ABSTRACT | PDF
Seminar III
Neuropeptides in Psychiatry
Pranjal Sharma
Postgraduate Trainee of Psychiatry
Silchar Medical College and Hospital
What are neuropeptides? By definition neuropeptides are a chain of two or more amino acids linked by a peptide bond and differs from other proteins only in length of the amino acid chains. Neuropeptides range in length from two amino acids (carnosine and anserine) to over 40 amino acids (corticotrophin-releasing hormone [CRH] and urocortin).
Types of neuropeptides 1. Hypothalamic neuropeptides: CRH, thyrotropin-releasing hormone (TRH), growth hormone-releasing hormone (GHRH), somatostatin (SOM), vasopressin, oxytocin (OT), prolactin releasing factor (PRF), prolactin inhibiting factor (PIF).
2. Brain-born pituitary neuropeptides: Adrenocorticotropic hormone (ACTH), α- melanocyte stimulating hormone (MSH), β-endorphine, thyroid stimulating hormone (TSH), luteinising hormone (LH), prolactin, growth hormone (GH).
3. Brain-born opioid peptides: Enkephalins, endorphins, dynorphins, endomorphines, nociceptin.
4. Brain-born gut peptides: Substance P (SUB-P), neuropeptide Y (NPY), vasointestinal peptide (VIP), cholecystokinin (CCK), galanin, gastrin, motilin, pancreatic polypeptide, neurotensin (NT).
5. Others: Calcitonin gene related peptide (CGRP), cocaine amphetamine related transcript protein (CARTP), atrial natriuretic peptide (ANP)/brain natriuretic peptide (BNP), orexin.
Biosynthesis of neuropeptides This can be studied under three headings:
1. Transcription of messenger ribonucleic acid (mRNA) from a specific gene.
2. Translation of a polypeptide preprohormone encoded by the mRNA.
3. Posttranslational processing of the prohormone.
Distribution of neuropeptides within the CNS In general neuropeptides are present in all major areas of brain but a high variation in concentration and expression of peptides are found in certain areas. The area richest in peptides within the CNS is the median eminence.
1. Cerebral cortex: Peptides contained in cortical neurons include SOM, NPY, VIP, CCK, enkephalin, NT.
2. Hypothalamus: CRH, TRH, GHRH, SOM, vasopressin, OT, PRF, PIF.
3. Thalamus: NT, galanin, enkephalin, CGRT, SUB-P.
4. Amygdala and hippocampus: Neuropeptides found in this area of brain are CRH, SOM, CCK, VIP, NYP, SUB-P, enkephalins, dynorphins, galanin, NT.
5. Brainstem and spinal cord: In some of the brainstem nuclei, like the nuclei of reticular formation, nucleus tractus solitarias (NTS), locus coeruleus (LC), neuropeptides are coexpressed with classical neurotransmitters (SUB-P, NPY, NT, CCK, VIP, SOM, enkephalin).
Neuropeptide receptors and signaling Receptors: Majority of neuropeptide receptors are G-protein coupled seven transmembrane domain receptors. Each neuropeptide receptor is specifically coupled to one type of G-protein e.g. Gi/Gs/Gq and receptor activation may result into stimulation or inhibition of second messenger pathways. The receptors and their subtypes can be modulated by more than one type of neuropeptides.
Signaling: Following binding of the peptide to its receptor a cascade of event takes place and the outcome of which depends mostly on the type of cell and circuits in which the receptors are expressed.
Clinical relevance of neuropeptides in psychiatric illnesses Much of these findings are based on: postmortem brain studies of neuropeptide content and their receptors; cerebrospinal fluid (CSF) neuropeptide levels in various psychiatric illnesses; and pharmacological effects of administration of neuropeptide agonist or antagonist.
