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Human (and mammal) brain neurons are different from the majority of cells in the body as they form a network where they communicate with one another by releasing chemical messengers called transmitters. This mode of communication accounts for many mechanisms like memory, learning, consciousness. Signal transmission occurs at specialized junctions called synapses. Neurotransmitter molecules are released from presynaptically located vesicles and then bind to proteins called receptors in the membrane of the target cell. This results in the subsequent change in the electric potential of the postsynaptic neuron, and postsynaptic reactions are triggered. (Direct transmission of action potentials in the form of electrical synapses,is also possible, but it will not be examined here).
The release of neuroactive substances is caused by arrival of an action potential at the presynaptic terminal, which elicits the opening of voltage-dependent Ca2+ channels (or L-type channels). There are two major types of receptors (depending on the nature of the neuroactive substance and the type of receptor to which they bind): those in which the receptor molecule is also an ion channel, and those in which the receptor and ion channel are separate molecules. The former are called ionotropic receptors or ligandgated ion channels, and produce effects that have a rapid onset and a brief duration (a few milliseconds) when a fast response is essential. The latter are called metabotropic receptors, and give rise to events of a slow onset and a more prolonged duration.
Abnormalities in the function of neurotransmitter systems account for a wide range of neurological and psychiatric disorders. Many neuropharmacological therapies are based on drugs that affect neurotransmitter release, binding, and/or removal. In fact, the drugs provide a remedy for disorders by copying mechanisms of neural transmission in the CNS.
Neuroactive Substances: Neurotransmitters and Neuromodulators (Neuropeptides)
SOURCES: (Von Bohlen et al. 2006), (Purves 2004).
The neuroactive messengers are generally considered to belong to two different classes: the neurotransmitters and the neuromodulators. The neurotransmitters are substances in charge of intersynaptic signal transmission, while neuromodulators are termed so because they mainly modulate postsynaptic events. Although the distribution of the two classes is not complementary (i.e. there is a functional overlap between them) this classification has proven quite practical.
To be classified as a neurotransmitter, a neuroactive substance has to fulfill the following criteria (Von Bohlen et al. 2006: 4):
_" It must be of neuronal origin and accumulate in presynaptic terminals, from
where it is released upon depolarization.
_ The released neurotransmitter must induce postsynaptic effects upon its target
cell, which are mediated by neurotransmitter-specific receptors.
_ The substance must be metabolically inactivated or cleared from the synaptic
cleft by re-uptake mechanisms.
_ Experimental application of the substance to nervous tissue must produce effects
comparable to those induced by the naturally occurring neurotransmitter". (Von Bohlen et al. 2006: 4).
Neurotransmitters can be further divided into biogenic amines and small amino-acids, basing on their chemical nature.
Fig. 1. Differentiation of neurotransmitters based on their chemical structures. (Von Bohlen et al. 2006 : 4)
Unlike neurotransmitters, neuromodulators fall into several subclasses. The largest subgroup is that of neuropeptides. These substances have large molecules composed various amino-acids (from 3 to 36). Neuropeptides, too, are synthesized by neurons and released from their presynaptic terminals, as is the case for neurotransmitters. However, most of the neuropeptides do not meet al of the criterias specified above - for instance, they might nor be subject to reuptake mechanisms. Moreover, not all neuropeptides have the workings of neuromodulators (e.g. neurohormones). Synthesis and packaging of neuropeptides are fundamentally different from those of small-molecule neurotransmitters in that they are secreted from non-neuronal cells like in the process of proteins synthesis.
Based on their amino acid sequences, neuropeptides can be further loosely divided into five groups: the brain/gut peptides, opioid peptides, pituitary peptides, hypothalamic releasing hormones, and a residue category composed of other peptides hard to classify.
There is a variety of other biologically active substances that can induce neurotransmitter or neuromodulator effects. Unlike "canonical" neurotransmitters or neuromodulators, they are not stored in synaptic vesicles and are not released from presynaptic terminals. For instance, Nitric oxide (NO) or carbon monoxide are gases produced within the cells by the action of specific sets of enzymes. They can permeate the plasma membrane and act in the proximity of neurons emiting them. Another group of "unconventional" neurotransmitters is made up by Endocannabinoids that interact with cannabinoid receptors.
Major neurotransmission systems
SOURCES: (Von Bohlen et al. 2006), (Anderson 2004).
ACh in the brain is mainly distributed in the mid- and hindbrain. ACh is formed by the enzymatic (choline acetyltransferase) conversion of choline and acetyl coenzyme-A (CoA) to Ach. After release it is metabolised by acetylcholine esterase (AChE) to form choline. Choline is taken up into the neurone by an active transport system and can then be re-used to sythesise ACh. Cholinergic receptors are subdivided into two classes: nicotinic and muscarinic. Nicotinic receptors are involved in fast excitatory synaptic transmission and are directly coupled to cation channels. Five muscarinic receptors (M1-M5) are G-protein coupled and can have both enhancing or inhibiting effect.
Î³-Aminobutyric acid (GABA)
GABA neurones are widely distributed within the brain with the highest densities in the basal ganglia, hypothalamus, amygdala and other limbic areas. It is the most ubiquitous inhibitory neurotransmitter in the brain. GABA is synthesized almost exclusively from glutamate. After release it can either be taken up into the nerve terminals by a specific transport system or it enters glial cells where it is metabolized back to glutamate. The receptor is directly coupled to a chloride ion channel and activation results in an influx of chloride ions and rapid hyperpolarisation (causing inhibition). GABA is released from the terminals of specific inhibitory neurons. GABA binds to its receptors and produces an increase in membrane permeability to Cl- ions, which elicit a hyperpolarization of the postsynaptic membrane. There are three types of GABA receptors: GABAA, GABAB and GABAC. GABAA receptors contribute to memory storage.
