receptor antagonist SR141716A increased...

Animal models of emesis and the established cannabinoid antiemetics

In the field of antiemetic research, as has been the case of marijuana in general, clinical research has often preceded animal experiments. From the discussion of the numerous cited clinical trials, it is clear that A9-THC and its tested synthetic analogs have demonstrated efficacy and safety as moderate antiemetics in patients receiving chemotherapy. Scant published animal studies also support the antiemetic properties of these cannabinoids (London et al., 1979 McCarthy and Borison, 1981...

Mutated receptors and binding site models Chimeric CBICB2 receptors

Cyp2c9 Thc Binding Site

The most prominent ligands used for investigating fine details of interactions with the cannabinoid receptors are CP 55,940, WIN 55212-2 and SR 141716A (Figure 21.5), because of their high affinity and especially their availability as tritiated molecules. Despite the structural difference between CBX and CB2, 3H CP 55,940 binds equally well to the two receptors and activates them with similar efficacy and potency. It was striking to find that 3H CP 55,940 also failed to discriminate any of a...

Acknowledgements

EF was supported in part, by a grant from the Israeli Ministry of Health. M.C.S.P. was supported by NIH grant DA 12999. Abood, M. E. and Martin, B. R. (1992) Neurobiology of marijuana abuse, Trends in Pharmacological Science 13 201-206. Abrahamov, A., Abrahamov, A. and Mechoulam, R. (1995) An efficient new cannabinoid antiemetic in pediatric oncology, Life Sciences 56 2097-2102. Aceto, M. D., Scates, S. M., Lowe, J. A. and Martin, B. R. (1995) Cannabinoid precipitated withdrawal by the...

Activity Dependent Regulation Of Cannabinoid Receptors

It is well established that tolerance develops to most pharmacological effects of can-nabinoids in vivo after a period of chronic exposure (McMillan et al, 1971 Pertwee, 1991 Pertwee et al., 1993 Fan et al., 1994), and are likely to be the response of activity dependent regulation of CBX receptors. Earlier studies looking at cannabinoid receptor density changes using ligand binding analysis gave conflicting results. Some investigators demonstrated decreases in the Bmax of cannabinoid receptors...

Clinical trials with A9THC

A9-THC is the most extensively studied antiemetic cannabinoid. Table 13.1 summarizes the antiemetic efficacy of orally administered A9-THC against chemotherapy-induced nausea and vomiting from 15 clinical trials. In these studies, patients were undergoing treatment with a variety of chemotherapeutic agents for a plethora of tumors and haematologic malignancies. The administered doses of A9-THC were between 5-15 mg m2 and its first dose was administered 1-24 h prior to the start of chemotherapy....

Animal studies

Bicher and Mechoulam (1968) found A9-THC and A8-THC (i.p.) were about 1 2 as effective as morphine (s.c.). On three tests of analgesia the hot plate test, the acetic-acid writhing test and the tail flick test, Sofia and colleagues (1975) conducted a comparison of the pain relieving effects of A9-THC, a crude marijuana extract (CME), cannabinol (CBN), cannabidiol (CBD), morphine SO-4 and aspirin (all p.o). They used acetic-induced writhing, hot plate tests and the Randall-Selitto paw pressure...

Stress Hormones

The hypothalamic-pituitary-adrenal axis is the major endogenous hormonal system responsible for maintaining homeostatic balance in response to stress. Beginning in the central nervous system, corticotropin-releasing hormone (CRH), synthesized in the hypothalamic parvocellular paraventricular nuclei of the hypothalamus, regulates the release of adrenocorticotropin hormone (ACTH) from the anterior pituitary gland. ACTH release stimulates the synthesis and secretion of the adrenal glucocorticoids...

Cardiovascular Effects Of Endocannabinoids Actions in vivo

One of the therapeutic indications for cannabis has been as an antihypertensive, although developments in this direction have been stifled by the stigma associated with cannabis. The relatively limited literature concerning the cardiovascular effects of exogenous cannabinoids contains variable observations with both vasodilator and vasoconstrictor actions being reported (Stark and Dews, 1980). In one of the most recent reports, Niederhoffer and Szabo (1999) demonstrated that CBrreceptor...

