Drug-induced synaptic plasticity in addiction : the mesolimbic dopamine pathway and benzodiazepines
Year: 2012
Type: dissertation
Abstract: Drug addiction is defined as a chronically relapsing disorder of the brain. The characteristic compulsive drug use behaviour despite the negative consequences has been explained by a maladaptive learning phenomenon. Synaptic plasticity, i.e. the ability of neuronal connections to change on demand, forms the basis for learning and memory storage in the brain. Interestingly, many drugs of abuse have been shown to converge in their actions on the mesolimbic dopamine (DA) pathway as they induce synaptic plasticity in the DA neurons of the ventral tegmental area (VTA) that also mediate the recognition of natural rewards and reward-driven learning. This drug-induced plasticity is thought to facilitate future use of the drug i.e. reinforce drug-seeking behavior. Benzodiazepines are anxiolytic and sedative drugs that unfortunately can be addictive in a subset of users. The role of the DA system in benzodiazepine addiction is still controversial and thus this thesis was aimed at studying possible synaptic alterations in the VTA DA neurons induced by acute administration of benzodiazepine ligands. Diazepam and zolpidem were shown to induce persistent plasticity at the glutamatergic synapses in VTA DA neurons; a phenomenon claimed to be a common feature of different kinds of drugs of abuse. The possible effects of this synaptic plasticity at the behavioral level were examined by challenging the locomotor activity of mice with morphine and amphetamine, as the DA system plays a central role in their actions. We found that indeed the locomotor reactions of mice were altered: morphine-induced hyperlocomotion and amphetamine-induced sensitization were attenuated in mice while there was diazepam-induced plasticity at VTA DA neurons (24-72 h after diazepam administration). These findings indicated that the effects of morphine and amphetamine on DA neuron activity might be blunted during diazepam-induced synaptic plasticity. Orexins are neuropeptides synthesized in the hypothalamus; they posses important roles in several behaviors such as the regulation of sleep-wake cycle, arousal, energy balance, stress, motivation and reward. In particular, orexinergic signaling in VTA has been postulated to be important for drug-induced plasticity. The effects of diazepam on the activity of this neuronal population were studied by c-Fos immunohistochemistry as the levels of c-Fos are believed to mirror the activity of neurons. An anxiolytic dose of diazepam prevented the stress-induced increment in the orexinergic activity whereas a clearly sedative dose reduced the activity of these neurons even from the basal levels. These findings led to the formation of the hypothesis that orexinergic activity in the brain could have a role in the anxiolytic, sedative and hypnotic actions of benzodiazepines. In conclusion, this project revealed new aspects about the brain areas and the mechanisms mediating both the therapeutic properties as well as the addictive features of benzodiazepines. New evidence was found for a role of the mesolimbic DA system in mediating the addictive potential of benzodiazepines and a novel hypothesis was devised about how the orexinegic system may play a role in the therapeutic actions of benzodiazepines.
Source: Työväentutkimus Vuosikirja
Author: Anne Panhelainen
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1530303595