EFFECTS OF CHRONIC Δ9-TETRAHYDROCANNABINOL AND CANNABIDIOL TREATMENTS ON ANTIDEPRESSANT RELATED PROTEIN EXPRESSION IN RAT BRAIN

Maha ElBatsh, Neda Assareh, Charles Marsden, David Kendall
School of Biomedical Sciences and Institute of Neuroscience, University of Nottingham, Nottingham, NG7 2UH, United Kingdom

Plant-derived cannabinoids such as, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been suggested to cause reductions in stress, anxiety and depressive symptoms. Brain-derived neurotrophic factor (BDNF) is considered to have a role in depression and the action of antidepressant drugs (Duman et al., 1997). Decreased expression of BDNF might contribute to the development of depression; an effect possibly reversed by antidepressants. BDNF through activation of tyrosine kinase B (TrkB) receptors causes phosphorylation and activation of signalling molecules, such as cyclic adenosine monophosphate response element binding protein (CREB). Butovsky et al. (2005) demonstrated an up-regulation of BDNF mRNA and protein in the nucleus accumbens and paraventricular nucleus after chronic treatment with THC. The aim of the present study was to investigate whether chronic administration of low doses of Δ9- THC or CBD to rats altered the expression of proteins associated with antidepressant drug action.

Male Lister hooded rats (150-200g, n=8 per group) received daily injections of either vehicle, THC (1mg/kg, i.p.) or CBD (10mg/kg, i.p.) for 14 days. The rats were subjected to two behavioural tests: locomotor activity (for 20 minutes on the 3rd and 9th days of treatment) and conditioned emotional response (CER)( 10th and 11th days of treatment). BDNF, Trk B and CREB/phospho-CREB expression were determined in frontal cortex and hippocampus using Western immunoblotting. Protein levels were calculated as optical densities of appropriate bands following correction for gel loading, and were analysed using one-way ANOVA plus Dunnett’s multiple comparison test.

There were no significant changes in the locomotor activity of the THC- and CBD- treated rats, nor were there any differences in rearing and grooming or freezing behaviour between the groups. There was a significant reduction in BDNF expression in the hippocampus of the CBD-treated animals, compared with the vehicle-treated group (to 73 ± 7.5 % (mean ±SEM), p < 0.01). CBD also caused a significant reduction in the Trk B expression in the hippocampus (to 74 ± 5.2 %, p < 0.05). Although THC produced no significant changes in BDNF levels in the hippocampus it significantly reduced TrkB expression (to 74 ± 9.4%, p < 0.05). CREB expression in the hippocampus was unaffected by either treatment and phospho-CREB was undetectable. CBD treatment tended to reduce BDNF expression in the frontal cortex (to 72 ± 4.8 %, p = 0.09) and had no effect on TrkB or CREB/phospho-CREB expression. THC treatment had no effect on expression of BDNF, TrkB or CREB/phospho-CREB in the frontal cortex.

In conclusion, the chronic administration of low doses of THC and CBD to normal rats did not increase the expression of proteins that have been associated with antidepressant drug activity. Neither was there any behavioural evidence to support anxiolytic effects of the phytocannabinoids. Future studies will focus on the effects of the drugs in animal models of affective disorder.

Butovsky, E. et al. (2005) Journal of Neurochemistry, 93, 802-811.
Duman, R.S., et al. (1997) Arch. Gen. Psychiatry, 54, 597-606.

This work was supported by the Egyptian Government.