Current Neuropharmacology - Volume 6, Issue 4, 2008

The increase in serotonin (5-HT) neurotransmission is considered to be one of the most efficacious medical approach to depression and its related disorders. The selective serotonin reuptake inhibitors (SSRIs) represent the most widely antidepressive drugs utilized in the medical treatment of depressed patients. Currently available SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and escitalopram. The primary SSRIs pharmacological action's mechanism consists in the presynaptic inhibition on the serotonin reuptake, with an increased availability of this amine into the synaptic cleft. Serotonin produces its effects as a consequence of interactions with appropriate receptors. Seven distinct families of 5-HT receptors have been identified (5-HT1 to 5-HT7), and subpopulations have been described for several of these. The interaction between serotonin and post-synaptic receptors mediates a wide range of functions. The SSRIs have a very favorable safety profile, although clinical signs of several unexpected pathologic events are often misdiagnosed, in particular, those regarding the eye. In all cases reported in the literature the angle-closure glaucoma represents the most important SSRIs-related ocular adverse event. Thus, it is not quite hazardous to hypothesize that also the other reported and unspecified visual disturbances could be attributed - at least in some cases - to IOP modifications. The knowledge of SSRIs individual tolerability, angle-closure predisposition and critical IOP could be important goals able to avoid further and more dangerous ocular side effects.

The development of effective pharmacotherapy for major depression is important because it is such a widespread and debilitating mental disorder. Here, we have reviewed preclinical and clinical studies on tianeptine, an atypical antidepressant which ameliorates the adverse effects of stress on brain and memory. In animal studies, tianeptine has been shown to prevent stress-induced morphological sequelae in the hippocampus and amygdala, as well as to prevent stress from impairing synaptic plasticity in the prefrontal cortex and hippocampus. Tianeptine also has memory-protective characteristics, as it blocks the adverse effects of stress on hippocampus-dependent learning and memory. We have further extended the findings on stress, memory and tianeptine here with two novel observations: 1) stress impairs spatial memory in adrenalectomized (ADX), thereby corticosterone-depleted, rats; and 2) the stress-induced impairment of memory in ADX rats is blocked by tianeptine. These findings are consistent with previous research which indicates that tianeptine produces anti-stress and memory-protective properties without altering the response of the hypothalamic-pituitary-adrenal axis to stress. We conclude with a discussion of findings which indicate that tianeptine accomplishes its anti-stress effects by normalizing stress-induced increases in glutamate in the hippocampus and amygdala. This finding is potentially relevant to recent research which indicates that abnormalities in glutamatergic neurotransmission are involved in the pathogenesis of depression. Ultimately, tianeptine's prevention of depression-induced sequelae in the brain is likely to be a primary factor in its effectiveness as a pharmacological treatment for depression.

Attention Deficit Hyperactivity Disorder (ADHD) is a childhood psychiatric condition characterized by severe impulsiveness, inattention and overactivity. Methylphenidate (MPH), a psychostimulant affecting both the dopaminergic and the noradrenergic systems, is one of the most frequently prescribed treatments for ADHD. Despite the widespread use of MPH and its proven effectiveness, its precise neurochemical mechanisms of action are under debate. For the most part, MPH's influence on subcortical dopamine neurotransmission is thought to play a crucial role in its behavioral and cognitive effects. In their hypothesis of biphasic MPH action, Seeman and Madras [42, 43] suggest that therapeutic doses of MPH elevate tonic dopamine while inhibiting phasic transmitter release in subcortical structures, leading to reduced postsynaptic receptor stimulation and psychomotor activation in response to salient stimuli. Volkow and colleagues [56] suggest that by amplifying a weak striatal dopamine signal, MPH increases the perception of a stimulus or task as salient. The enhanced interest for the task is thought to increase attention and improve performance. Recent animal studies have however shown that when administered at doses producing clinically relevant drug plasma levels and enhancing cognitive function, MPH preferentially activates dopamine and noradrenaline efflux within the prefrontal cortex relative to the subcortical structures [5]. Overall, we suggest that the delineated theories of MPH therapeutic action should not be discussed as exclusive. Studies are outlined that allow integrating the different findings and models.

Adenosine is perhaps the most important and universal modulator in the brain. The current consensus is that it is primarily produced in the extracellular space from the breakdown of previously released ATP. It is also accepted that it can be released directly, as adenosine, during pathological events primarily by equilibrative transport. Nevertheless, there is a growing realization that adenosine can be rapidly released from the nervous system in a manner that is dependent upon the activity of neurons. We consider three competing classes of mechanism that could explain neuronal activity dependent adenosine release (exocytosis of ATP followed by extracellular conversion to adenosine; exocytotic release of an unspecified transmitter followed by direct non-exocytotic adenosine release from an interposed cell; and direct exocytotic release of adenosine) and outline discriminatory experimental tests to decide between them. We review several examples of activity dependent adenosine release and explore their underlying mechanisms where these are known. We discuss the limits of current experimental techniques in definitively discriminating between the competing models of release, and identify key areas where technologies need to advance to enable definitive discriminatory tests. Nevertheless, within the current limits, we conclude that there is evidence for a mechanism that strongly resembles direct exocytosis of adenosine underlying at least some examples of neuronal activity dependent adenosine release.

