Hello my friends!

I hope you guys are as excited as I am that we have entered a new era in nootropic experimentation. 

I like to name things so I will very ‘creatively’ call it The Circadian Era. lol

Honestly, the recent discoveries in circadian biology have changed everything. 

We now have to take into account how every substance that we take affects our body’s response to LIGHT hitting the retina. 

Additionally, we have to take into account circadian TIMING rules in our experimentation so as not to throw off our body’s daily rhythms of genetic expression, hormone secretion, receptor trafficking, etc.

Today, however, I want to focus on light.

We all know that caffeine and modafinil affect wakefulness.

I propose that each substance affects wakefulness primarily by changing the retina’s response to light, the retinohypothalamic tract’s response to light AND the suprachiasmatic nucleus’ response to light. 

The increased activity of the suprachiasmatic nucleus in response to light thereby increases orexin secretion which increases norepinephrine secretion and thereby wakefulness. 

Here’s how it looks:

IF more dopamine, THEN more melanopsin in ipRGCs. (see study on circadian dopamine below)

IF more melanopsin, THEN greater response of ipRGCs to light.

IF greater response of ipRGCs THEN greater release of excitatory glutamate onto suprachiasmatic nucleus neurons. 

IF greater release of glutamate on to suprachiasmatic nucleus neurons, THEN greater release of glutamate onto orexin secreting neurons.

IF greater release of glutamate onto orexin secreting neurons, THEN greater orexin neuron excitation THEN enhanced wakefulness THEN enhanced locus coeruleus release of norepinephrine THEN even greater increased wakefulness. 

ipRGCs = intrinsically photosensitive retinal ganglion cells.

Note: exercise increases orexin production so use my Day Frame below to schedule exercise into your day to enhance this pathway further. We want to enhance orexin production AND orexin release for optimal cascading wakeful and cell synchronizing effects to our entire body. 

Look at our Reference Frame below to get clear on the sequence. 

So, caffeine increases dopamine which could increase melanopsin expression in ipRGCs. 

Modafinil increases dopamine which could also increase melanopsin expression in ipRGCs. 

Caffeine inhibits adenosine receptors on retinohypothalamic tract neurons which will increase glutamate release onto the suprachiasmatic nucleus. (see studies below)

Modafinil enhances glutamatergic signaling in the brain which could increase glutamate release onto the suprachiasmatic nucleus. (see studies below)

Of course, substances have MANY different effects in MANY different areas of the brain and body, but the is THE most upstream area there is. 

We are talking about the chromophore’s (melanopsin in this case) interaction with light itself. 

The VERY interface of our body with photonic input from the external environment.

Note: ALWAYS focus on fundamental interfaces. There are always surprises here. If we change the interface then we can change EVERY downstream affect from that fundamental source. Additionally, we can control the fundamental INPUT to that interface by controlling light. It’s incredible what we can do now days. We can control the input into the interface (light) AND the response of that interface (melanopsin) to the input. This has cascading affects throughout our ENTIRE body. It’s crazy. We’ve seriously found The Grail. 

https://www.frontiersin.org/articles/10.3389/fncel.2017.00091/full

Dopamine: A Modulator of Circadian Rhythms in the Central Nervous System

Abstract

Circadian rhythms are daily rhythms that regulate many biological processes – from gene transcription to behavior – and a disruption of these rhythms can lead to a myriad of health risks. Circadian rhythms are entrained by light, and their 24-h oscillation is maintained by a core molecular feedback loop composed of canonical circadian (“clock”) genes and proteins. Different modulators help to maintain the proper rhythmicity of these genes and proteins, and one emerging modulator is dopamine. Dopamine has been shown to have circadian-like activities in the retina, olfactory bulb, striatum, midbrain, and hypothalamus, where it regulates, and is regulated by, clock genes in some of these areas. Thus, it is likely that dopamine is essential to mechanisms that maintain proper rhythmicity of these five brain areas. This review discusses studies that showcase different dopaminergic mechanisms that may be involved with the regulation of these brain areas’ circadian rhythms. Mechanisms include how dopamine and dopamine receptor activity directly and indirectly influence clock genes and proteins, how dopamine’s interactions with gap junctions influence daily neuronal excitability, and how dopamine’s release and effects are gated by low- and high-pass filters. Because the dopamine neurons described in this review also release the inhibitory neurotransmitter GABA which influences clock protein expression in the retina, we discuss articles that explore how GABA may contribute to the actions of dopamine neurons on circadian rhythms. Finally, to understand how the loss of function of dopamine neurons could influence circadian rhythms, we review studies linking the neurodegenerative disease Parkinson’s Disease to disruptions of circadian rhythms in these five brain areas. The purpose of this review is to summarize growing evidence that dopamine is involved in regulating circadian rhythms, either directly or indirectly, in the brain areas discussed here. An appreciation of the growing evidence of dopamine’s influence on circadian rhythms may lead to new treatments including pharmacological agents directed at alleviating the various symptoms of circadian rhythm disruption.

