Neurosteroids are an awesome and fascinating bunch of compounds we know so little about. they are literally a goldmine of opportunity to manipulate brain function for beneficial purposes. they are like a cross between traditional neurotransmitters, psychoactive drugs and a key to epigenetic modulation making them excellent therapeutic treatments for mental illnesses, neurodegenerative disorders and drug addiction.
The most well-known neurosteroids can be categorised into two distinct subsets, these are the GabaAergic and Glutamatergic subtypes. The GabaAergic class have effects very similar to the benzodiazepines and barbiturate type sedatives, reducing stress, suppressing seizures and anxiety, promoting States of tranquility, ranging from conscious calm to deep sleep and even general anaesthesia depending on dose. they can also produce behavioural disinhibition just like alcohol and benzodiazepines. interestingly, these steroids preferentially act on extra synaptic GABAA receptors meaning their effects might not be exactly the same as other sedatives meaning that they can modulate and possibly bypass the tolerance induced bye traditional sedative drugs. it could also be the reason why a neurosteroid based epilepsy drug called ganoxalone if I remember correctly has a considerably lower abuse potential compared to other sedative drugs used for this purpose. given their effects, such steroids can be used in the treatment of drug addiction and are likely to have huge benefits, however, research is in the very early stages and it will take a long time for researchers to discover how to use such steroids, the correct dosage, and when exactly in the addiction cycle to administer them.
The other category of neurosteroids are the excitatory class which generally act as positive allosteric modulators of the NMDA receptor, more specifically, the synaptic NMDA receptor. they may also act as very weak antagonists of the GABAA receptor. At first glance, this sounds like a disaster waiting to happen since NMDA receptors play a major role in excitotoxicity of neurodegeneration, mental illness, and brain injuries. w however, NMDA receptor function is vital for neuronal survival, creating new connections between neurons and thus good cognition and memory as well as good mood and well-being. actually, NMDA receptors are so important in keeping us connected to both our inner and outer worlds and allow us to respond emotionally and rationally to our experiences. improving NMDA receptor function can improve all types of schizophrenia symptoms in animal models and human trials, ranging from psychosis/Delusions/heightened locomotor activity, (positive symptoms) to low mood, apathy and depression (negative symptoms). excitatory neurosteroids activate the NMDA receptor in a manner that might initially slightly stress the neurons due to calcium influx. However, this small calcium influx then triggers a massive set of Chemical and genetic changes in the neuron which make it resistant to future, much larger stresses, including very high glutamate and calcium levels. furthermore, the NMDA receptor activation by these steroids promotes New brain cells to grow, as well as enhancing the creation of new synapses between neurons and strengthening the existing ones. collectively, these effects can dramatically improve cognitive/ memory performance, Problem-solving ability and well-being, making such steroids ideal tools in the fight against Alzheimer’s and neurodegeneration.
In terms of human behaviour, endogenous naturally occurring neurosteroids are believe to play a yet seriously underestimated role in emotional processing related to activities, ranging from food, sleep and socialisation to sexual behaviour, drug abuse and emotional disorders related to the menstrual cycle in women. in regards to the female menstrual cycle, there is a very large amount of literature on the role of neurosteroids but much less is known about the role of these steroids in The day-to-day behaviour of both male and female humans.
Last, but not least, neurosteroids may have The remarkable property of modifying the downstream effects of dopamine receptor signalling in a manner unrelated to their effects on glutamate and GABA. to be specific, a study showed that progesterone, found in both males and females could trigger the phosphorylation of a signalling protein called DARPP32 at one of its specific residues(THR 34). this occurred independently of dopamine D1 receptors, yet this action creates a positive feedback loop that strongly enhances and amplifies the strength of D1 dopamine receptor signalling. D1 receptor activation, especially the PKA downstream pathway, which is magnified bye DARPP32-THR34 is vital for memory and cognitive function, reward processing including the actual experience of pleasure as well as reward learning and last but not least in promoting resilience/resistance to psychological stress especially chronic long-term stress, depression, and despair. D1 receptor signalling also plays a very special and strong role in encoding sexual reward and reinforcement and insured continuation of psychological awareness and seeking of this experience.
All I’ve said so far is just the Tip of the iceberg in terms of neurosteroid actions, much more is available in the literature and much more is yet to be discovered.