Abstract

The reward substrates of the central nervous system CNS consist of 1 a core dopam-inergic enkephalinergic neural system synaptically interconnecting the ventral tegmental area, nucleus accumbens, and ventral pallidum, and which appears to mediate reinforcement 2 a glutamatergic neural network originating in the frontal cortex and deep temporal lobe, which feeds into the core dopaminergic enkephalinergic system and which appears to mediate aspects of reward-related incentive motivation and 3...

Effect Of Cannabinoids On Phospholipid Enzymes And Arachidonic Acid Biosynthesis

A phospholipid messenger system constitutes a major function of the lipid bilayer and involves signal-mediated hydrolysis of phospholipids within the membrane. The best characterized of these systems is that originating from arachidonic acid, which is released from phospholipids following activation by a phospholipase. Psychoactive cannabinoids and some of their non-psychoactive acid metabolites also release arachidonic acid from phosphatidylcholine in a dose-related manner (Hunter et al., 1985...

Possible role of other neurotransmitter systems in the antiemetic properties of cannabinoids

Although the cholinergic neurotransmitter system per se is not directly involved in chemotherapy-induced vomiting (see section 2.1), dopaminergic and serotonergic mechanisms do appear to be important downstream in cannabinoids' antiemetic actions. Indeed, in the feline, nabilone dose-dependently prevents emesis produced by the dopamine D2 receptor agonist apomorphine (London et al., 1979). In a similar manner, A9-THC prevents vomiting produced by dopamine D2 D3 receptor agonists such as...

Nissar A Darmani

In the last two decades, there have been considerable advances in our understanding of emetic circuits and the mechanisms by which chemotherapeutics produce emesis. Cancer chemotherapy is often accompanied by severe nausea and vomiting, which can lead to refusal or delay of treatment by patients. A number of different classes of antiemetics have been employed clinically to control chemotherapy-induced emesis. These include dopamine D2 antagonists (butyrophenones, phenothiazines), cannabinoids,...

Pharmacological Profile Of Cannabinoids

In the absence of a behavioral or physiological response which is unique for cannabinoids, Martin and colleagues (1991) have developed a multiple in vivo assay for the evaluation of cannabimimetic effects. These procedures have been shown to be predictive of psychoactive cannabinoid activity and to highly correlate with affinity for the - predominantly central- cannabinoid CB x receptor (Abood and Martin, 1992 Compton et al., 1993 Martin et al., 1991 Razdan, 1986). The full battery includes a...

Central nervous system CNS

There have been several studies aimed at elucidating the effects of natural cannabinoids on CNS. The cerebral blood flow and cerebral metabolic rate are two parameters of brain activity. Cannabinoid-induced changes in these parameters represent a change in brain function (Mathew and Wilson, 1993). Initial exposure to A9-THC reduces global cerebral blood flow, while prolonged exposure produces increased global cerebral blood flow mainly in the frontal and left temporal regions (Mathew and...

Effects Of Cannabinoids On Neurotransmitter Receptors

THC has been reported to affect the activity of several neurotransmitter receptor systems. THC, however, does not interact directly with the active site of the receptors, but rather causes an allosteric modification of the receptor, which in turn modifies its response to other agonists and antagonists. After THC administration, the effects of subsequent exposure to the receptor agonists acetylcholine (Domino, 1981 Gessa et al., 1997) and opioids (Vaysse, 1987) and NMDA (Hampson et al., 1998)...

Neurobehavioral and in vitro actions of cannabinoids

Bolleke Pijl

Despite the decades of extensive investigations and recent developments in can-nabinoid research, the identification of specific mechanisms for the actions of cannabinoids have been slow to emerge. We therefore do not attempt to provide a comprehensive account of the numerous in vivo and in vitro effects of canna-binoids but a few examples from our studies and those of others. The discovery of endocannabinoids such as anandamide and 2-arachidonyly glycerol and the widespread localization of...

Human functional studies

In chronic marijuana users, a clinical condition, loosely described as amotiv-ational syndrome associated with apathy, reduced drive and ambition, impaired ability to carry out complex tasks, loss of initiative and effectiveness, failure to pursue long-term plans, difficulty in concentrating and decline in school and work performance has been reported (McGlothlin and West, 1968 Gold, 1989 Nahas, 1984). Although firm objective data in support of this syndrome are lacking, several data based...