Glutamate and Aspartate
The amino acids L-glutamate and L-aspartate are the most abundant excitatory neurotransmitter in the central nervous system. Glutamate is the major fast-acting excitatory neurotransmitter with a wide distribution in the brain. Brain glutamate and aspartate are derived solely by local synthesis, as neither amino acid can cross the blood-brain barrier. Released glutamate is restored to presynaptic terminals by a specific re-uptake mechanism or cleared from the synaptic region by high-affinity membrane transporters. There are ionotropic and metabotropic excitatory amino acid receptors. The metabotropic receptors are coupled to G proteins, and the signal transduction involves different second-messenger systems. Ionotropic glutamate receptors include the NMDA receptor, which has attracted most attention, as well as AMPA receptors and kainite receptors. Activation of the receptor can lead to changes in Na+, Ca2+ and K+ conductance through the channel.
Histamine was first known to be a substance released in response to allergen stimulation. Histamine has many features in common with the monoamines, such as catecholamines (dopamine, epinephrine and norepinephrine) or indolamines (like serotonin), with respect to release, metabolic pathway and mode of action at the cellular level. Histaminergic neurons are predominantly located in the tuberal area of the posterior hypothalamus. The enzyme L-histidine-decarboxylase (HDC or HD) is responsible for the biosynthesis of histamine in the central nervous system. The highest activity of L-histidine-decarboxylase has been detected in the posterior hypothalamus. In this area, the mRNA coding for HDC is expressed at high levels. Histamine synthesized in neurons is stored in synaptic vesicles and is released from these stores in a calcium-dependent manner. Three different receptor subtypes, termed H1, H2 and H3, bind histamine specifically. Histamine is involved in sleep regulation and the regulation of the energetic balance of the body.
DA-containing neuronal cell bodies are located in Substantia nigra, Ventral tegmental area, Tuberoinfundibular DA pathway. and are actively involved in the initiation of motor plans and motor co-ordination as well as motivation, reward behaviour and dependence. DA is formed by the hydroxylation of tyrosine to dihydroxyphenylanine an after release, DA is taken back up into the presynaptic terminal by the DA transporter. DA is also metabolised by mitochondrial monoamine oxidase (MAO) and by the membrane-bound catechol-O-methyltransferase (COMT) enzyme to form the endproduct homovallinic acid. Five DA receptors have been identified that consist of two families: the 'D1 like' and D5 receptors, which are positively coupled to cyclic adenosine monophosphate (cAMP), important second messenger; and the 'D2 like' (D2, D3, D4) which inhibit cAMP.
The principal location of NA-containing neurones is the locus coeruleus (LC). They are involved in arousal and maintaining the cortex in an alert state (cortical projections) as well as with drive, motivation, mood and response to stress (limbic prjections). NA is formed by the action of dopamine-Î²-oxidase, which converts DA to NA; NA is inactivated after release by re-uptake. and metabolised by MAO. The receptors on which noradrenaline acts are divided into Î±- and Î²-adrenoceptors with further subdivisions. Î±1 Receptors are excitatory while Î±2 Receptors are inhibitory. Î²-Adrenoceptors (Î²1, Î²2, Î²3) are stimulatory and increase cAMP.
The catecholamines constitute a family of neurotransmitters (dopamine, epinephrine, norepinephrine). The synthesis of the catecholamines starts from the amino acid tyrosine and runs through several enzymatic steps. The degradation of norepinephrine and its inactivation is through its re-uptake from the synaptic cleft. Norepinephrine transporters (NET) mediate the removal of norepinephrine from the extracellular space. The activity of norepinephrine transporters depends on the transmembrane Na+ gradient. MAO is involved in the degradation of epinephrine and norepinephrine converting them to 3,4-dihydroxymandelic acid. When released from the nerve varicosities, norepinephrine interacts with adrenoceptors on the plasma membrane of neurons from the central and peripheral nervous system. Signal transduction involves stimulation of G-proteins. The functional consequences of noradrenergic receptor activation can be either inhibitory or excitory.
Serotonin (5-hydroxytryptamine; 5-HT)
The neurones containing 5-HT are located in the midbrain and brainstem raphe nuclei from where extend long ascending (dorsal and median raphe) or descending (obscurus, magnus and pallidus raphe nuclei) pathways. The ascending pathways innervate the hippocampus, striatum, amygdala and hypothalamus. They have a wide modulatory role in various aspects of behaviour including mood and emotion, sleep/wakefulness, control of consummatory behaviours (feeding, sex), body temperature, perceptions and vomiting. The descending pathways terminate in the spinal cord where they are involved in the inhibition of pain transmission and regulation of motor neurone output. 5-HT is formed by the hydroxylation of tryptophan. The release of terminal 5-HT is caused by various amfetamines. The major mechanism for removing 5-HT from the synaptic cleft is reuptake by the 5-HT transporter. 5-HT is also metabolised by MAO to form 5-hydroxyindole acetic acid (5-HIAA), which is actively transported across the blood-brain barrier out of the brain, in common with other low molecular weight organic acids (e.g. HVA; uric acid). There are 14 5-HT receptors, all are G-protein coupled apart from 5-HT3 (ligand-gated cation channel). The 5-HT1 group, (5-HT1A, 5-HT1B, 5-HT1D) are inhibitory and are negatively coupled to cAMP. 5-HT2 receptors (5-HT2A, 5-HT2B, 5-HT2C) are excitatory and act through the phosphate pathway. The 5-HT4, 5-HT5, 5-HT6 and 5-HT7 receptors are positively coupled to cAMP and are thus excitatory.
Glycine, like GABA, is an important inhibitory neurotransmitter acting through ionotropic receptors. Glycine in the central nervous system is synthesized from glucose via serine. Glycine has two distinct functions in the central nervous system: an inhibitory function in the spinal cord and the brain stem through activation of a specific glycine receptor; and an excitatory function in the forebrain as a co-activator of NMDA receptors.
