Cannabis (marijuana, hashish, or cannabinoids) has been used for medical and recreational purposes for many centuries and is likely the only medicine or illicit drug that has constantly evoked tremendous interest or controversy within both the public domain and medical research.
Cannabinoids appear to be able to modulate pain, nausea, vomiting, epilepsy, ischemic stroke, cerebral trauma, multiple sclerosis, tumors, and other disorders in humans and/or animals.
However, marijuana has been the most commonly used illicit drug in developed countries, producing acute memory impairment and dependence/withdrawal symptoms in chronic users and animal models.
Cannabis acts on 2 types of cannabinoid receptors, the CB1 and CB2 receptors, which are distributed mainly in the brain and immune system, respectively.
In the brain, CB1 receptors are also targeted by endogenous cannabinoids (i.e., endocannabinoids) such as anandamide (AEA), 2-arachidonylglycerol, and arachidonylethanolamide.
The recent discovery that the hippocampus is able to generate new neurons (i.e., neurogenesis) throughout the lifespan of mammals, including humans, has changed the way we think about the mechanisms of psychiatric disorders and drug addiction.
The subgranular zone of the dentate gyrus (SGZ) in the adult brain contains neural stem/progenitor cells (NS/PCs) capable of producing thousands of new granule cells per day.
We, and others, have shown that these newborn hippocampal neurons are functionally integrated into the existing neuroanatomical circuitry and are positively correlated with hippocampus-dependent learning and memory processes and the developmental mechanisms of stress and mood disorders. …
Chronic administration of the major drugs of abuse including opiates, alcohol, nicotine, and cocaine has been reported to suppress hippocampal neurogenesis in adult rats, suggesting a potential role of hippocampal neurogenesis in the initiation, maintenance, and treatment of drug addiction.
The recent finding of prominently decreased hippocampal neurogenesis in CB1-knockout mice suggests that CB1 receptor activation by endogenous, plant-derived, or synthetic cannabinoids may promote hippocampal neurogenesis.
However, endogenous cannabinoids have been reported to inhibit adult hippocampal neurogenesis.
Nevertheless, it is possible that exo- and endocannabinoids could differentially regulate hippocampal neurogenesis, as exo- and endocannabinoids act as full or partial agonists on CB1 receptors, respectively.
The goal of the present study was to test the hypothesis that the potent synthetic cannabinoid HU210 is able to promote hippocampal neurogenesis, leading to the anxiolytic and antidepressant effects of cannabinoids.
We demonstrate here that both HU210 and the endocannabinoid AEA promote proliferation of embryonic hippocampal NS/PCs without significant effects on their differentiation, resulting in more newborn neurons.
The effects of HU210 on adult hippocampal neurogenesis were quantified in freely moving rats and were correlated with behavioral testing.
We show that 1 month after chronic HU210 treatment, rats display increased newborn neurons in the hippocampal dentate gyrus and significantly reduced measures of anxiety- and depression-like behavior.
Thus, cannabinoids appear to be the only illicit drug whose capacity to produce increased hippocampal newborn neurons is positively correlated with its anxiolytic- and antidepressant-like effects.