Clinical trials with nabilone

Nabilone is a synthetic cannabinoid which was developed by the Lilly laboratories. The general structure of nabilone is similar to A9-THC as they are both dibenzopyr-ans, with a dimethyl at the position 6, and a hydroxyl at the position 1. However, nabilone differs from A9-THC as it contains a dimethylheptyl side chain (instead of pentyl) at the position 3, and a ketone (instead of methyl) in the position 9. In both animals (Razdan, 1986) and humans (Archer et al., 1986), the psychoactivity of...

Cannabinoid Receptor Activation Of Ion Channels

Activation of the CBX receptor can lead to alterations in the function of multiple ion channels (Figure 15.1). Most notable is the ability of cannabinoids to inhibit voltage dependent N- and Q-type calcium channel currents both in transfected cell lines and in cell lines that contain the native receptor (Caulfield and Brown, 1992 Mackie and Hille, 1992 Mackie et al., 1995). More recently, it was demonstrated that cannabinoid CB1 receptors can inhibit L-type Ca2+ current in cerebral arterial...

Chemical dependence

Dependence to cannabinoids appears to occur in humans and develop slowly with increased risk at higher doses and frequency of use (Gold, 1994 Martin and Hubbard, 2000). Compulsive use has been reported antidotally and in survey studies (Ashton, 1999). Like other drugs of abuse, cannabinoids has been shown to stimulate release of dopamine in neuroanatomical reward centers of the brain (Gardner and Lowinson, 1991). Cannabis dependence is estimated to be about 4 of the population (Gold, 1994...

Mechanisms of cannabinoid action on CNS reward substrates

Just as different addictive drugs act at different sites of action within the CNS to enhance reward substrates, so too do different addictive drugs enhance reward substrates by acting through different mechanisms. Amphetamines (and probably some phencyclidine-like dissociative anesthetics) act as presynaptic DA releasers, cocaine as a presynaptic DA reuptake blocker, opiates and nicotine as transsynaptic enhancers of DA neuronal firing, and other addictive drugs by yet other mechanisms (for...

Structural features of the cannabinoid receptors

Many studies have been undertaken to determine the nature of ligand-cannabinoid receptor interactions at the molecular level. The clear objective is to arrive at more potent and more subtype specific ligands, associating therapeutic effectiveness with a minimum of undesirable psychoactive and other side-effects. Most of the past efforts have concentrated on classical structure-activity relationships to determine the cannabinoid pharmacophore using different series of classical and non-classical...

Marijuana Addiction Introduction

Nausea and vomiting are the common side effects associated with cancer chemotherapy that profoundly affects the patient's quality of life and may lead to refusal of further chemotherapy treatment (Coats et al., 1983). In the interest of enhancing patient compliance and for humanitarian reasons, it is essential to develop new drugs which can prevent the discomfort of chemotherapy without decreasing its effectiveness. In the past two decades, there have been significant advances in the...

Antiemetic Properties Of Clinicallyuseful Cannabinoids

During 1970s and 1980s, dopamine D2 antagonists were the mainstay of antinauseant-antiemetic agents in cancer patients receiving chemotherapy. However, they had limited clinical success. Because of anecdotal reports by young cancer patients that smoking marijuana alleviated the nausea and vomiting caused by chemotherapeutic agents, both government and industry sponsored clinical trials were initiated to test the antiemetic potential of cannabinoids. These trials began in 1975 and have continued...

Anxiety Animal studies

Musty et al. (1985) found CBD increased licking for water in the lick suppression test in a dose related fashion (mg kg). Equivalent effects were found with the classic anxiolytic drug diazepam. In an effort to find more potent effects, they tested two analogs, 2-pinyl-5-dimethylheptyl resorcinol (PR-DMH) and Mono-methyl canna-bidiol (ME-CBD-2). ME-CBD-2 had anxiolytic activity, but was less potent than CBD, while PR-DMH had no anxiolytic properities. Of the two active compounds, both were less...

Limitations Of Human Studies On Marijuana

Marijuana has been an area of significant social and scientific interest for many years, yet many questions remain unanswered or not fully answered. In part, this is due to the inherent difficulties of human research on any illegal substance and in part it is due to special characteristics of marijuana. For example, marijuana has a very long half-life making the cause and effect less obvious, and marijuana is not a specific chemical, but rather a substance derived from the cannabis sativa plant...