Survey of Disorders Treated by Psychoactive Drugs.
SOURCES: (Panksepp 2004), (Stahl 2004), (Anderson 2004).
A drug changes the functioning of a neuron either interacting at one of its key receptors or inhibiting one of its important enzymes. However, enzymes and receptors in their various neuronal pathways and circuits can also be the mediators of disease actions. Behavioral or motor abnormalities expressed by patients who suffer from psychiatric and neurological disorders are caused by abnormal neurotransmission. Different brain disorders affect different aspects of neurotransmission .
According to (Stahl 2004: 133), diseases modify neurotransmission in the brain by at least eight mechanisms.
(1) modifications of molecular neurobiology - a person can inherit vulnerability to a mental illness arising from the fact that normal functioning of the genes had been disrupted;
(2) loss of neuronal plasticity - if some neurons during the fetus developement in utero fail to migrate properly that can result in epilepsia, mental retardation and schizophrenia; if synaptogenesis is interrupted during early development that can cause serious disorders like autism; healthy synapses can also be improperly interrupted in later life (e.g. aging).
(3) excitotoxicity - i.e. "excitatory neurotransmission with glutamate ranges from talking to neurons, to screaming at them , to strangling their dendrites, and even to assassinating them" (Stahl 2004: 122); in some diseases, glutamate also acts as neuron killer - e.g. Parkinson's disease, Alzheimer's disease etc.
(4) absence of neurotransmission subsequent to neuronal loss;
(5) excess neurotransmission;
(6) an imbalance among neurotransmitters - e.g. between dopamine and acetylcholine in movement disorders;
(7) the wrong rate of neurotransmission that is a possible cause of disrupted sleep or biorhythms.;
(8) the wrong neuronal wiring.
Diseases examine here mostly involve mechanisms 1, 4-6.
1. Depression and bipolar mood disorder
A major depressive episode is a pathological condition, characterized primarily by persistent negative mood (anhedonia) accompanied by changes in (1) sleep pattern, (2) body weight, and (3) motor and mental speed, (4) fatigue, loss of energy, (5) poor concentration and apathy, (6) feelings of worthlessness or inappropriate guilt, and (7) recurrent thoughts of death with suicidal ideations or suicide attempts (APA, 1994 via HBP - Handbook Biological Psychiatry 198 199)
Problems with mood are called affective disorders. Depression and mania are often seen as opposite ends of an affective or mood spectrum. With unipolar depression patients just experience the down or depressed pole. Bipolar disorder is a disorder in which "patients at different times experience either the up (manic) pole or the down (depressed) pole". (Stahl 2004:136).
According to DSM IV, depression is characterized by depressed mood, absence of pleasure or interest, significant weight (loss or gain) or appetite changes, disrupted sleeping regime, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, inability ot think or concentrate, recurrent thoughts of death or suicidal ideation. (Stahl 2004:138)
Among DSM-IV criteria for a manic episode are: distinct periods of abnormally and persistently elevated, expansive, or irritable mood, inflated self-esteem or grandiosity, decreased need for sleep, excessive talkativeness, rush of ideas and thoughts, distractability, increase in goal-directed activity, "excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)" (Stahl 2004:139).
The theories of bipolar mood disorder postulate the involvement of three monoamine neurotransmitter systems-noradrenergic (norepinephrine (NE)), dopaminergic, and serotonergic. (Stahl, HBP, NT and NM). Another hypothesis about the origin of depression involves neuropeptides called neurokinins.
Schizophrenia is a debilitating psychiatric disorder that is generally diagnosed basing on two groups of symptoms: positive (such psychotic symptoms as hallucinations, delusions, disorganized speech, catatonic behaviour) and negative or affective symptoms (manic symptoms, depression, anxiety, blunted affect, diminished emotional range, poor speech, avolition and loss of motivation) (Panksepp 2004: 268 based on DSM-IV).
The causes of shizophrenia are no longer thought to be strictly neurochemical, but there is a lot of evidence suggesting abnormalities in the dopamine system (i.e. hypofunction of dopamine in the mesocortical dopamine neurons might contribute to the negative symptoms such as blunted affect and poverty of speech). However, further evidence shows that there are other abnormal neurotransmitters in this disorder - e.g. glutamatergic dysfunction, GABAergic Hypofunction, Nicotinic Hypofunction.
3. Panic disorder and Obsessive-Compulsive Disorder (OCD) Spectrum
The syndrome of panic disorder was first described by Sigmund Freud as "anxiety neurosis". The central features of panic disorder (DSM IV) are recurrent unexpected panic attacks accompanied by the anticipation and fear of another attack as well as the fear of the consequence of the attack.
Typical panic symptoms might include pounding heart or accelerated heart rate, sweating, trembling or shaking, sensations of shortness of breath or smothering, feeling of choking, chest pain or discomfort, nausea or abdominal distress, feeling dizzy, lightheaded, unsteady or faint, feelings of unrealness or depersonalization (feeling detached from oneself), fear of losing control or going crazy, fear of dying, paresthesias (numbness or tingling sensations), and chills or hot flushes. Panic patients often report problems with physical and emotional health, show higher rate of alcohol and drug abuse as well as attempted suicide.
There are two major hypotheses about the biological basis of the panic disorder: (i) an initial excess of norepinephrine and a dysregulation in the noradrenergic system and (ii) the ability of benzodiazepines to modulate GABA is out of balance.
In the current literature, the spectrum of obsessive-compulsive disorders is described to comprise such disorders as body dysmorphic disorder, hypochondriasis, eating disorders, and self-mutilation as well as sometimes pathologic gambling and sexual impulse control problems. The common core of these disorders is "that a person performs an action or has repetitive thoughts that reduce their anxiety. This performance of a ritualistic behavior to alleviate anxiety is what maintains their Disorder" (Panksepp 2004: 373).