https://onlinelibrar…68.2005.04512.x

Dopamine regulates melanopsin mRNA expression in intrinsically photosensitive retinal ganglion cells

Abstract

In mammals a subpopulation of retinal ganglion cells are intrinsically photosensitive (ipRGCs), express the photopigment melanopsin, and play an important role in the regulation of the nonimage-forming visual system. We have recently reported that melanopsin mRNA and protein levels in the rat retina are under photic and circadian control. The aim of the present work was to investigate the mechanisms that control melanopsin expression in the rat retina. We discovered that dopamine (DA) is involved in the regulation of melanopsin mRNA, possibly via dopamine D2 receptors that are located on these ipRGCs. Interestingly, we also discovered that pituitary adenylate cyclase-activating peptide (PACAP) mRNA levels are affected by DA. Dopamine synthesis and release in the retina are regulated by the rod and the cone photoreceptors via retinal circuitry; our new data indicate that DA controls melanopsin expression, indicating that classical photoreceptors may modulate the transcription of this new photopigment. Our study also suggests that DA may have an important role in mediating the light signals that are used for circadian entrainment and for other responses that are mediated by the nonimage-forming visual system.

https://www.ncbi.nlm…les/PMC2104795/

Presynaptic Adenosine A1 Receptors Regulate Retinohypothalamic Neurotransmission in the Hamster Suprachiasmatic Nucleus

Abstract

Adenosine has been implicated as a modulator of retinohypothalamic neurotransmission in the suprachiasmatic nucleus (SCN), the seat of the light-entrainable circadian clock in mammals. Intracellular recordings were made from SCN neurons in slices of hamster hypothalamus using the in situ whole-cell patch clamp method. A monosynaptic, glutamatergic, excitatory postsynaptic current (EPSC) was evoked by stimulation of the optic nerve. The EPSC was blocked by bath application of the adenosine A1 receptor agonist cyclohexyladenosine (CHA) in a dose-dependent manner with a half-maximal concentration of 1.7 µM. The block of EPSC amplitude by CHA was antagonized by concurrent application of the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). The adenosine A2A receptor agonist CGS21680 was ineffective in attenuating the EPSC at concentrations up to 50 µM. Trains of four consecutive stimuli at 25 ms intervals usually depressed the EPSC amplitude. However, after application of CHA, consecutive responses displayed facilitation of EPSC amplitude. The induction of facilitation by CHA suggested a presynaptic mechanism of action. After application of CHA, the frequency of spontaneous EPSCs declined substantially, while their amplitude distribution was unchanged or slightly reduced, again suggesting a mainly presynaptic site of action for CHA. Application of glutamate by brief pressure ejection evoked a long-lasting inward current that was unaffected by CHA at concentrations sufficient to reduce the evoked EPSC amplitude substantially (1 to 5 µM), suggesting that postsynaptic glutamate receptor-gated currents were unaffected by the drug. Taken together, these observations indicate that CHA inhibits optic nerve-evoked EPSCs in SCN neurons by a predominantly presynaptic mechanism.

https://www.ncbi.nlm…les/PMC2696807/

Effects of Modafinil on Dopamine and Dopamine Transporters in the Male Human Brain: Clinical Implications

Abstract

Modafinil, a wake-promoting drug used to treat narcolepsy, is increasingly being used as a cognitive enhancer. Although initially launched as distinct from stimulants that increase extracellular dopamine by targeting dopamine transporters, recent preclinical studies suggest otherwise.

Objective

To measure the acute effects of modafinil at doses used therapeutically (200 mg and 400 mg given orally) on extracellular dopamine and on dopamine transporters in the male human brain.

Design, Setting, and Participants

Positron emission tomography with [11C]raclopride (D2/D3 radioligand sensitive to changes in endogenous dopamine) and [11C]cocaine (dopamine transporter radioligand) was used to measure the effects of modafinil on extracellular dopamine and on dopamine transporters in 10 healthy male participants. The study took place over an 8-month period (2007–2008) at Brookhaven National Laboratory.

Main Outcome Measures

Primary outcomes were changes in dopamine D2/D3 receptor and dopamine transporter availability (measured by changes in binding potential) after modafinil when compared with after placebo.