Schizophrenia Recent hypothesis that schizophrenia is caused by disturbance in neuronal development has come to be understood widely in relation to functional insufficiency of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and NT. Schizophrenia is not caused by an abnormality of a single neurotransmitter but by a disturbance of balance among several neurotransmitters that interact with each other. The greatest number of reports concerning neuropeptides in schizophrenic patients was about brain-gut peptides.
Neurotensin: NT gene is located in chromosome number 12q21 and its actions are mediated by 3 receptors, NT1, NT2 and NT3, out of which NT1 and NT2 are G-protein-coupled receptors and NT-3 is a type 1 amino acid receptor. NT is closely related to the transmission of neurotransmitters in the mesolimbic, mesocortical and nucleus accumbens pathways which are the major sites of dysregulation in schizophrenia. NTs are predominantly located on gamma-aminobutyric acid (GABA)-ergic neurons which releases GABA on dopaminergic nerve terminals and thereby inhibiting their release. Postmortem studies on brain tissues of schizophrenic patients showed decrease expression of NT receptors and also a decrease in CSF concentration of NT compared to their controls and after 4 weeks of treatment with antipsychotics the levels of NT increased with improvement of symptoms. Thus NT may act as an endogenous antipsychotic like substance and awaits the development of NT receptor agonist that can penetrate the blood-brain barrier (BBB).
Cholecystokinin: CCK was originally discovered in the gastrointestinal tract and found in areas of brain that are associated with emotion, motivation and sensory processing. It is colocalised with dopamine (DA) in the ventral tegmental area (VTA) neurons in the mesolimbic and mesocortical DA circuits. CCK inhibits DA. Postmortem brain quantitative analysis showed reduced expression of CCK mRNA by 83% in the frontal lobe, 63% in the temporal lobe and in the layer 3 and layer 4 of entorhinal cortex and CA1 region of hippocampus.
Opioid peptides: Opioid neuropeptides frequently coexist with other neuropeptides or neurotransmitters in the hypothalamic paraventricular nucleus (PVN), nucleus accumbens, substantia niagra and spinal dorsal root neuron. CSF studies of schizophrenic patients showed higher fraction-1 (opioid receptor active fraction) level of endorphins and a higher level of this fraction was related to low level of homovanillic acid (HVA), a metabolic product of dopamine. Postmortem brain studies showed high level of γ and ∝ endorphine levels in the hypothalamus. It was found that β-endorphine inhibits the release of dopamine mediated by N-methyl-D-aspartic acid (NMDA) receptors in the nucleus accumbens and caudate nucleus and putamen. Again infusion of dynorphin into bilateral dorsal part of hippocampus showed impairment of spatial learning and memory that is mediated through the opioid receptor. This impairment was blocked by the administration of naloxone (an opioid receptor antagonist). Thus it seems that opioid peptides may be responsible for the cognitive and learning impairments in schizophrenia and which can be reversed by the use of opioid receptor antagonist.
Mood and anxiety disorders The relationship between peptides and mood disorders is a new frontier that bears further investigation. Studies of peptides in mood illness in humans have mostly sampled unipolar depression and the relevance of these investigations to bipolar disorders is yet to be established. Some peptides in this regard are –
Corticotropin-Releasing Factor: It is a 41 amino acid peptide located in chromosome number 8q13 with two receptors CRF1 and CRF2. CRF along with urocortin globally coordinate response to stressors. Patients with early life trauma (child abuse or neglect) exhibit increase CSF CRF concentration as has now been demonstrated in patients with major depression, posttraumatic stress disorder (PTSD) and antisocial personality disorder. Chronic hyperactivation of the stress system leads to increase and prolong production of CRF which is regarded to play a pivotal role in the manifestation of chronic stress syndrome. If CRF hypersecretion is a factor in pathophysiology of depression then reducing or interfering CRF neurotransmission might be an effective strategy to alleviate depressive symptoms. Thus ‘CRF receptor antagonist’ that can penetrate BBB is a new class of agent for treatment of anxiety and depression e.g. R-121919 and ∝-helical CRF 9-41.