Though the biological and neurological basis of OSD still remains the subject of studies, neurotransmitter abnormalities that are thought to contribute to the OCD disorder are again the impaired functioning of the serotonin and dopamin systems.
5. Anxiety disorders.
Anxiety disorder is a umbrella term for many types of disorders including various acute stress reactions and also specific phobias, including social phobias and agoraphobia. "The most common clinical symptom of all these disorders is excessive worry and sustained feelings of mental anguish" (Panksepp 2004: 499). Other symptoms may involve "uncontrollable apprehensive expectations, jumpiness, and a tendency for excessive vigilance and fidgeting" (ibid.) and apart from psychological distress sometimes accopmpanied by such physiological symptoms as gastrointestinal irritability, diarrhea, frequent urination, and even tachycardia, chronic dryness of the mouth, increased but shallow respiration.
The neurochemical basis for anxiety has been related to BZ (benzodiazepine) receptors that "quell anxiety by hyperpolarizing neurons that distribute fearful messages within the brain". (Panksepp 2004: 503). Modulation of the GABA-benzodiazepine receptor complex is therefore not only thought to underlie the pharmacological actions of antianxiety drugs but is also theorized to serve as the vehicle for mediating the emotion of anxiety itself.
As for panic disorder, one theory about its biological basis claims that there is an excess of norepinephrine, causing intermittent and chaotic discharge of noradrenergic neurons from the locus coeruleus. The neurobiology of social phobia remains obscure. A state of noradrenergic overactivity in social phobia is suggested by the symptoms of tremor, tachycardia, and blushing. Besides, it is likely that the ability of benzodiazepines to modulate GABA is out of balance. This may be due to changes in the amounts of endogenous benzodiazepines (i.e., "the brain's own Xanax" or "Valium-like compound" - (Stahl 2004: 349)), or to alterations in the sensitivity of the benzodiazepine receptor itself.
6. Attention deficit and hyperactivity disorder (ADHD)
The last type of disorder that is treated with psychoactive drugs examined here is attention deficit disorder (ADHD) for which there is the greatest use of stimulant medications as therapeutic agents.
Attention deficit disorder is usually diagnosed basing on the following symptoms: failure to give close attention to details, careless mistakes; difficulties with sustaining attention, inability to listen or to understand and follow instructions, failure to organize tasks or activities, unwillingness to take tasks requiring sustained mental effort, often losing necessary things, being easily distracted or forgetful (DSM IV). "The catecholamine neurotransmitters dopamine and norepinephrine have the best documented roles in attention, concentration, and associated cognitive functions such as motivation, interest, and learning tasks dependent on being adequately aroused, yet focused". (Stahl 2004: 460). Norepinephrine and prefrontal noradrenergic pathways play a role in sustaining and focusing attention, in mediating energy, fatigue, motivation, and interest. Mesocortical dopamine projection mediates cognitive functions such as verbal fluency, serial learning, vigilance for executive functioning, sustaining and focusing attention, prioritizing behavior, and modulating behavior based upon social cues. (ibid).
Arousal is usually considered to be a state of increased dopamine and norepinephrine and inattentiveness is considered to reflect deficiencies in these neurotransmitters in these pathways. However, too much of dopamine or norepinephrine will, too, lead to hyperarousal and inability to concentrate.
PART II. MECHANISMS BY WHICH PHARMACOLOGICAL AGENTS AFFECT BRAIN ACTIVITY
SOURCES: (Panksepp 2004), (Stahl 2004), (Anderson 2004).
1. General Principles of Drug Action
Drug discovery is generally based on the studies of naturally occuring neurotransmitters. For example, the brain produces its own morphine (i.e., beta endorphin), its own marijuana (i.e., anandamide), its own antidepressants, anxiolytics, and even hallucinogens. The drugs' workings in the CNS mimc the brain's natural neurotransmitters. The drugs targeting the CNS mostly act in two ways: (i) either as stimulators (agonists) or blockers (antagonists) of neurotransmitter receptors; or (ii) as inhibitors of regulatory enzymes. (Stahl 2004:35). Here are some examples of mechanisms on which the drug action is based:
A) Inhibition (blocking) of serotonin reuptake. Used in antidepressants, anxiolytics as well as for the treatment of panic disorder and OCD.
B) Blocking of brain dopamine receptors, as hyperactivation of dopamine receptors contributes to psychotic symptoms: antipsychotic drugs used in schizophrenia treatment.
C) Monoamide oxidase (MAO) inhibitors block the breakdown or reuptake of amines (e.g. norepinephrine) and are used in antidepressants.
E) Amphetamine stimulates the release of norepinephrine from nerve terminals - this mechanism is again used in antidepressants.
F) Anticholinergic agents block the cholinergic/muscarinic receptors thus contributing to the antidepressant effect.
G) Methylphenidate and dexamphetamine stimulate dopamine release from presynaptic dopamine terminals blocking dopamine transporters. Used in cognitive stimulators.
H) Benzodiazpines act at the GABA-BZ receptors BZs and enhance GABA inhibitory function (sedative, anxiolytic action).
Next I will examine six examples of pharmacological agent types used in clinical practice.
The first effective modern antidepressant agents appeared in the late 1950s. These are Iproniazid (monoamine oxidase inhibitor, MAOI - its antidepressant effect was discovered serendipitously, as the drug was developed for the treatment of tuberculosis) and Imipramine (tricyclic): they interact with monoamine systems (dopamine, noradrenergic, 5-HT serotonin receptors), and the hypothesis underlying the use of the drug is that of the monoamine basis of depression.
Currently, antidepressant action mechanism is that of increasing neurotransmission at the serotonin 5-HT receptors by altering receptor sensitivity. "For example, chronic 5-HT re-uptake blockade with SSRIs results in down-regulation of 5-HT1A receptors on the cell bodies of serotonergic neurones in the brain stem, thus disabling negative feedback, restoring cell firing rate resulting in increased synaptic 5-HT" (Anderson 2004: 68).