Decreased resistance to infection with viruses

Guinea pigs and mice have been used extensively to document the effects of cannabinoids on resistance to infectious agents and to define elements of the immune system targeted by these compounds. Morahan et al. (1979) demonstrated that THC administered intraperitoneally to BALB c mice decreased resistance to Listeria monocytogenes or herpes simplex virus type 2 (HSV-2), pathogens infectious also in humans. Animals inoculated intravenously with Listeria exhibited a significant dose-dependent...

Cannabinoid effects on neuronal activity in CNS reward loci

It is well established that some addictive drugs (e.g. opioids, nicotine) enhance mesoaccumbens DA reward substrates by enhancing the firing rate of the second-stage DA neurons within these reward substrates (see, e.g. Gysling and Wang, 1983 Grenhoff et al., 1986). To assess whether cannabinoids act similarly, several research groups have combined cannabinoid administration in laboratory animals with in vivo single-neuron electrophysiological recording techniques. With one exception (Gifford et...

Cannabinoid selfadministration in animals

Given all the data reviewed above, it is quite to be expected that cannabinoids would be reliably self-administered by animals. Until recently, that did not seem to be the case. A number of older studies failed to demonstrate reliable cannabinoid self-administration in laboratory animals (Kaymakgalan, 1972 Corcoran and Amit, 1974 Harris et al., 1974 Leite and Carlini, 1974 Carney et al., 1977 Takahashi and Singer, 1981). In those older studies, the few instances of cannabinoid...

Behavioral measures of movement turning

When a treatment that affects movement is applied bilaterally in the brain, the result obtained is increase or decrease in locomotor activity depending on the effect of the treatment. However, when the treatment is applied unilaterally (only in one side of the brain) the resulting increase in movement will be expressed as contralateral turning. The imbalance created between the two sides of the brain, higher motor output in the treated versus the untreated side, makes the animal turn towards...

Clinical trials with levonantradol

Levonantradol is another synthetic cannabinoid. It was synthesized by Pfizer researchers, and belongs to the nonclassical cannabinoids group . Levonantradol is a tricyclic analog of A9-THC where the oxygen in its pyran ring is replaced by a nitrogen atom. Levonantradol is one of the four stereoisomers of nantradol. Levonantradol possesses analgesic (Johnson and Melvin, 1986), cannabimimetic (Levitt, 1986 Compton et al., 1991) and antiemetic action (Table 13.3 Johnson and Melvin, 1986) in both...

Adverse Effects Of Chronic Marijuana Abuse

Evidence for adverse effects from chronic marijuana is difficult to establish in both research studies and anecdotally because of the numerous uncontrolled variables over a long period of time. Overall, however, available data suggests that long-term marijuana abuse may adversely effect behavior, mental functioning, the cardiovascular system, immune system, respiratory system, reproductive system and others as discussed below (Tables 24.3 and 24.4). In addition, chronic abuse of marijuana can...

Human studies

Reviews and critiques of the clinical literature on spasticity effects have been published (Consroe and Snider, 1986 Consroe and Sandyk, 1992 Pertwee, 1987). Scott Imler, who managed one of the cannabis buyers clubs in California illustrates I have a videotape of a quadriplegic whose legs are bucking and bouncing. A couple of puffs and the spasms stop cold____Our quad members tell us this happens every morning They wake up with knees in their mouths, stiff as a board, and two or three puffs...

Prostaglandins and cannabinoids in peripheral systems

Since their discovery, the prostaglandins have been known to have important roles in the reproductive systems. This has prompted investigators looking for mechanisms to explain the effects of cannabinoids on reproduction to study a possible role for the prostaglandins (Jordan and Castracane, 1976 Ayalon et al, 1977 Dalterio et al, 1978, 1981 Rettori et al., 1990). Cannabinoids appear to modulate PG levels in male and female models where they show both stimulatory and inhibitory actions. In...

Cannabinoid receptors and cellular actions of cannabinoids

The first cannabinoid receptor was cloned a decade ago. It was called CBj. This was soon followed by the cloning of a second subtype of cannabinoid receptor that was accordingly called CB2. Both receptor subtypes belong to the family of seven transmembrane domain G-protein coupled receptors (Matsuda et at., 1990 Munro et at., 1993). The CB2 cannabinoid receptor is mainly associated with the immune system. The CBX cannabinoid receptor is the receptor expressed by neurons and therefore will be...

