Neurobiological effects of early life cannabis exposure in relation to the gateway hypothesis

The use of Cannabis sativa preparations, such as hashish and marijuana, is wide-spread among young people, including pregnant women. Despite this concern, the consequences of cannabis exposure on the brain during periods of active brain development, such as the prenatal phase and adolescence, is not well known. Several epidemiological studies support the cannabis gateway hypothesis, where early cannabis use is suggested to increase the risk of initiating use of other illicit drugs, e.g., amphetamine or heroin. However, the nature of such direct links are unclear. Therefore, the aim of this thesis was to test experimentally the cannabis gateway hypothesis, i.e., to determine whether cannabis exposure during periods of active brain development alters reward-related behavior and neurobiology for psychostimulant and opioid drugs by the use of animal models.

In the first study, we examined the effects of early adolescent exposure (postnatal day; PND; 28-32, one injection per day) with the synthetic cannabinoid CB1 receptor agonist WIN55,212-2 and the main psychoactive substance in C. sativa, Δ9-tetrahydrocannabinol (THC) on amphetamine-induced motor behavior and dopamine release in the nucleus accumbens during adolescence. No alterations were evident in the cannabinoid exposed rats, results which did not support the cannabis gateway hypothesis in relation to subsequent psychostimulant abuse.

Next, we investigated the effects of adolescent exposure on subsequent opioid reward-related behavior and the neurobiology of opioid and cannabinoid systems during adulthood. We studied THC exposure across the full adolescent period (PND 28-49), and administered the drug once every third day in order to better mimic the pattern of intermittent use seen in teenagers. The results revealed discrete opioid-related alterations within brain regions highly implicated in reward and hedonic processing (e.g., increased proenkephalin gene expression in the nucleus accumbens and increased mu opioid receptors in the ventral tegmental area). This was coupled to increased heroin intake in a self-administration paradigm and increased morphine conditioned place preference, indicating altered sensitivity to the reinforcing properties of opioids.

Furthermore, in evaluating the adolescent ontogeny of the opioid and cannabinoid systems within limbic-related brain areas, we found that active endocannabinoid- and opioid- related neurodevelopment takes place to a very high extent during this period. Most pronounced were the alterations in endocannabinoid levels in cognitive brain areas, even though alterations were also apparent in reward-related regions.

Finally, we investigated the effects of prenatal cannabis exposure (gestational day 5- PND 2) on subsequent opioid reward-related behavior and neurobiology of the opioid and cannabinoid systems in adulthood. Similar to adolescent cannabis exposure, prenatal exposure induced discrete opioid-related alterations within brain regions highly implicated in reward and hedonic processing. Moreover, elevated heroin-seeking observed during extinction and after food deprivation was evident in the THC exposed rats, suggesting an increased motivation for drug use under conditions of stress.

Taken together, this thesis presents neurobiological support for the cannabis gateway hypothesis in terms of adult opiate, but not amphetamine, abuse, with underlying long-term disturbances of discrete opioid-related systems within limbic brain regions.

List of scientific papers

I. Ellgren M, Hurd YL, Franck J. (2004). "Amphetamine effects on dopamine levels and behavior following cannabinoid exposure during adolescence." Eur J Pharmacol 497(2): 205-13.
https://doi.org/10.1016/j.ejphar.2004.06.048

II. Ellgren M, Spano SM, Hurd YL. (2006). "Adolescent Cannabis Exposure Alters Opiate Intake and Opioid Limbic Neuronal Populations in Adult Rats. " Neuropsychopharmacology. [Accepted]
https://doi.org/10.1016/j.ejphar.2004.06.048

III. Ellgren M, Artmann A, Gupta A, Tkalych O, Hansen HS, Hansen SH, Devi LA, Hurd YL. (2007). "Time course of limbic-related alterations within the endogenous cannabinoid and opioid systems in a rat model of adolescent cannabis use." [Manuscript]

IV. Spano MS, Ellgren M, Wang X, Hurd YL. (2006). "Prenatal Cannabis Exposure Increases Heroin Seeking with Allostatic Changes in Limbic Enkephalin Systems in Adulthood." Bill Psychiatry. [Accepted]
https://doi.org/10.1016/j.biopsych.2006.03.073