Figure 1 (Anderson 2004: 68) Current HT-receptor hypothesis of the antidepressants working mechanism.
Most antidepressants have acute boosting effects on monoamine (dopamine D2 receptors, noradrenergic, 5-HT serotonin receptors) neurotransmission. "This includes desensitization of neurotransmitter receptors, leading to both therapeutic action and tolerance to side effects". (Stahl 2004: 204). Classical Antidepressants are Monoamine Oxidase Inhibitors (MAOI) and Tricyclic Antidepressants.
The original MAO inhibitors are all irreversible enzyme inhibitors, which bind to MAO and destroy its function forever. Monoamine oxidase exists in two subtypes, A and B. The A form metabolizes the neurotransmitter monoamines serotonin and norepinephrine, which are thought to account for depression disorders.
Figure 2 (Stahl 2004:220) Workings of Monoamine oxidase inhibitors (MAOI).
The tricyclic antidepressants were named so because their organic chemical structure contains three rings. The tricyclics were discovered to block the reuptake pumps for both serotonin and norepinephrine, and to a lesser extent, dopamine. Some tricyclics have more potency for inhibition of the serotonin reuptake pump (e.g., clomipramine); others are more selective for norepinephrine over serotonin (e.g., desipramine, maprotilene, nortriptyline, protriptyline). Most, however, block both serotonin and norepinephrine reuptake. In addition, essentially all the tricyclic antidepressants have at least three other actions: blockade of muscarinic cholinergic receptors, blockade of H1I histamine receptors, and blockade of alpha 1 adrenergic receptors. Whereas blockade of the serotonin and norepinephrine reuptake pumps is thought to account for the therapeutic actions of these drugs, the other three pharmacologic properties are thought to account for such side-effects as cognitive functions (memory and attention) impairement. For instance, "tertiary tricyclic antidepressants (TCAs), such as amitriptyline, block histaminergic, adrenergic and cholinergic receptors, which may cause sedation and performance deterioration across a wide range of tasks. Moreover, drugs with anticholinergic properties may interfere particularly with attention and memory functions" (van Laar et al 2001: 351). Van Laar et al. (2001) compared the effects of three antidepressants, amitriptyline, nefazodone and paroxetine, on selective attention and working memory. Healthy subjects taking the drugs did tasks on working memory (memorizing items) and visual selective attention (visual search taks). It was expected that, basing on the sedative potentials of the antidepressants in the present study, the performance would be most impaired by amitriptyline because of its anticholinergic properties, next by nefazodone and finally paroxetine. "Expectations concerning the specificity of the effects of amitriptyline on ocused attention and working memory were confirmed. Subjects under amitriptyline reacted slower to targets under focused but not under divided attention conditions and they made more errors when they had to keep more items in memory" (van Laar et al 2001: 360).
Figure 3 (Anderson 2004: 72) Acute pharmacology of antidepressants.
Selective serotonin re-uptake inhibitors (SSRIs - fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram) are increasingly the first-line treatment for depression because they are less impairing for cognitive functions and at the same time have more powerful and selective serotonin reuptake inhibiting properties than the tricyclic antidepressants.
Figure 4 (Stahl 2004: 229). Serotonine re-uptake inhibition.
The term 'mood stabiliser' has been applied to drugs used to treat one or both poles of bipolar disorder without causing a switch to the other pole (e.g. antidepressants which can cause a switch to mania). One of the types of the drug used for mood stabilizing is lithium based drugs. Lithium is an alkaline metal element and is well known for its sedative and depressant properties due to its effect (among others) on the cholinergic system in the brain: lithium affects cholinergic neurotransmission by increasing choline levels and enhances cholinesterase inhibitor toxicity. So, its cholinomimetic effects may contribute to antimanic actions. Besides, Lithium has protective effects on neural function and integrity and can have long-term benefits in the treatment of mood disorders via neuroprotective effects.
Another type of drugs used for treatment of acute mania is anticonvulsant drugs, though their antimaniac action remains unclear. The use of anticonvulsants for acute mania treatment is suggestive of the common pathophysiology between epilepsy and severe psychotic disorder. In general anticonvulsants enhance the actions of GABA and thus strengthen inhibitory circuits in the CNS. At the cell membrane, anticonvulsants act on ion channels, including sodium, potassium, and calcium channels. "By interfering with sodium movements through voltage-operated sodium channels, for example, several anticonvulsants cause use-dependent blockade of sodium inflow. That is, when the sodium channels are being "used" during neuronal activity such as seizures, anticonvulsants can prolong their inactivation, thus providing anticonvulsant action. Whether such a mechanism is also the cause of the mood-stabilizing effects of anticonvulsants is yet unknown". (Stahl 2004: 267-268). Anticonvulsants interfere with neurotransmission affecting both the excitatory neurotransmitter, glutamate, and the inhibitory neurotransmitter, GABA. They reduce the excitatory neurotransmission reducing the release of glutamate, while enhancing inhibitory transmission: they can augment the synthesis of GABA and at the same time inhibit its breakdown and reuptake.
Valproic acid (often mixed with sodium valporate) is a licensed antimanic agent in the UK. Its action is based on inhibiting sodium and/or calcium channel function, which possibly boosts GABA inhibitory action as well as reduces glutamate excitatory action. Other antimaniac agents based on the same mechanism (enhancing GABA function and reducing glutamate function by interfering with both sodium and calcium channels) are topiramate, carbamazepine and gabapentin.
The pharmacological treatment of anxiety was revolutionized with the arrival of benzodiazepines (agents like diazepam (Valium) to clonazepam (Klonopin)). "The efficacies of BZs in dissolving anticipatory fearfulness, reducing anxiety neuroses, and, with some extremely potent agents, even panic attacks (e.g., clonazepam and alprazolam), have repeatedly been affirmed in many well-controlled clinical trials (Panksepp 2004: 500).