Effects on macrophages

Recently, Baldwin et al. (1997) evaluated the function of alveolar macrophages recovered from the lungs of nonsmokers and habitual smokers of tobacco, marijuana, or crack cocaine. Macrophages recovered from marijuana smokers were deficient in the ability to phagocytose Staphylococcus aureus and were severely limited in the capacity to kill bacteria and tumor cells. Experiments in which NG-monomethyl-L-arginine monoacetate, an inhibitor of nitric oxide synthase, was used suggested that...

Changes effected through alterations in membranes

At high concentrations (i.e. 10-5M or greater), THC and other cannabinoids can cause membrane perturbation and disrupt cell membranes (Figure 9.4). Physical disruption of cellular membranes may affect translational events and post-transla-tional modifications such as glycosylation, phosphorylation, and proteolytic cleavage of precursor molecules. In addition, intracellular and extracellular communication through signaling molecules may be affected. Furthermore, since THC is a highly lipophilic...

Drug discrimination

In the drug discrimination paradigm (see review by Balster and Prescott, 1992), laboratory animals learn to recognize the presence of a certain drug (such as nicotine, morphine, LSD, A9-THC) and express the discrimination between the drug under investigation and a control substance (placebo) in a two choice situation, where the correct choice is rewarded. Results from numerous studies indicate that animals will learn to discriminate cannabinoids from drugs from different classes and they will...

Concluding Remarks And Future Directions

Faster progress has been achieved in marijuana research within the last decade than in the thousands of years that marijuana has been used in human history. For many decades, research on the molecular and neurobiological bases of the physiological and neurobehavioral effects of marijuana was hampered by the lack of specific research tools and technology. The situation started to change with the availability of molecular probes and other recombinant molecules that have led to the major advances....

The mouse tetrad

The mouse tetrad consists of 4 simple evaluations, which may be measured in sequence in the same animal Motor activity in an open field is measured for various lengths of time, but typically for 10min, by digitized or manual observation. Next, the amount of time in which the mouse is immobile after it is placed on a metal ring of 5.5 cm diameter, held at about 16 cm above a table top, is recorded for 4-5 min. This method was developed by Pertwee (1972) and is taken as a measure of catalepsy....

Sex Hormones Male

Serum Testosterone Hourly Fluctuation

In the male, the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are synthesized and released from the anterior pituitary gland in response to the hypothalamic peptide releasing hormone GnRH or gonadotropin-releasing hormone. Once released, LH and FSH bind to receptors within the testes where these hormones maintain spermatogenesis and testosterone secretion. Exposure to cannabinoids can result in altered levels of LH, FSH and testosterone in the male. In human...

Possible mechanisms for effects on brain morphology

The data we present show group differences related to age of first use of marijuana. Early users were defined as those who started before the age of 17. The effects manifest themselves in 3-dimensions. (1) Both males and females who are early users have reduced cortical gray matter (as a percentage of whole brain volume) when compared to those who started use later. Differences are greater over the frontal cortex (2) The CBF in males who are early users is significantly higher compared to other...

Spinal cord and dorsal root ganglion

Numerous fibers labeled for CBX receptors are found in the spinal cord and are especially numerous in the dorsal horn. At least half of the binding in the dorsal horn has a presynaptic origin on dorsal root ganglion input terminals. Fibers extending from the white matter into the grey matter are observed under the central canal. Cells with a very light sheet of immunoreactivity are observed throughout the grey matter of the spinal cord. Very lightly labeled neurons and their processes are...

Brain Damage From Head Injury Excitotoxins Ischemia Infection And Poison

A nonpsychotropic cannabinoid, HU-211, has cerebroprotective effects. HU-211 Dronabinol is a synthetic, nonpsychotropic cannabinoid, which has been shown to act as a noncompetitive N-methyl-D-aspartate NMDA receptor antagonist Shohami et al., 1993 . These authors administered HU-211 1, 2 and 3 h after closed head injury in anesthetized rats. The drug reduced blood-brain barrier breakdown and improved motor functions on beam walking and balancing tasks. Raising NMDA and glutamate levels in the...

