Ontogeny [on-toj-uh-nee] biological development or history of development of an individual organism

Endocannabinoids and Neural Development

CB1 receptors have many profound developmental effects on the brain.  During pre-, peri-, and post-natal brain development in a young organism, CB1 receptors are on elongating neuronal axons in the process of travelling to distant areas of the brain. During a young brain’s development, CB1 Receptors are present in the white matter, specifically in the elongating neuronal axons whose cell bodies are located at sites distant from the location of functioning receptors. These receptors have been implicated as important in developmental events, such as the process of proliferation and migration of neuronal or glial cells, the process of axonal elongation and synaptogenesis, and the formation of myelin (Fernández-Ruiz et al, 2001).  CB1 pharmacological stimulation appears to modulate neurogenesis as activation of the CB1 receptors has been shown to promote neurogenesis in vivo (in life) (Jin K, et al., 2004).  This is one of two possible pathways to neurogenesis.  The second can be activated through a receptor that recognizes the CB1 antagonist, which has resulted in a false negative making it appear as though cannabinoids inhibit as opposed to excite neurogeneration (Rueda et al, 2002).

Through CB1 receptor activation, cannabinoids can promote both neurosphere generation and neuroprogenitor proliferation. Neurospheres are free-floating, spherical aggregates of neural stem cells. Cells in the neurospheres can proliferate in culture while retaining the potential to differentiate into neurons and glia.  Neuroprogenitor cells (NPCs, variously referred to as neural progenitor cells or multipotent neural precursors) comprise a relatively undifferentiated population of cells capable of giving rise to neurons and glia of the central nervous system (Di Giorgi-Gereveni et al, 2005). 

Cannabinoids prevent apoptosis of multiple factors that promote the cell death of oligodendrocytes through a defined route that begin with CB1 receptor activation.  Oligodendrocytes are type of cell in the central nervous system responsible for making myelin and supporting re-myelination in cases such as multiple sclerosis.  Oligodendrocytes are highly vulnerable to hypoxia-ischemia, and humoral and cellular immune-mediated attack (Molina-Holgado et al, 2002). 

Normal functioning of cannabinoid receptors are crucial for correct brain development. Cannabinoid receptors play an important role in fetal development of the brain.  In post-natal (after birth) development, cannabinoids also play an extensive, yet still not fully understood role.  Recent research shows that cannabinoids actually promote the production of neural stem cells and help maintain the fragile coverings over neurons (the myelin sheath, which helps maintain the speed of nerve impulses). These effects and interactions are far from completely understood, but the one thing that is certain is that cannabinoids have profoundly extensive affects on the brain and its development.

Endocannabinoid response to brain injury

Endocannabinoids are generated on demand as a consequence of brain injury  and reduce brain damage.  Significant reduction of brain edema (the swelling after brain injury resulting from increased water content in the brain), better clinical recovery, and reduced infarct volume (the area of tissue death due to a local lack of oxygen) and hippocampal cell death are noted. This neuroprotective mechanism may involve inhibition of transmitter release and of inflammatory response.  The endocannabinoid system may also function to help restore vasculature to the brain (Mechoulam et al., 2002).  CB1 receptor engagement is responsible for the endocannabinoid neuroprotective action (Marsicano et al., 2003).  Moreover, cannabinoid administration immediately after brain injury protects neurons from different brain insults, such as ischemia, glutamatergic excitotoxicity, oxidative stress, and trauma (Mechoulam et al., 2002).

Internally produced cannabinoids help to mitigate the consequences of brain injury, thereby reducing brain damage after trauma.  These internal cannabinoids likely achieve this by, increasing blood flow to the brain, and reducing swelling and inflammation of the injured area.   

Endocannabinoids and Memory

Cannabinoid receptors modulate synaptic strength and neural networks through long-term depression of inhibition and long-term depression of excitation.  The cannabinoid receptors are therefore very important for helping one extinguish irrelevant memories.  A recent experiment in birds indicates that the CB1 receptor may be very important in not just extinguishing irrelevant memories but also consolidating new and potentially conflicting memories.  In this experiment the researchers blocked the CB1 receptor in birds while they learned that food is stored in a given location (place A).  This blocking of the CB1 receptor actually  improved the birds memory storage for place A as they were able to locate the food 72 hours later better than control birds with unblocked CB1 receptors.  However, if within the 72 hours the food was moved to place B, the birds with blocked CB1 receptors had a much more difficult time remembering place B 24 hours later.  This means that the first memory was so prevalent that the new information was not being properly incorporated with the old information.  Thus CB1 receptors have an important function in memory consolidation (Shifflet et al, 2004).

Although the effects are very complex and not completely understood, blocking cannabinoid receptors (i.e. with external cannabinoids) does affect memory formation and storage.  The recent experiment with birds described above indicates that blocking the CB1 receptor inhibits the removal of irrelevant memories and prevents new memories from being properly incorporated into the brain.