Moreover, BZs showed substantial benefits of in ameliorating alcohol withdrawal, which suggested that alcohol and BZs act upon common brain substrates, namely BZ-GABA receptor complex.
BZs enhance GABA function and thus are effective in the treatment of anxiety, while inhibitors of GABA-BZs receptors like pentylenetetrazol can, on the contrary, causes extreme anxiety symptoms and seizures. Another BZ inhibitor, flumazenil may cause panic in panic patients but not in healthy controls which possibly indicates an abnormality of BDZ receptor sensitivity in panic disorder.
Benzodiazepines act at the GABAA-BDZ receptor complex. The complex consists of five subunits from seven families of subunits (alpha, beta, gamma, delta, epsilon, pi, ro) each of which contains a number of subtypes of units. "The most common type of GABAA-BDZ receptor (50% of total) contains two alpha1, two beta2 and one gamma2 subunit arranged around the Cl- ion channel. GABA is the main inhibitory transmitter in the CNS. Two GABA molecules are required to increase Cl- ion channel conductance (by increasing the time the channel is open). This reduces the likelihood of an action potential. When a BDZ occupies its own receptor it enhances the action of GABA at its receptor resulting in greater flow of Cl- into the neurone". (Anderson 2004: 104). Type I BDZ receptors are mainly located in the cerebellum and are responsible for sleep whereas type II BDZ receptors tend to occupy the spinal cord and limbic regions and account for anxiolytic and anticonvulsant effects. Newer hypnotic drugs - zolpidem, zaleplon and zopiclone - modulate the GABAA-BDZ receptor complex but are more selective with respect to receptor types.
However, although BZs are remarkably effective antianxiety drugs, they show a number of shortcomings (e.g. risk of dependency and other side effects, like memory loss), and the research continues to identify agents that have fewer shortcomings.
In the 1970-80s it was recognized that some antidepressants were (tricyclic as well as MAO inhibitors) were effective in treating anxiety disorder as well. By the 1990s antidepressants from the serotonin selective reuptake inhibitor (SSRI) class became recognized as preferred first-line treatments for anxiety disorder subtypes. This is because of the involvement of the serotonin brain system in anxiety states. Animal models of anxiety show, too, complex role for 5-HT system. "5-HT acts at different levels of the brain aversion system, inhibiting brainstem hardwired panic system but increasing anxiety in temporal lobe structures involved in condition/generalised anxiety". (Anderson 2004: 103). Mombereau et al. (2010) showed the beneficial effect of SSRI in the animal model of anxiety. Antidepressants such as SSRIs exert their long-lasting beneficial properties through the desensitization of somatodendritic 5-HT1A receptors SSRIs were demonstrated to have positive effect after chronic administration, as opposed to acute efficacy of benzodiazepines: while a single injection of citalopram (SSRI) induced anxiogenic effects, three administrations of citalopram were sufficient to elicit anxiolytic effects in mice.
Partial agonist at the 5-HT1A serotonin receptors (e.g. buspirone) can decrease anxiety in generalised anxiety disorder (GAD) but are not effective in panic disorder. Buspirone continues to be first-line treatment for anxiety disorder, as well as Paxil, a selective serotonin reuptake inhibitor (SSRI). SSRIs are effective in treating a wide range of anxiety disorders (Generalized Anxiety Disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder ), but can make anxiety symptoms worse in the initial phase of treatment of panic disorder. The therapeutic effect of these agents appears to be based on the ability of the serotonin [5-hydroxytryptamine (5-HT)] systems to modulate anxiety. Buspirone reduces serotonin neuronal activity selectively for the 5-HT1A receptors. It drastically diminishes serotonin release in higher brain areas, which can lead to long-term up-regulation of postsynaptic serotonin receptors due to a compensatory functional elevation of brain serotonin activity.
There also drugs for reducing the undesired peripheral physiological symptoms of anxiety resulting from the involvement of the noradrenergic system. "Palpitations and sweating can be reduced with ß-noradrenergic blockers (e.g., propranolol). Such "beta-blockers" effectively control the outward symptoms of anxiety such as those that commonly accompany public speaking and musical performances. Within the brain, it is also clear that ß-noradrenergic synapses promote the consolidation of fear memories" (Panksepp 2004: 502).
OCD, panic disorder, phobias
FIGURE 5. (Stahl 2004: 341). Therapeutic options for treating obsessive-compulsive disorder
There are several pharmacological options in the treatment of panic disorder and obsessive-compulsive disorder.
Serotonin reuptake inhibitors. These drugs have proved to be most effective for OCD. Recent research on the pathophysiology of OCD have centered largely around the role of the neurotransmitter serotonin (5HT).. Clomipramine (CMI) was the first SRI to be shown to be effective for OCD, and then antiobsessional effects were documented for the following SRIs (SSRIs): fluoxetine, fluvoxamine, sertraline, paroxetine, and citalopram (in order of increasing selectivity). Now it has been recognized (Stahl 2004: 342-343) that clomipramine has unique anti-OCD effects independent of its antidepressant effects in OCD patients. Since clomipramine is a potent inhibitor of serotonin reuptake, it is hypothesized that the anti-OCD effects of clomipramine are linked to its serotonin reuptake blocking properties. This is strongly supported by the findings that all five of the SSRIs are also effective in treating OCD. SSRI and tricyclic antidepressants have been found very efficient in the treatment of panic disorders as well..