Sar Of Endocannabinoids For Cannabinoid Receptors Anandamide Amidase And The Anandamide Transporter

Cannabinoids produce a wide range of pharmacological effects, which include anticonvulsant, antiglaucoma, antiemetic, antianxiety, analgesic, and antiasthmatic activity. The structure-activity relationships of cannabinoids and anandamide analogs indicate that their pharmacological activities are significantly influenced by their chemical structures and stereochemical features. The chemical structure of anandamide can be divided into two major molecular fragments (a) a polar ethanolamido head...

Role of neurotransmitters involved in chemotherapyinduced emesis

Several well-established neurotransmitters (acetylcholine, dopamine, histamine and serotonin) are known to act via their specific receptors to induce emesis. Indeed, selective activation of serotonergic 5-HT3-, dopaminergic D2- or muscarinic Mj receptors in both CTZ and NTS (and also histamine Hx receptors in the NTS), can induce vomiting. More recently, it has been suggested that the neuropeptide, substance P, also plays an important role in the emetic reflex (Bountra et al., 1996). Several...

Implication for the medical use of marijuana

The use of cannabis for both recreational and medicinal purposes dates back to thousands of years. In recent times, there has been an increase in calls for marijuana to be legalized for medicinal use in AIDS, cancer, multiple sclerosis and other medical conditions where patients might benefit from the biological effects of cannabis. Synthetic cannabinoids such as dronabinol, marinol and nabilone already have an established use as antiemetics in nausea and vomiting associated with cancer...

Cannabinoid effects on naturally rewarding behaviors

There exists an extensive published literature dealing with cannabinoid effects on naturally rewarding behaviors. This literature can be divided into two areas (1) cannabinoid effects on sexual behavior and (2) cannabinoid effects on consumption of highly rewarding (e.g. sweet) foods and liquids. The literature dealing with cannabinoid effects on sexual behavior is extensive, and beyond the present scope. The interested reader is referred to that literature (e.g. Bloch et al., 1978 Sieber et...

Endogenous Opioid Mediation Of Cannabinoid Effects On Cns Reward Substrates

As noted above, acute enhancement of CNS reward substrates appears to be the single essential commonality of drugs with addictive potential. Strikingly, this drug-induced enhancement of CNS reward substrates is blocked or attenuated by such highly specific and selective opiate antagonists as naloxone and naltrexone. This holds not only for addictive drugs of the opiate class but also for non-opiates such as ethanol, amphetamines, cocaine, barbiturates, benzodiazepines, and phencyclidine (for...

Sites of cannabinoid action on CNS reward substrates

As noted above, different addictive drugs enhance reward by acting at different sites within the reward substrates of the CNS. Nicotine, ethanol, benzodiazepines, and barbiturates appear to act - transsynaptically - within somatic and dendritic regions of the second-stage DA neurons in the ventral tegmental area cocaine, amphetamines, and dissociative anesthetics appear to act primarily on the axon terminal projections of the second-stage DA neurons within the nucleus accumbens. Opiates act on...

Potential effects of marijuana use in early adolescence

We have recently published findings suggestive of brain morphological changes in marijuana smokers (Wilson et al., 2000). MRI was utilized to determine brain volumes for gray, white and lateral ventricles, and PET was used to determine CBF in 57 subjects with a history of marijuana use. The relationships of three variables - age at first use, duration of use (defined as current age minus age at first use) and current level of use - to brain volume measures (whole brain, gray matter, white...

Other Hormones

Less is known regarding cannabinoid effects on other hormonal systems. Several hormones involved either directly or indirectly in the regulation of metabolism, i.e., growth hormone (GH), thyroid-stimulating hormone (TSH), and insulin, are affected as a result of cannabinoid exposure. The secretion of GH by the anterior pituitary gland is regulated by two hormones from the hypothalamus, GH-releasing hormone (GHRH), which stimulates GH secretion, and somatostatin, which inhibits the release of...

Introduction Marijuana and movement

The recreational and medicinal properties of the marijuana plant have been known by humankind since ancient times. Today, the plant is primarily used for its euphorogenic properties, despite its continuing illegal status. But even for the common user, one of the many physiological effects known to be induced by the active ingredients in the plant is especially striking, that is, the effects on movement. The major recognized effect of marijuana on movement is the induction of hypoactiv-ity....