Endocannabinoids and Metabolism

It is well-known that marijuana increases appetite, particularly for palatable foods, and can also result in significant weight gain (Donovan, 1845; Berry and Mechoulam, 2002).  However, the appetite-inducing effect is only seen with relatively low doses of THC, as with higher doses the significant sedation and motor impairment interferes with the animals’ ability to initiate feeding, as demonstrated by animal studies (Abel, 1975).  The orexigenic or (appetite-inducing) effect of THC can be inhibited by the CB1 antagonist SR141716 (inhibits the CB1 receptor from functioning).  The administration of the endocannabinoids anandamide and 2-AG into the hypothalamus and the limbic forebrain have an orexigenic effect, suggesting their involvement in the homeostatic and hedonic control of eating. 

Endocannabinoids probably also have effect on the gastrointestinal tract.  It has been shown in certain neurons that CB1 mRNA (the mRNA that will be transcribed into the CB1 receptor) is upregulated by fasting and down-regulated by re-feeding.  Thus, one may have more pleasure from eating after fasting due to increased levels of CB1 receptors and there appears to be an eating-dependent level of expression of CB1 (Burdyga et al., 2004).  CB1 knockout mice eat less than their litter-mates with CB1 receptors.  Giving wild-type mice with CB1 the antagonist SR141716 similarly results in reduced food intake under both free-feeding and operant conditions.  This means that hunger-induced increases in food intake is partially mediated by endocannabinoids acting at CB1 receptors.

One method by which the body regulates food intake is through leptin, which is produced by adipose tissue (aka fat cells).  Leptin then works by inhibiting the release of certain peptides that have orexigenic effects including neuropeptide Y (NPY).  However, NPY does not have an orexigenic effect in CB1-knockout mice or mice treated with the CB1 antagonist SR141716.  Also, in leptin-deficient mice and rats, endocannabinoid levels were elevated, and endocannabinoid levels were subsequently lowered after a leptin-treatment.  This demonstrates that leptin levels control eating through interactions with the endocannabinoid system.  There is an inverse relationship between leptin levels and endocannabinoid levels in the brain areas associated with appetite control (but not other areas).  The presence of both CB1 and leptin receptors in areas of the brain where the neurons project to dopaminergic neurons demonstrate that this pathway could represent a sight of integration between the endocannabinoid and leptin system involved in modulating the food reward pathway.

Cannabinoids have multiple effects on appetite and feeding behavior in animals.  Low levels of CB1 agonists increase both appetite and food consumption.  However, high doses of cannabinoids induce lethargy and impair motor functions, thereby decreasing an animals ability to consume food.  The CB1 receptors play an important role in inducing animals to eat, as higher levels of CB1 receptors result in more food consumption and theoretically more "pleasure" from consumption.  The endocannabinoid system is important for normalizing appetite levels and regulating food consumption.

Endocannabinoids and Peripheral Energy Metabolism

In a study looking at marijuana smokers over a 21-day observation period, the marijuana-induced increase in caloric intake leveled off after a few days, but weight gain continued throughout the rest of the 21-day period (Greenberg et al., 1976).  This suggests that marijuana has independent effects on appetite and peripheral energy metabolism.  After treatment with SR141716, reduced caloric intake leveled off after a few days, but the weight reduction was maintained throughout the treatment period (Rinaldi-Carmona et al., 1994).  Cannabinoids affect peripheral lipid metabolism by increasing lipogenesis (fat production) and decreasing the breakdown of fat for energy use.  However, this affect on lipogenesis appears to be subject to modulation by sex hormones.  Male mice without CB1 receptors are more lean than female mice lacking the cannabinoid receptors.  CB1 knockout mice do not gain weight when on a high-fat diet, while wt mice on the same diet do gain weight, which indicates that high-fat diet-indicued decreases in energy expenditure are mediated by the activation of CB1 receptors with endocannabinoids.  

Cannabinoids decrease peripheral energy metabolism, meaning that they decrease the breakdown of fats for energy.  Therefore increased cannabinoid levels can lead to weight gain since fat in the body will not be efficiently broken down.  This affect seems to be more pronounced in females compared to males.

Is Food a Drug: The Endocannabinoid Modulation of the Dopamine Reward System

The CB1 neurons that are part of the food reward pathway also appear to be involved in endocannabinoid-mediated drug reward.  Other factors that the endocannabinoids interact with that are also part of the drug reward system are cocaine and amphetamine-related transcript (CART) and endogenous opioids. The endogenous opioid and cannabinoid systems function in a synergistic method to mediate the reinforcing effect of food.  CB-1 knockout mice fail to self-administer morphine or to release dopamine into the brain in response to morphine, suggesting that the site of the opioid-endocannabinoid system is the mesolimbic dopaminergic pathway, which is involved in both food and drug reward.

Cannabinoids strongly influence both the food and drug reward systems.  These reward systems are based on the release of dopamine.  Dopamine is a potent neural transmitter released in the brain when an unexpected reward is received and is believed to be instrumental in the ability of animals to learn new beneficial behaviors. Dopamine also plays a key role in addiction, recent research suggests that, contrary to popular belief, marijuana's interactions with the dopamine reward system  may in fact make the drug chemically addictive.