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Ellgren M, Spano SM, Hurd YL. 
“Adolescent Cannabis Exposure Alters Opiate Intake and Opioid Limbic Neuronal Populations in Adult Rats”. 
Neuropsychopharmacology. 2006 July 5;ponline.
Cannabis use is a hypothesized gateway to subsequent abuse of other drugs such as heroin. We currently assessed whether D-9- tetrahydrocannabinol (THC) exposure during adolescence modulates opiate reinforcement and opioid neural systems in adulthood. Long–Evan male rats received THC (1.5 mg/kg intraperitoneally (i.p.)) or vehicle every third day during postnatal days (PNDs) 28–49. Heroin self-administration behavior (fixed ratio-1; 3-h sessions) was studied from young adulthood (PND 57) into full adults (PND 102). THC-pretreated rats showed an upward shift throughout the heroin self-administration acquisition (30 mg/kg/infusion) phase, whereas control animals maintained the same pattern once stable intake was obtained. Heightened opiate sensitivity in THC animals was also evidenced by higher heroin consumption during the maintenance phase (30 and 60 mg/kg/infusion) and greater responding for moderate–low heroin doses (dose–response curve: 7.5, 15, 30, 60, and 100 mg/kg/injection). Specific disturbance of the endogenous opioid system was also apparent in the brain of adults with adolescent THC exposure. Striatal preproenkephalin mRNA expression was exclusively increased in the nucleus accumbens (NAc) shell; the relative elevation of preproenkephalin mRNA in the THC rats was maintained even after heroin self-administration. Moreover, m opioid receptor (mOR) GTP-coupling was potentiated in mesolimbic and nigrostriatal brainstem regions in THC-pretreated animals. mOR function in the NAc shell was specifically correlated to heroin intake.

The current findings support the gateway hypothesis demonstrating that adolescence cannabis exposure has an enduring impact on hedonic processing resulting in enhanced opiate intake, possibly as a consequence of alterations in limbic opioid neuronal populations. Neuropsychopharmacology advance online publication, 5 July 2006; doi:10.1038/sj.npp.1301127
Comments and Responses to this Article
Apr 17, 2011 1:59
Scientists Should Stay Out of Politics #

This paper is marred by the authors' desire to join the political debate about the 'Gateway Theory'. The senior author, Yasmin Hurd, is quoted by Nature in a news article saying that she is strongly against 'softening' laws regarding cannabis, calling such ideas 'ridiculous'. See Nature news July 5, 2006

The abstract for the article makes a statement supporting the Gateway Theory, although the article itself provides little to no basis for this political position. In fact, the authors seem to be confused about what the Gateway Theory is in the first place. It seems to suggest willful ignorance, given how easy it is to find out what GT entails.

It is Ellgren et al's contention that the Gateway Theory is NOT that cannabis use later predisposes individuals to using heroin, but rather, based on their study of rats, that the peak amount of heroin used by regular heroin users will increase if they used cannabis as adolescents.
'In summary, the current findings provide direct evidence in support of the gateway hypothesis that adolescent cannabis exposure contributes to greater heroin intake in adulthood.' [Ellgren et al 2006]
Contradicting the actual Gateway Theory (that adolescent cannabis exposure increases likelihood of future 'hard drug' use through physiological changes), the authors write:
'The periodic exposure to low-dose THC during adolescence did not appear to predispose animals to an increased sensitivity to initiate heroin self-administration.' [Ellgren et al 2006]
While their findings are interesting, their political conclusions are distracting and misleading. The research conducted here attempts to tease out extremely minor effects that are difficult to simply extrapolate to humans from the original rat data.

The researchers first injected half of the rats (5-6 in each group) with THC (1.5mg/kg) every three days for 24 days. Within a week, the rats were catheterized (a tube surgically inserted into their neck into a major artery), restrained, and their diet restricted. They were then injected with heroin and offered two levers (and nothing else). One lever does nothing, the other injects a small amount of heroin into their neck if they press it enough times. The 'training' period continues for 14 days, with heroin training sessions going for 3 hours per day.

After the rats are trained to self-administer heroin, the test 'begins'. A number of different dosages of heroin (delivered when the rats pressed the levers) were tried, from 7.5ug/kg/infusion to 100ug/kg/infusion.

The primary effect they measured was that the rats that were pre-treated with THC continued to increase the amount of heroin they injected at the 30ug/kg/infusion dosage level over a longer period than the rats who had not been given THC weeks before. For the first 7 sessions at 30ug/kg/infusion, the THC and non-THC rats increased their dosage at identical rates. It was only on the next four sessions that the THC rats increased the number of doses they self-administered while the non-THC rats appeared to settle into a lower total amount of heroin per session.

On the dose-response test, where the researchers tried varying the amount of heroin given by the lever pressings, the THC and non-THC rats self-administered statistically identical amounts of heroin at the highest dosage level (100ug/kg/injection).

An odd reported effect was that non-THC rats pressed the heroin lever more times when no heroin was delivered than THC rats. That is to say that when the test was set up to not deliver any heroin, no matter how many times the lever was pressed, the non-THC rats pressed the heroin lever more times than the rats who had been given THC weeks before.

This research also involved doing brain slicing and looking at receptor binding. Their results are preliminary, but include some interesting possible findings about changes in the endogenous opioid system.

It is finally worth noting that time between the THC administration and heroin administration was between a week and a few weeks. The researchers imply that the changes are permanent, but it is also possible that the brain and behavioral changes caused by the THC administration could reduce or revert over longer periods of time.

Unfortunately, the mixture of science and politics is, once again, a total disaster for this paper and suggests that the researchers intended to help provide support for a political theory through their research. While this is probably good for their funding, it also shows the compromised nature of some psychoactive research.
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