Studies reporting deleterious effects on immunity and host resistance

In contrast, other studies have suggested that cannabinoids or marijuana exert deleterious effects as they relate to the immune system and resistance to infection in humans. Gross et al. (1991) indicated that marijuana consumption altered responsiveness of human Papillomavirus (HPV) to systemic recombinant interferon alpha 2a treatment. Tindall et al. (1988) conducted immunoepidemiological studies using univariant and multivariant analyses and implied an association between marijuana use and...

Antiemetic effect in cancer chemotherapy

Cannabinoids can prevent the nausea and vomiting induced by cancer chemotherapy Dewey, 1986 . Both clinical and animal studies indicate that certain cannab-inoids have therapeutic potential as antiemetic agents. Vomiting is the expulsion of contents of the gut, largely by forces generated by the respiratory muscles Levitt, 1986 . Cannabinoids can affect cerebral function, above the level of the vomiting reflex Steele, 1980 . Therefore, cannabinoids may suppress vomiting through descending...

Additional synaptic inputs to the core reward system

There are several additional neural inputs to the core reward system that may modulate drug reward by modulating DA function within the core system. GABAergic efferents from the nucleus accumbens form a feedback loop to the ventral tegmental area, and nucleus accumbens medium spiny GABAergic neurons also project to other GABAergic neurons synaptically linked to both the accumbens and ventral tegmental area (Alexander and Crutcher, 1990 Kalivas et al., 1993 Van Bockstaele and Pickel, 1995)....

Vascular actions of endocannabinoids

Anandamide was first shown to be a vasodilator in the rat cerebral vasculature, but these effects were sensitive to indomethacin, suggesting that cannabinoids may cause relaxation through the stimulation of the metabolism of arachidonic acid (Ellis etal., 1995). Dependence on prostanoids was also found for the vasorelaxant effects of A9-tetrahydrocannabinol. In the rat isolated mesenteric and coronary vasculatures, anandamide is a vasodilator (Randall et al., 1996 Randall and Kendall, 1997...

Function Of The Endocannabinoid System In The Neonate

The endocannabinoids appear to play a major role in fertility and reproductive functions, which is described elsewhere in this book (S. K. Dey, Cannabinoids and reproduction). Recent work on the medicinal aspects of marijuana have indicated that the plant may be used beneficially to combat weight loss in AIDS and cancer patients by enhancing appetite (Mechoulam et al., 1998b). More recently we have uncovered evidence that the above mentioned observations may just be the tip of the iceberg of...

Respiratory system

Smoking marijuana is believed to have several dangerous effects on the respiratory system. Like tobacco smoke, cannabis smoke contains both tar carbon monoxide and carcinogens (Gold, 1994 Nahas and Latour, 1992). Unlike cigarettes, marijuana joints do not have filters, and smokers often inhale deeply and keep the smoke in their lungs for extended time to get the full euphoric effect. Marijuana smoke has about three times more tar and five to six times more carbon monoxide than cigarette smoke...

Hypothetical models of cannabinoid action on CNS reward substrates

From many of the considerations reviewed above, hypothetical models of cannab-inoid action on CNS reward substrates can be developed. One model (Gardner and Lowinson, 1991 Gardner, 1992) takes as its starting point the observations that (1) intracranial cannabinoid microinfusion into the nucleus accumbens enhances accumbens DA while cannabinoid microinjection into the ventral tegmental area does not (2) the electrochemical signature of can-nabinoid-induced enhancement of forebrain DA resembles...

Cannabinoid effects on conditioned place preference

One of the most widely used behavioral techniques for inferring appetitiveness or aversiveness of pharmacological agents in laboratory animals is conditioned place cue preference (or aversion). Conditioned place or cue preference is the learned approach to a previously neutral set of environmental stimuli which have been paired with administration of a rewarding treatment (for review, see van der Kooy, 1987). When used to assess the rewarding properties of drugs, animals are given drug...