Results

Modafinil decreased mean (SD) [11C]raclopride binding potential in caudate (6.1% [6.5%]; 95% confidence interval [CI], 1.5% to 10.8%; P=.02), putamen (6.7% [4.9%]; 95% CI, 3.2% to 10.3%; P=.002), and nucleus accumbens (19.4% [20%]; 95% CI, 5% to 35%; P=.02), reflecting increases in extracellular dopamine. Modafinil also decreased [11C]cocaine binding potential in caudate (53.8% [13.8%]; 95% CI, 43.9% to 63.6%; P<.001), putamen (47.2% [11.4%]; 95% CI, 39.1% to 55.4%; P<.001), and nucleus accumbens (39.3% [10%]; 95% CI, 30% to 49%; P=.001), reflecting occupancy of dopamine transporters.

Conclusions

In this pilot study, modafinil blocked dopamine transporters and increased dopamine in the human brain (including the nucleus accumbens). Because drugs that increase dopamine in the nucleus accumbens have the potential for abuse, and considering the increasing use of modafinil, these results highlight the need for heightened awareness for potential abuse of and dependence on modafinil in vulnerable populations.

https://pubmed.ncbi….h.gov/30468674/

Modafinil and orexin system: interactions and medico-legal considerations

Abstract

Modafinil (Mo) is increasingly being used as an enhancement drug rather than for its therapeutic effects. The effects of this drug have been examined in attention deficit disorders, depression, mental fatigue, and in enhancing concentration. The drug possesses wakefulness-promoting properties which are mediated through the interaction of orexinergic system with the activated sympathetic nervous system. Mo exerts a synergistic effect on the orexin system, controls energy expenditure and strengthens the ability of the individual to exercise. Some view Mo as a drug that enhances sports performance, since it induces a prolonged wakefulness and decreasing the sense of fatigue. These characteristics being similar to conventional stimulants have allowed Mo to emerge as a novel stimulant requiring medico-legal considerations. However, more studies are needed to better understand the mid and long-term effects of the drug on user/abuser.

https://pubmed.ncbi….h.gov/14521986/

Stimulant doses of caffeine induce c-FOS activation in orexin/hypocretin-containing neurons in rat

Abstract

Although caffeine is a commonly used CNS stimulant, neuronal mechanisms underlying its stimulatory effect are not fully understood. Orexin (hypocretin)-containing neurons play a critical role in arousal and might be activated by acute administration of caffeine. We examined this possibility by using dual-immunostaining for orexin B and c-Fos protein as a marker for neuronal activation. Rats were administered intraperitoneally with 10, 30 or 75 mg/kg caffeine, or saline. As previously reported, caffeine increased locomotion at 10 and 30 mg/kg, but not at 75 mg/kg. The numbers of orexin-immunoreactive and non-orexin-immunoreactive neurons expressing c-Fos were analysed using three counting boxes within the orexin field in the posterior hypothalamus. Compared with saline, all doses of caffeine increased the number of cells immunoreactive for both orexin and c-Fos. The average magnitude of this increase across doses in orexin neurons differed amongst regions; c-Fos expression increased by 343% in the perifornical area and by 158% in the more medial, dorsomedial nucleus. In the lateral hypothalamic area, c-Fos expression increased by 226% at 10 and 30 mg/kg but no change was seen at 75 mg/kg. In contrast, caffeine significantly increased the number of non-orexin-immunoreactive neurons expressing c-Fos only in the dorsomedial nucleus. These results indicate that systemically administered caffeine preferentially activates orexin neurons over non-orexin neurons in the same field, and that this activation is most pronounced in the perifornical region where orexin neurons are most concentrated. The activation of orexin neurons might play a role in the behavioural activation by caffeine.

https://pubmed.ncbi….ih.gov/9376524/

The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus

Abstract

The antinarcoleptic drug modafinil [(diphenyl-methyl)-sulfinyl-2-acetamide; Modiodal] dose-dependently inhibits the activity of GABA neurons in the cerebral cortex and in the nucleus accumbens, as well as in sleep-related brain areas such as the medial preoptic area and the posterior hypothalamus. This study examined the effects of modafinil (30-300 mg/kg, i.p.) on dialysate glutamate and GABA levels in the ventromedial (VMT) and ventrolateral (VLT) thalamus and hippocampal formation (Hip) of the awake rat. The results show a maximal increase in glutamate release in these brain regions at the 100 mg/kg dose, associated with a lack of effect on GABA release. Thus modafinil may increase excitatory glutamatergic transmission in these regions, altering the balance between glutamate and GABA transmission.