Long-term potentiation (LTP) is one of the fundamental neurobiologic mechanisms involved in learning and memory. Alcohol produces more inhibition of LTP in adolescent rats than adults. This could directly relate to the increase sensitivity of alcohol induced cognitive impairments a seen in adolescence.

Alcohol Produces More Inhibition of Long Term Potentiation (LTP) in Adolescent Rats than Adult Rats

There is extensive evidence that LTP is a fundamental neurobiological mechanism involved in learning and memory and the increased potency of alcohol in impairing LTP in adolescent rats is consistent with the increased potency of alcohol in impairing memory in adolescent rats compared to adult rats. LTP was recorded from stimulation and recording in the stratum radiatum region of the CAI region of hippocampal slices, before a theta-burst stimulus train that was delivered at the end of the slice exposure to 1, 10 or 30 mM alcohol for 30 min and the then the slice was exposed to normal fluid for 30 min when the response to the test stimuli was recorded.pEPSP = population excitatory post synaptic potential , 10 mM alcohol is approximately the peak blood alcohol level following 2 drinks in a 70 Kg person.* = compared to control.(Constructed from data in Pyapali, G.K. et al. Alcohol, 19: 107, 1999) ©2009 NBEP
Neurogenesisis off great importance during development and in the hippocampus it continues throughout adult hood. Neurogenesis has been linked to learning and memory. There is a much greater production of new cells in the hippocampus in juvenile animals and it progressively decreases in to adult hood including middle aged and aged animals.

There is a Marked Decrease in Hippocampus Dentate Gyrus Cell Proliferation Across the Life Span of a Rat Which is Larger the Younger the Rat

Across 17 days of Adolescence there is a decrease of 12.5% of P14 and across 210 days of adulthood to middle age. There is a decrease of 10% of P14 in dentate gyrus cell proliferation. 5-bromodeoxyuridine incorporation into cells was assessed in rats in Study A 2 hr following a single injection in Study B 24 hr after the last of 3 daily injections. * Proliferation at P90 assumed to be the same as P60 and P300 and P600 calculated relative to P90. (Constructed from data in Dong, H. et al. J Neuroscience, 23: 1742, 2003 and Nacher, J. et al. Neurobiology of Aging, 24: 273, 2003) ©2008 NBEP
It has been demonstrated that adolescent rats are very sensitive to alcohol effects on inhibition of neurogenesis at levels of alcohol that are relevant to the amount of alcohol consumed in humans.

Adolescent Rats are Very Sensitive to Alcohol Inhibition of Neurogenesis.

A single administration to 3 groups of adolescent rats (post natal 35-40 days) of three different doses of intragastric alcohol (1.0, 2.5 or 5.0 g/kg) produces peak alcohol levels similar to those found in humans after drinking 2-6 drinks. Proliferation was measured as bromodeoxyuridine-immunoreactivity 5 hr after a single injection of bromodeoxyuridine Neurogenesis was measured 3 days later using double cortin which labels immature neurons, and survival was measured 28 days later as bromodeoxyuridine containing cells that also contained neuronal markers. Similar findings were obtained for cells in the forebrain subventricular zone and rostral migratory stream. (Constructed from data in Crews, F.T. et al. Neuroscience, 137: 437, 2006) ©2008 NBEP
It is of major interest that alcohol induced impairment of neurogenesis is greater and adolescent rats compared to adults even though and the blood-alcohol levels were lower in the adolescent rats. The increased sensitivity of impairment of neurogenesis in adolescence could be an important factor contributing to the greater impairment of cognitive function in adolescence following alcohol.

Adolescent Rats are More Sensitive to Alcohol Induced Inhibition of Neurogenesis than Adults.

Following intragastric alcohol administration to adult (post natal day 90) and adolescent (post natal day 35-40) rats, bromodeoxyuridine was administered to label nonproliferating cells. Brains were taken 5 hrs following the alcohol dose. There was a greater percent inhibition of neurogenesis in the adolescent rats despite lower blood alcohol levels.(Constructed from data in Adults: Nixon, K. and Crews, F.T. et al. J Neurochem, 83:1087, 2002 and Adolescents: Crews, F.T. et al. Neuroscience, 137: 439, 2006)©2008 NBEP
One of the major common effects of drugs of abuse is to increase dopamine levels in the nucleus accumbens. It has been found that exposure to alcohol during adolescence increases dopamine levels in the nucleus accumbens in adult hood.

Alcohol Exposure During Adolescence Produces Increased Dopamine Levels in the Nucleus Accumbens in Adulthood.

Dopamine uptake was also increased by about 10% (but this did not reach statistical significance in this small number of rats), which suggests increased dopamine production secondary to alcohol exposure in adolescence. This may be a mechanism by which alcohol exposure in adolescence increases the risk of developing alcohol dependence. Male Sprague - Dawley rats were injected with a daily dose of alcohol (0.75g/kg) or saline from postnatal day 30 to day 50 and then had no injections for 14 days (days 51-65). Dialysis Probes were then implanted into the nucleus Accumbens shell and dopamine levels and uptake of dopamine were measured with the no net flux paradigm. (Constructed from data in Badanich, K.A. et al, Alcohol Clin Exp Res, 31: 895, 2007) ©2008 NBEP
When acute doses of alcohol were administered to adult rats, those that were exposed to alcohol during adolescence had increased elevation of dopamine levels. The exposure to alcohol during adolescence can produce increased dopamine effects of alcohol that persist into adult hood and this may serve as the basis for the increased alcohol preference in those animals exposed to alcohol during adolescence

Alcohol Drinking During Adolescence in Alcohol-Preferring Rats Produces Increased Dopamine Uptake and an Increased Elevation of Dopamine Levels Following Alcohol Administration in Adulthood.

Baseline dopamine levels in adulthood were not different between rats drinking water or drinking alcohol during adolescence so the increased dopamine clearance with normal basal levels suggests alcohol drinking in adolescence increases dopamine neurotransmission, this is seen in the increased dopamine response to alcohol in the adult rats that had drunk alcohol in adolescence. Drinking alcohol in adolescence produces long lasting alterations in dopamine neurotransmission that could be the basis for the increased risk of alcohol dependence following adolescent alcohol exposure. Male alcohol-preferring rats drank about 8gm/kg/day of alcohol in a 15% solution or water from postnatal day 30 to 60. They had dopamine uptake measured with dialysis probes placed into the nucleus accumbens core and shell using the no net flux paradigm on day 84, on day 85 they received an injection of alcohol 2.5g/kg or saline. Motor activity assessed in the open field did not differ between the 2 groups. * ANOVA interaction (Constructed from data in Sahr, A.E. et al. Alcohol Clin Exp Res 28: 702, 2004) ©2008 NBEP