Using c-fos labeling, researchers have shown that modafinil induces arousal through mechanisms distinct from those of amphetamine and methylphenidate. In particular, c-fos immunoreactivity was found in the tuberomammillary nucleus and hypocretin/orexin neurons of the perifornical cortex.

Hypothalamic-pituitary axis

The hypothalamic-pituitary-adrenal (HPA) axis is a complex set of neuroendocrine pathways and feedback loops that maintain physiological homeostasis. Its abnormal development can result in long-term alterations in peptide and neurotransmitter production within the central nervous system and glucocorticoid hormone synthesis in the peripheral tissues. This complex set of interactions also regulates neuroendocrine and behavioral responses to stress and environmental cues.

Modafinil Australia has been shown to activate arousal-related neurons in the brainstem, and its effects on behavior are consistent with these neurophysiologic data. Modafinil at doses of 150 and 300 mg/kg induced dose-dependent increases in wakefulness in rats housed on a 12:12 hr LD cycle. However, these changes did not affect the amount of sleep or the duration of REM sleep. Moreover, the administration of modafinil did not cause any changes in body temperature.

These results suggest that the modulation of specific arousal-related neuronal populations may be responsible for modafinil’s wake-promoting activity. These cells are associated with the reticular activating system,7 which originates in the brainstem and posterior hypothalamus and sends projections throughout the forebrain. These projections are cholinergic in the pedunculopontine and laterodorsal tegmental nuclei, noradrenergic in the locus coeruleus, and serotonin-ergic in the dorsal raphe and ventral tegmental area.

The hypothalamus acts as a consolidation center for signals derived from upper cortical inputs, autonomic function, external cues such as light and temperature, and peripheral endocrine feedback. This information is delivered to the pituitary gland, which then releases a variety of hormones that influence most endocrine systems in the body.

Anterior cingulate cortex

The anterior cingulate cortex (ACC) is a region of the forebrain that forms a collar around the front part of the corpus callosum. It is divided into two distinct areas, the dorsal anterior cingulate cortex (dACC) and the ventral anterior cingulate cortex (ACC). ACC is involved in attention allocation, error, and novelty detection, and working memory modulation, and is also implicated in cognitive control functions including response conflict, selection, and inhibition. vACC is implicated in emotion regulation, notably perceiving both physical and psychological pain, and in mediating the association between actions and their consequences for others.

In one study, modafinil was found to induce a large increase in the activity of vACC neurons during a task requiring decision-making, and this increased vACC activation was associated with improved performance. In another fMRI study, the administration of a low dose of modafinil (2 mg/kg) was associated with enhanced working memory performance. This finding was correlated with increased fMRI activity in a small cluster of vACC neurons and the tuberomammillary nucleus (TMN) and orexin neurons of the perifornical area.

In a recent study, 19 schizophrenia patients underwent a double-blind placebo-controlled trial of modafinil and a working memory test with functional magnetic resonance imaging (fMRI). The authors found that increased fMRI signals in the anterior cingulate cortex during the modafinil ( Waklert 150 mg ) condition were positively correlated with improved Pauli Test performance. However, it should be noted that increased anterior cingulate cortex activation was not necessarily indicative of enhanced cognition, as the majority of the patients did not exhibit an improvement in their Pauli Test performance.

Prefrontal cortex

The prefrontal cortex (PFC) plays an important role in regulating emotions, thoughts, and actions. This region is a key element of executive functions, such as inhibition, self-control, and attention. It also has extensive connections with other cortical and subcortical regions, including those involved in emotion regulation and memory. The PFC is organized in a topographical manner, with regions that regulate emotion situated ventrally and medially, while those that regulate thoughts and actions are situated more dorsally and laterally.

The PFC contains a sub-region called the cingulate cortex, which is associated with emotional responses and is involved in regulating behavior. The cingulate cortex also projects to the hypothalamus, and the activation of this pathway is responsible for the stimulant effects of modafinil and other wakefulness-promoting drugs.

The PFC also interacts with other brain regions, such as the hippocampus and thalamus. The interaction between the hippocampus and the PFC is a critical factor in memory consolidation, as evidenced by studies using hippocampal lesions. The hippocampus and the prefrontal cortex are also associated with arousal, and their activation is responsible for the stimulant effects of modafinil. The thalamus is also important in the control of sleep, and its activation can induce drowsiness. Moreover, the thalamus is associated with the regulation of adenosine levels, which are responsible for promoting sleepiness. Modafinil reduces adenosine levels in the basal forebrain, which results in increased vigilance and reduced drowsiness.

Midbrain

The midbrain is a region of the brain that is located between the left and right hemispheres of the brain. It is also known as the “inter-brain” because it links and consolidates the functions of each brain file. The midbrain also facilitates the flow of information from one hemisphere to another.

The structure of the midbrain is distinct from that of the other brain structures, as it contains four large underlying clusters of neurons. These are known as the superior and inferior colliculi, and they are involved in directing behavior toward external stimuli. Modafinil can activate the midbrain by increasing serotonin levels in this region. This can lead to a feeling of wakefulness and increased attention. This effect may be mediated by the interaction of the drug with dopamine neurons, which are associated with alertness.

In addition, modafinil can affect the release of glutamate in this region. This may be a mechanism for its effects on memory, as it can improve performance on a delayed nonmatching-to-position task. It also enhances working memory performance in rats exposed to stress. Modafinil does not directly bind to the dopamine transporter (DAT), but it has been shown to increase DAT activity in cells expressing this receptor.

Moreover, it enhances the increase in extracellular serotonin induced by the antidepressant fluoxetine and by the adrenergic agent imipramine in the frontal cortex of the awake rat. It has also been demonstrated that the vigilance-promoting drug modafinil decreases GABA release in this area.