However, as a large percentage of OCD patients (40%) do not respond to SRI, other systems might be affected in the OCD disorder. Several lines of evidence show that increased dopaminergic neurotransmission may be implicated in the mediation of some obsessive-compulsive behavior. In animal studies high doses of various dopaminergic agents (amphetamine, bromocriptine, apomorphine) induce stereotyped movements in animals, which resemble compulsive behaviors in OCD patients. Human studies consistently report that abuse of stimulants such as amphetamine can cause seemingly purposeless, complex, repetitive behaviors, which resemble those occurring in OCD. So, at least in some forms of OCD both 5HT and DA systems can be involved in the pathology. "Thus, it may be that decreases in 5HT tonic inhibitory influences on DA neurons could lead to increased dopaminergic function due to the functional connections between DA and 5HT neurons in the basal ganglia". (Stahl 2004: 340)
FIGURE 6. (Stahl 2004: 353)Therapeutic options for treating panic disorder.
Monoamine Oxidase (MAO) Inhibitors. MAO inhibitors, both the classical irreversible and reversible are favorable for the treatment of panic disorder. However, they have a number of disadvantages that make them second- or third-line treatments for panic disorder: weight gain, sexual dysfunction, dietary restrictions (low tyramine diet).
Benzodiazepines. Benzodiazepines have become adjunctive treatment to antidepressants (particularly SSRIs), especially for long-term treatment when dependence on benzodiazepines can become problematic. The primary advantage to using benzodiazepines is rapid relief from anxiety and panic attacks. The disadvantages of benzodiazepines include sedation, cognitive clouding, interaction with alcohol, physiological dependence, and the potential for a withdrawal syndrome. High-potency benzodiazepines (alprazolam, clonazepam) generally are more effective in panic disorder than low-potency benzodiazepines (diazepam, lorazepam, etc.). Although less research has been done on the low-potency benzodiazepines, it is generally accepted that they frequently result in sedation prior to adequately relieving panic attacks. Benzodiazepines can often be helpful when treatment is initiated or when a rapid-onset therapeutic effect is desired. Benzodiazepines can also be useful to "top up" the patient's treatment on an as-needed basis for sudden and unexpected decompensation or short-term psychosocial stressors.
Newer agents for panic disorder treatment include:
PARTIAL AGONISTS AT BENZODIAZEPINE RECEPTORS should have the same efficacy as full agonists but less potential for sedation, dependence, and withdrawal effects.
NONBENZODIAZEPINE LIGANDS AT BENZODIAZEPINE SITES act at the same or similar site as benzodiazepines but are not structurally related to them.
REVERSIBLE INHIBITORS OF MONOAMINE OXIDASE A clinical experience with RIMAs in those countries where these agents are approved for marketing or testing suggests potential utility as antipanic agents.
FIGURE 7. (Stahl 2004: 361) Therapeutic options for treating social phobia.
Combination treatments are similar to those for panic disorder, but there is less experience with them and less documentation of how they work uniquely for patients with social phobia. Legitimate therapeutic drugs for social phobia are now SSRIs - paroxetine and several other SSRIs and antidepressants are rapidly accumulating evidence of their efficacies in this condition as well. Currently, SSRIs are considered first-line treatments for social phobia. Next, MAO inhibitors are second- or third-line treatments for patients resistant to treatment with SSRIs or other newer antidepressants. Benzodiazepines, especially clonazepam, appear efficacious in social phobia, although there have been relatively few trials and small numbers of patients studied.
Treatment-relevant domains of schizophrenia include "positive symptoms (delusions, hallucinations, suspiciousness, disorganized thinking), negative symptoms (impoverished speech and thinking, lack of social drive, flatness of emotional expression, apathy), cognitive and neuropsychological dysfunction [average intelligence quotient (IQ) in schizophrenia is 80 to 84, with prominent memory and learning difficulties], and mood symptoms (depression, anxiety)". (Panksepp 2004: 300)
In classical schizophrenia and psychosis treatment, antipsychotic action consisting in the reduction of acute positive (i.e. hallucinations, delusions, some aspects of thought disorder) is related to DA receptor-blocking action specifically in the mesolimbic dopamine pathway. This has the effect of reducing the hyperactivity in this pathway that is postulated to cause the positive symptoms of psychosis. Effectiveness of such antipsychotic drugs as chlorpromazine, haloperidol, and benperidol drugs is correlated with their ability to block brain dopamine receptors, as the activation of dopamine receptors contributes to some types of psychotic illness. The greater the D2 receptor binding affinity of an antipsychotic, the greater the clinical potency. Although antipsychotics, both typical and atypical, can have different pharmacological profiles, basically they all block the D2 receptor subtype. However, conventional antipsychotics cannot selectively block just D2 receptors in the mesolimbic dopamine (DA) pathway because these drugs are delivered throughout the entire brain after oral ingestion, so they block just D2 receptor throughout the brain. This accounts for the most-common side-effects of the classical antipsychotic drugs: neurolepsis, extrapyramidal symptoms and tardive dyskinesia.
The class of antipsychotic drugs represents the primary pharmacological treatment of schizophrenia. There are approximately 40 antipsychotics available in the world. In the 2000s, several second generation or "atypical" antipsychotics have been introduced into clinical practice.
The atypical antipsychotics have the ability to separate the antipsychotic effect from the extrapyramidal side effect or neurolepsis (movement disorders such as dystonia, tremor, akathisia, tardive dyskinesia) inherent in the first generation antipsychotics
Figure 8 (Panksepp 2004:302) Antipsychotic Therapy
From a pharmacological perspective, the atypical antipsychotics as a class may be defined in part as serotonin-dopamine antagonists (SDAs). Atypical antipsychotics include, for example, such drugs as clozapine, risperidone, olanzapine, quetiapine, and ziprasidone that have the following common properties:
(1) serotonin 2A-dopamine 2 antagonist pharmacological properties, whereas conventional antipsychotics do not act at the serotonin sites;
(2) cause fewer EPS than first generation "neuroleptics";
(3) improve positive symptoms as well as conventional antipsychotics.
