Selective neurotoxic effects of nicotine on axons in fasciculus retroflexus further support evidence that this a weak link in brain across multiple drugs of abuse.

When administered continuously for several days at relatively low plasma levels, a variety of drugs of abuse with strong dopaminergic actions induce degeneration in axons traveling from the lateral habenula through the sheath of fasciculus retroflexus to midbrain monoaminergic nuclei. With some of these drugs, such as cocaine, this is virtually the only degeneration induced in brain. Nicotine given continuously also selectively induces degeneration in fasciculus retroflexus, but in the other half of the tract: the cholinergic axons running from medial habenula in the core of the tract to the interpeduncular nucleus. Fasciculus retroflexus appears to be a weak link in brain for diverse drugs of abuse when administered incessantly for several days. Alterations in this tract would be predicted to be especially important for the genesis of the symptomatology which develops during drug binges, residual effects of such binges, and the processes underlying relapse.