We use a variety of biomedical methods ranging from optogenetics and electrophysiology through histological techniques to behavioral animal models, chemogenetics and, of course, pharmacological tools.
In the past years, we at the Korpi lab have focused on the long-term effects of the GABAA receptor modulating drugs, and on their effects on the dopamine neurons of the ventral tegmental area (VTA), and on other drugs that might counteract the effects of the drugs of abuse.
We have found that single ex vivo exposures to addictive, dependence-causing, synaptically active benzodiazepines, diazepam and zolpidem, and to two non-benzodiazepines, extrasynaptically active gaboxadol and ganaxolone, induce glutamate receptor neuroadaptation in mouse VTA dopamine neurons. This process involves cellular plasticity and represents long-lasting neuroadaptation of the glutamatergic system in the VTA through, at the systems level, the disinhibition of the DA neurons.
Interestingly, these latter drugs do not show rewarding properties in mice or baboons, but induce conditioned place aversion in mice. This result fits with a dichotomous functional/structural organization of VTA dopamine neuron populations both in monkeys and mice.
We have also found interesting "anti-addictive" effects of pregabalin (a presynaptic Ca2+ channel downregulator) and rac-BHFF (a GABAB receptor positive allosteric modulator) on the VTA neuroplasticity and behaviours induced by drugs of abuse.
The current projects of the lab, aiming to elaborate the neuronal circuits behind the addictive behaviours, are described below.
We have recently reviewed the regulation and neuroplasticity of midbrain neurons as the critical part of reward/aversion circuitry for a number of drugs of abuse, and found that the idea of diverse populations of VTA dopamine and GABA neurons is still waiting for more detailed neurobiological and behavioural assessment and verification.
Nagaeva, Schäfer et al. Somatostatin-Expressing Neurons in the Ventral Tegmental Area Innervate Specific Forebrain Regions and Are Involved in Stress Response. eNeuro, 2023
Nagaeva et al. Heterogeneous somatostatin-expressing neuron population in mouse ventral tegmental area. eLife, 2020
Nagaeva et al. Electrophysiological Properties of Neurons: Current-Clamp Recordings in Mouse Brain Slices and Firing-Pattern Analysis. Bio-Protocol, 2021.
Serotonin is thought to play a part in the formation of addictive behavior. This has been interestingly reflected in clinical studies, conducted in between 1950's and 1970's and again more recently, showing that nonselective serotonin receptor agonists, psychedelics lysergic acid diethylamide (LSD) and psilocybin, can reduce alcohol drinking, and help people with smoking cessation.
In this new project we aim to elucidate the biological mechanisms behind these clinically shown effects.
Elsilä et al. Effects of acute lysergic acid diethylamide on intermittent ethanol and sucrose drinking and intracranial self-stimulation in C57BL/6 mice. Journal of Psychopharmacology, 2022
Elsilä et al. Acute Lysergic Acid Diethylamide Does Not Influence Reward-Driven Decision Making of C57BL/6 Mice in the Iowa Gambling Task. Frontiers in Pharmacology, 2020
Hynninen et al. Psykedeelien kliiniset vaikutukset ja biologiset mekanismit. Duodecim, 2020 (review in Finnish)