Pharmacological Profile Of Endocannabinoids

The endogenous ligands for the cannabinoid receptors discovered thus far (the endocannabinoids ), include the anandamides (Devane et al., 1992 Hanus et al., 1993), 2-arachidonoyl glycerol (2-AG, Mechoulam et al., 1995) and noladin ether (Hanus et al., 2001). Thus far, the prototypical anandamide, arachidonoyl ethanol amide (Devane et al., 1992) is the most thoroughly studied endocannabinoid. Although the overall pharmacological activity is similar to the psychoactive plant constituent A8-THC...

Effects on lymphocytes other immunocytes and cytokines

Kusher et al. (1994) assessed the effect of THC (0.005-5.0 g ml) on the synthesis of TNFa by human large granular lymphocytes (LGL) in culture. These investigators reported that THC at physiological levels down-regulated TNFa production and diminished LGL cytolytic activity against K562 tumor cells. Furthermore, it was suggested that since the NK polymorphonuclear neutrophil axis represents an important early defense against the opportunistic fungus Candida albicans, repression of this system...

Cannabinoids affect encoding strength but not encoding functions

The loss of Sample firing correlates described above (Figure 23.5) confirmed an earlier report that exposure to A9-THC reduced firing of hippocampal cells during the Sample phase of DMS, but not the Nonmatch phase (Heyser et al, 1993). In terms of the behavioral cascade, this means that more trials show weak encoding (red arrow, Figure 23.4b), and consequently, LDEs and miscodes are increased. The frequency distributions of ensemble Sample phase firing rates (Hampson and Deadwyler, 2000)...

Other invertebrate Cnr genes

Sequence from the Caenorhabdities elegans (C. elegans) genome share weak similarity to Cnrs (Wilson et al., 1994). Cnr binding activity has been reported in the marine cyanobacterium, Lyngbya majuscula (Sitachitta and Gerwick, 1998). Cannabinoids can inhibit the growth of pathogenic amoeboflagellate Naegleria fowleri and prevents enflagellation and encystment, but do not impair amoeboid movements of this organism (Pringle et al., 1979). Cannabinoids influence the social behavior of ants...

The Interaction Of Cannabinoids With The Membrane Lipid Bilayer

Lawrence and Gill (Lawrence and Gill, 1975), in 1976, first demonstrated that THC at low concentrations (1 micromolar) increases the molecular disorder of the liposome. At higher concentration, the effects level off and do not increase as the molecular ratio of THC to lecithin is increased. The maximum degree of fluidization (disordering) produced by THC does not approach that required to produce anesthesia and THC has been designated a partial anesthetic. The term incomplete could also be...

Longterm potentiation

Long-term potentiation of synaptic transmission, a long-lasting increase of synaptic strength, is the leading experimental model for the synaptic changes that may underlie learning and memory (Malenka and Nicoll, 1999). Long-term potentiation is observed as the increase of an evoked synaptic response that can last hours, and is induced by rapidly delivering a high frequency stimulation (tetanus) to the synaptic afferences of the recorded region. The stimulation paradigm usually comprises 2...

Conclusion

Neurophysiology research is rapidly progressing to further uncover the mode of action of marijuana and cannabinoids. At the cellular level, electrophysiological data indicate that THC and cannabinoids have complex effects and affect a wide range of neuronal properties at the pre- and postsynaptic levels. Thus, canna-binoids depress neuronal activity via inhibition of Ca2+ channels to decrease excitatory neurotransmission at glutamatergic synapses, increase the K+ IA, and may increase inhibitory...

Endogenous Cns Cannabinoid Involvement In Opioid Effects On Cns Reward Substrates

Since endogenous CNS opioid mechanisms are so clearly involved in mediating at least some cannabinoid effects on CNS reward substrates, it might logically be asked whether endogenous CNS cannabinoid systems are involved in mediating opioid effects on CNS reward substrates. There is little work addressing this possibility, but the few published studies are highly provocative to this reviewer's mind, notably the facts that morphine's rewarding properties and its ability to enhance nucleus...

Acute Adverse Effects Of Marijuana

Many acute adverse effects of marijuana have been reported after recent use as shown in Table 24.1. Some of these effects include headache, dry mouth, decreased coordination, tachycardia, changes in pulmonary functioning, altered body tem- Table 24.1 Acute adverse physical effects of marijuana Decreased coordination task performance Changes in pulmonary functioning Reduced muscle strength Decreased cerebral blood flow perature, reduced muscle strength, increased appetite, decreased cerebral...