Serotonin 2A antagonism reverses dopamine 2 antagonism in the nigrostriatal dopamine pathway, so that only 70-80% of D2 receptors remain blocked as compared with 90% blockage with the use of conventional antipsychotics. In many patients, 70-80% of D2 receptors blockage would not be enough to produce EPS. Stimulating 5HT2A receptors inhibits dopamine release, while blocking 5HT2A receptors enhances dopamine release. When dopamine release is enhanced by an atypical antipsychotic via blockade of 5HT2A receptors, this allows the extra dopamine to compete with the atypical antipsychotic and reverse the blockade of D2 receptors.
Adjunctive medication can be used in schizophrenia treatment to target side effects or specific nonpsychotic symptoms such as agitation, anxiety, depression, or mood elevation. For example, anticholinergic agents effectively treat the EPS associated with 'conventional' neuroleptics, though the use of anticholinergics with atypical antipsychotics is less justified. Those conventional antipsychotics that have stronger anticholinergic properties, also cause less EPS. "The reason seems to be that dopamine and acetylcholine have a reciprocal relationship in the nigrostriatal pathway. Dopamine neurons in the nigrostriatal dopamine pathway make postsynaptic connections with cholinergic neurons. Dopamine normally inhibits acetylcholine release from postsynaptic nigrostriatal cholinergic neurons, thus suppressing acetylcholine activity there. If dopamine can no longer suppress acetylcholine release because dopamine receptors are being blocked by a conventional antipsychotic drug, then acetylcholine becomes overly active". (Stahl 2004: 409). Anticholinergic drugs diminish the excess acetylcholine activity caused by removal of dopamine inhibition after the blockage of the dopamine receptors are blocked.
Another possible direction of antipsychotic drug development is targeting the glutamatergic transmission and N-methyl-D-aspartate (NMDA) receptors ((Tsai 2008), (Lane et al. 2010)). "The psychosis induced by the NMDA antagonists causes not only positive symptoms similar to the action of dopaminergic enhancers but also negative symptoms and cognitive deficits typical of schizophrenia in normal volunteers and worsening of the psychotic symptoms in patients with schizophrenia". (Tsai 2008: 275). Accordingly, enhancing NMDA neurotransmission is beneficial both for the treatment of positive and negative symptoms of schizophrenia, as well as for cognitive deficits and mood disorders. Lane et al. (2010: 451) found that "enhancing N-methyl-D-aspartate (NMDA) neurotransmission with the treatment of NMDA/glycine site agonists, such as D-serine, or a glycine transporter-1 (GlyT-1) antagonist, N-methylglycine (sarcosine), can improve symptoms of schizophrenia".
Studies of attention deficit and hyperactivity disorder demonstrate deficits in higher-order cognitive functions, including working memory and inhibition, motivational processes, memory, timing and time perception. Evidence for the catecholamine disregulation being involved comes from treatment data, animal models, molecular genetics, functional imaging.
The most commonly used agents to enhance attention in attention deficit disorder are the stimulants methylphenidate and dexamphetamine. They act predominantly by releasing dopamine from presynaptic dopamine terminals and not only block the dopamine transporter but also reverse its direction and make dopamine reverse out of the nerve terminal. Methylphenidate is a DA transporter blocker. Dexamfetamine blocks the DA transporter and stimulates synaptic DA release.
Gronier (2011) showed that MPH activates the firing activity of medial prefrontal cortex neurones in anaesthetised rats (The role of PFC in attention and memory has been well documented). The aim of the author's study was "to determine the respective contribution and location of the different types of catecholamine receptors inmediating these excitatory effects and to compare these effects with those induced by other selective dopamine or noradrenaline uptake blockers". The study showed that the activation of firing elicited by administration of MPH was D1 receptor dependent and potentiated by dopamine but not by noradrenaline. In all, the results of the in vivo study show the involvement of cortical dopamine D1 and noradrenergic alpha 2 receptors in the effects of MPH on PFC neurones. The author hypothesize concerning the therapeutic effect of this drug that "the therapeutic effects of low doses of MPH are associated with a moderate increase in excitability of PFC neurones dependent on a complex antagonistic interplay between D1 and alpha 2 receptors; while the deleterious effects of MPH on cognition, occurring at higher dose, is rather associated with D1 receptor overactivation (likely along with other catecholamine receptor stimulation)". (Gronier 2011: 202).
Both methylphenidate and dexamphetamine "increase DA levels in the nucleus accumbens and therefore have abuse potential. However, the best available evidence suggests that treatment of ADHD with stimulants reduces rather than increases the likelihood of later substance misuse". (Anderson 2004). The conclusion that stimulants can have beneficial effects on addictive patients was shown by (Zack & Poulos 2009) in their study on pathological gamblers. Pathological gambling is a serious psychiatric disorder, affecting 1-3% of the population. The atypical stimulant modafinil has been studies as a potential pharmacotherapy for stimulant and gambling addiction. Modafinil has a unique pharmacological profile - it enhances glutamate, norepinephrine, DA, serotonin, histamine and has been shown to improve ADHD symptoms as well as reduce impulsivity and risky decision-making in adults with ADHD. "The glutamatergic effects of modafinil further support its promise in PG in light of recent accounts that amino acid-induced glutamate enhancement reduces craving in PG subjects". (Zack & Poulos 2009: 661).
Other compounds acting on the noradrenergic system that can be beneficial for symptoms of inattentiveness in attention deficit disorder include alpha 2 agonists such as clonidine and guanfacine wich are both direct-acting alpha 2 adrenergic agonists, and thus enhance cognition and attention. In some cases antidepressants (buproprion) can also help improve attention. In general, there is a growing body of evidence showing that serotonin 5-HT6 receptor antagonists are a promising mechanism for treating cognitive dysfunction and that the serotonin (5-hydroxytryptamine, 5-HT), system, acting via multiple receptors, modulates normal, pathophysiological and therapeutic aspects of learning and memory (Marcos et al. 2010).