Running can be addictive and reinforcing, and it also has an antidepressant effect in humans. There are two major sites in the brain for adult neurogenesis, the sub-granular zone of the dentate gyrus and the sub-ventricular zone. New cells formed in the sub-ventricular zone migrate along the rostral migratory stream to the olfactory bulb whereas those formed in the sub-granular zone remain within the dentate gyrus. All commonly used antidepressive treatments such as ECT, tricyclics and SSRI increase neurogenesis [33
] (). Moreover, running also increases hippocampal neurogenesis [34
]. To investigate whether running is antidepressant in experimental animals a genetic model of depression, the Flinders Sensitive Line (FSL) [35
], were given access to running wheels during a month. Interestingly, cell proliferation was lower in the depressed FSL rats compared to the non-depressed Flinders resistant line rats (FRL) in the sub-granular zone of the dentate gyrus, Moreover, running was antidepressant in FSL rats and was also associated with increased cell proliferation in the sub-granular zone of the dentate gyrus and increased levels of NPY mRNA in the dentate gyrus (). None of these effects were seen in the non-depressed FRL rats [36
]. Thus running as well as all antidepressants used in treatments of depressed humans, seems to increase cell proliferation in the sub-granular zone [33
] and NPY in dentate gyrus [36
] () [35
]. In contrast, running had no effect on cell proliferation in the non-depressed FRL strain that served as a control [38
Treatment effects on cellproliferation/neurogenesis and NPY levels in hippocampus
In a recent study [39
], female spontaneous hypertensive rats with free access to running wheels for 24 days inhibited proliferation of hippocampal progenitor cells by approximately 50 %, whereas a shorter time, 9 days of running with free access to the running wheels resulted in a 5-fold increase in proliferation. Also, with the long-term free access to running wheels, animals run approximately 20 km/day and had increased levels of plasma corticosterone, weight of the adrenal glands and the thymus. When distance allowed to run in the running wheels during 24 days was restricted to 6 km/day, animals did not develop this response [39
]. These results indicate that different doses of running can cause dynamic regulation of hippocampal cell proliferation together with an altered hormonal balance in hypertensive rats. Whether these effects can be repeated in non-hypertensive rats or if they in any way could mirror a development of an overtraining syndrome in humans remains to be shown.
There are several reports that repeated administration of addictive drugs has neurotoxic effects in the adult mammalian brain. For example, met-amphetamine has damaging effects on particularly the 5-HT [40
] and dopamine terminals [41
]. Phencyclidine is another drug that has long-lasting toxic effects on the brain [42
] possibly remaining for the rest of an individual’s life. Long term administration of morphine and heroin self-administration decreases neurogenesis in hippocampus [43
]. Also, alcohol has neurotoxic effects in parts of the cerebral cortex [44
] after long term use. In many rodent studies, very high and toxic doses of ethanol, which rarely are reached in human consumers, have been given. This has generated reports of neurodegenerative effects of ethanol in hippocampus. In contrast, in humans, when using stereological analysis methods the number of nerve cells in hippocampus is unchanged even after very long time of alcohol abuse. Instead, a decrease in the size of hippocampus, caused by a reduction of white matter and astrocytes has been reported [45
]. As with other drugs the effects of alcohol can persist for the rest of an individual’s life. It has been suggested that even after long periods without alcohol intake the brain remains reprogrammed; a drug-paired alcohol memory has been formed, and thus the risk to relapse persists.
We recently reported that single housed female C57BL/6 mice that voluntarily consumed moderate levels of alcohol during 2 months in fact have increased cell proliferation and neurogenesis in the dentate gyrus and that there were no overt neurotoxic effects () [47
]. The reason for these results seemingly opposite effects of ethanol compared to certain other studies could be that our mice at the time of sacrifice had a blood alcohol level of 0.24%thou and most likely never reached neurotoxic concentrations. The mice in our experiment thus consumed ethanol in amounts that what would correspond to levels seen in recreational consumers rather than heavy drinkers. Since the mice in our study were single-housed it is conceivable that they developed a degree of stress and anxiety and consequently that the alcohol intake had anxiolytic effects. It can be hypothesized that cells born in hippocampus under the influence of ethanol will differentiate to neurons and become integrated into functional neuronal networks that carry alcohol-paired memories. Although speculative, this possibility should be viewed against the background of paucity of neurobiological mechanisms that have been put forward to explain the long-term functional adaptations caused by alcohol and other drugs of addiction. It is not understood why detoxified addicts remain at high risk of relapsing. One hypothesis is that a stable drug-paired memory with a high emotional impact is formed following reinforcing or rewarding experiences of alcohol or other drugs and stored by as yet unknown mechanisms. Hypothetically, this drug-paired memory can be activated by drug-paired cues and craving for the drug develops.
While formation of new neurons is one possible effect of drug intake, other structural rearrangements that have been reported include decreased complexity of dendritic branching and spine numbers on medium spiny neurons in nucleus accumbens after chronic morphine [48
]. Chronic morphine treatment also decreases the size of the dopamine cells in the ventral tegmental area [49
]. In contrast, repeated administration of psychostimulants increases the number of dendritic branching points and spines in nucleus accumbens and prefrontal cortex [50
]. Thus, examples of structural rearrangement that involves, dendritic branching, and fluctuations in the size of the nerve cells hippocampus, accumbens, prefrontal cortex and the ventral tegmental area [47
] both after administration of addictive drugs and antidepressant treatments, including running, have been documented and are likely of importance to understanding of the neurobiological basis of addiction and antidepressant treatments. Since antidepressant treatments, addictive drugs and naturally rewarding behaviors, such as running, affect the levels of transcription factors, growth and trophic factors it is reasonable to assume that these proteins may have a role in mediating the structural rearrangement processes in the brain.