Cannabinoids, Neurogenesis and Antidepressant Drugs : Is there a Link ?

Manoela Viar Fogaça, Ismael Galve-Roperh, Francisco Silveira Guimarães and Alline Cristina Campos

Current Neuropharmacology, 2013, 11, 263-275

Abstract

Similar to clinically used antidepressants, cannabinoids can also regulate anxiety and depressive symptoms. Although the mechanisms of these effects are not completely understood, recent evidence suggests that changes in endocannabinoid system could be involved in some actions of antidepressants. Chronic antidepressant treatment modifies the expression of CB1 receptors and endocannabinoid (EC) content in brain regions related to mood and anxiety control. Moreover, both antidepressant and cannabinoids activate mitogen-activated protein (MAP) kinase and phosphoinositide 3- kinase(PI3 K)/Akt or PKB signaling, intracellular pathways that regulate cell proliferation and neural cell survival. Facilitation of hippocampal neurogenesis is proposed as a common effect of chronic antidepressant treatment. Genetic or pharmacological manipulations of cannabinoid receptors (CB1 and CB2) or enzymes responsible for endocannabinoid metabolism have also been shown to control proliferation and neurogenesis in the hippocampus. In the present paper we reviewed the studies that have investigated the potential contribution of cannabinoids and neurogenesisto antidepressant effects. Considering the widespread brain distribution of the EC system, a better understanding of this possible interaction could contribute to the development of therapeutic alternatives to mood and anxiety disorders.

Keywords : Neurogenesis, antidepressant drugs, cannabinoids.

 

1. ADULT NEUROGENESIS

Until the early 60´s, a central dogma of neuroscience had been that no new neurons are added to the adult mammalian brain. For more than 100 years it has been assumed that neurogenesis, or the production of new neurons, occurs only during development and stops before puberty. Although the
very first reports about neurogenesis came from Dr Rita Levi- Montalcini’s work with Nerve Growth Factor, it was Joseph Altmanin the early 60´s that published a series of papers presenting evidence that new neurons are added in specific regions of the young and adult rat brain, including the neocortex, hippocampal formation and olfactory bulb [1-3]. Subsequently, Eriksson and colleagues (1998) confirmed that new neurons are indeed generated in the hippocampus of adult humans [4] and established one of the most stimulating recent fields in neuroscience: neurogenesis in the adult brain.

Although a low proliferative activity has been reported in several brain regions such as the hypothalamus and the cell layers surrounding the third ventricle [5], a body of evidence supports the idea that in the adult mammalian brain only two regions show neurogenesis under physiological conditions: the subventricular zone (SVZ) of the lateral walls of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus of the hippocampal formation [6, 7].

Adult neurogenesis is a complex process that involves the initial division of a precursor cells and lasts until the existence of a new functionally new neuron. In the words of Dr. G. Kempermann: “neurogenesis is a process, not an event”. It can be more precisely defined as an in vivo process that involves division, survival (not all dividing cells will survive), migration and differentiation [7, 8].

The physiological impact of adult neurogenesis is not yet completely understood. And importantly its relevance and existence in humans is matter of debate. SVZ neurogenesis seems to be regulated by the olfactory experience of animals [9, 10]. Odor exposure can increase the survival of newborn neurons and improve memory in a learned odor discrimination task [11], suggesting that in this region neurogenesis plays a role in learning and memory processes related to olfactory stimulation [11]. In the hippocampus
SGZ, another major site of adult neurogenesis [12, 13], an association between this process and learning and memory has been found in rodents and humans [14-17]. Moreover, stimuli known to improve learning and memory processes, such as voluntary running and exposure to enriched environments [16, 18], increase SGZ cell proliferation and the survival of new neurons generated in this region [19, 20]. As a consequence, hippocampal neurogenesis has been suggested to be important for at least some forms of learning and memory [14-17]. Despite these pieces of evidence, adult neurogenesis is not necessarily always good to brain function. For example, increased neurogenesis after hippocampus injury could be involved in the development of temporal seizures [7].

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