Depression has been associated with impaired neurotransmission of serotonergic, norepinephrinergic, and dopaminergic pathways, although most pharmacologic treatment strategies for depression enhance only serotonin and norepinephrine neurotransmission. Current drug development efforts are aimed at a new class of antidepressants which inhibit the reuptake of all three neurotransmitters in the hope of creating medications with broader efficacy and/or quicker onset of action. The current review explores limitations of presently available antidepressants and the history and premise behind the movement to devise triple reuptake inhibitors. The evidence for and against the claim that broader spectrum agents are more efficacious is discussed. Examples of triple reuptake inhibitors in development are compared, and preclinical and clinical research with these agents to date is described.

Sigma (σ) receptors, initially described as a subtype of opioid receptors, are now considered unique receptors. Pharmacological studies have distinguished two types of σ receptors, termed σ1 and σ2. Of these two subtypes, the σ1 receptor has been cloned in humans and rodents, and its amino acid sequence shows no homology with other mammalian proteins. Several psychoactive drugs show high to moderate affinity for σ1 receptors, including the antipsychotic haloperidol, the antidepressant drugs fluvoxamine and sertraline, and the psychostimulants cocaine and methamphetamine; in addition, the anticonvulsant drug phenytoin allosterically modulates σ1 receptors. Certain neurosteroids are known to interact with σ1 receptors, and have been proposed to be their endogenous ligands. These receptors are located in the plasma membrane and in subcellular membranes, particularly in the endoplasmic reticulum, where they play a modulatory role in intracellular Ca2+ signaling. Sigma1 receptors also play a modulatory role in the activity of some ion channels and in several neurotransmitter systems, mainly in glutamatergic neurotransmission. In accordance with their widespread modulatory role, σ1 receptor ligands have been proposed to be useful in several therapeutic fields such as amnesic and cognitive deficits, depression and anxiety, schizophrenia, analgesia, and against some effects of drugs of abuse (such as cocaine and methamphetamine). In this review we provide an overview of the present knowledge of σ1 receptors, focussing on σ1 ligand neuropharmacology and the role of σ1 receptors in behavioral animal studies, which have contributed greatly to the potential therapeutic applications of σ1 ligands.

Increased attention to the prevalence of excessive sleepiness has led to a clear need to treat this symptom, thus reinforcing the need for a greater understanding of the neurobiology of sleep and wakefulness. Although the physiological mechanisms of sleep and wakefulness are highly interrelated, recent research reveals that there are distinct differences in the active brain processing and the specific neurochemical systems involved in the two states. In this review, we will examine the specific neuronal pathways, transmitters, and receptors composing the ascending arousal system that flow from the brainstem through the thalamus, hypothalamus, and basal forebrain to the cerebral cortex. We will also discuss the mutually inhibitory interaction between the core neuronal components of this arousal system and the sleep-active neurons in the ventrolateral preoptic nucleus, which serves as a brainstem-switch, regulating the stability of the sleep-wake states. In addition, we will review the role of homeostatic and circadian processes in the sleep-wake cycle, including the influence of the suprachiasmatic nucleus on coordination of sleep-wake systems. Finally, we will summarize how the above processes are reflected in disorders of sleep and wakefulness, including insomnia, narcolepsy, disorders associated with fragmented sleep, circadian rhythm sleep disorders, and primary neurological disorders such as Parkinson's and Alzheimer's diseases.

Methylphenidate is a psychostimulant that inhibits the neuronal dopamine transporter. In addition, methylphenidate has the intriguing ability to provide neuroprotection from the neurotoxic effects of methamphetamine and perhaps also Parkinson's disease; both of which may likely involve the abnormal accumulation of cytoplasmic dopamine inside dopaminergic neurons and the resulting formation of dopamine-associated reactive oxygen species. As delineated in this review, the neuroprotective effects of methylphenidate are due, at least in part, to its ability to attenuate or prevent this abnormal cytoplasmic dopamine accumulation through several possible neuropharmacological mechanisms. These may include 1) direct interactions between methylphenidate and the neuronal dopamine transporter which may attenuate or prevent the entry of methamphetamine into dopaminergic neurons and may also decrease the synthesis of cytoplasmic dopamine through a D2 receptor-mediated signal cascade process, and 2) indirect effects upon the functioning of the vesicular monoamine transporter-2 which may increase vesicular dopamine sequestration through both vesicle trafficking and the kinetic upregulation of the vesicular monoamine transporter-2 protein. Understanding these neuropharmacological mechanisms of methylphenidate neuroprotection may provide important insights into the physiologic regulation of dopaminergic systems as well as the pathophysiology of a variety of disorders involving abnormal dopamine disposition ranging from substance abuse to neurodegenerative diseases such as Parkinson's disease.