Thyrotropin-Releasing Hormone: Gene for TRH is located in chromosome number 3q13.3-q21. TRH is known to modulate several different neurotransmitters including DA, serotonin (5-HT), acetylcholine (Ach) and opioids. Chronic stress causing activation of the hypothalamic-pituitary-thyroid (HPT) axis is associated with decrease production of thyroid-stimulating hormone (TSH) and inhibition of conversion of relatively inactive thyroxin (T4) to more biologically active triiodothyronin (T3) in peripheral tissues. Radioimmunoassay studies of the HPT axis along with observations that primary hypothyroidism is associated with depressive symptomatology ensured the involvement of this axis in affective disorders. It was found that a TRH stimulation test done in patients with major depression revealed blunting of TSH response. This blunting is a reflection of pituitary TRH receptor downregulation due to median eminence hypersecretion of endogenous TRH. CSF quantitative estimation for TRH concentration showed elevated levels in depressed patients. Thus TRH hypersecretion may be associated with depression and an antagonist to it may help in treating the condition.
Vasopressin and oxytocin: The human OT and arginine vasopressin (AVP) genes are situated in head to tail fashion on chromosome number 20p13. The action of OT is mediated through single receptor subtype (OTR) distributed in periphery and limbic system whereas the action of AVP is through three receptor subtypes V1a, V1b (CNS) and V2 (kidney). AVP is colocalised with CRF neurons in the parvocellular neurons of PVN and acts through the V1b receptors present in the adenohypophysis. Postmortem studies have shown an increase in the number of PVN AVP neurons colocalised with CRF cells in depressed patients compared to controls. Recently a nonpeptide V1b receptor antagonist SSR 149415 has been developed and reported to possess both anxiolytic and antidepressant effects in animal models. OT/AVP neurons projections from PVN to forebrain and brain stem regulate learning, memory, complex social behaviour, female sexual behaviour and facilitate maternal behaviour. CSF studies of OT levels in persons with early exposure to stressful life situations showed a reduced concentration of OT indicating that a dysregulation of this peptide in psychiatric illnesses like autism.
Neuropeptide Y: A 36 amino acid peptide found in hypothalamus, limbic structures, spinal cord and is involved in the regulation of appetite, reward, anxiety. Plasma levels of NPY is elevated in soldiers subjected to uncontrollable stress of interrogation and NPY levels correlate with the feeling of dominance and confidence. CSF and plasma levels are found to be reduced in depressive patients. Postmortem brain studies of suicide victim showed decrease expression of NPY in the PFC.
Cholecystokinin: Distribution in the areas of brain associated with emotion, motivation and sensory processing. CCK is colocalised with dopaminergic neurons in the VTA that comprise of mesocorticolimbic circuits and can modulate the release of DA.
Pentagastrin: A synthetic CCK agonist, on administration produced the physical symptoms of panic. Thus the CCK receptor might be considered as a possible site for treatment to enhance reward or reduce anxiety.
Substance abuse The study for the role of neuropeptides in relation to drug abuse comes mostly in relation to activation of the hypothalamic-pituitary-adrenal (HPA) axis and the level of glucocorticoids. Glucocorticoids seem to increase the motivation of an individual to self administer drugs by stimulation of drug induced DA release in the nucleus accumbens (reward-reinforcement pathway) and suppression of glucocorticoid secretion decreases stimulant and reinforcing effects of drugs.
Changes in the HPA axis during different phases of drug abuse –
During drug exposure: Exposure to drug of abuse profoundly modifies the release of glucocorticoids but not in a homogenous way. Acute exposure to cocaine, alcohol, nicotine increases secretion of glucocorticoids whereas opposite effect is seen with opioids.
During withdrawal: During withdrawal from drug a more homogenous change in glucocorticoid secretion have been observed. Increase glucocorticoid observed during withdrawal could have two effects. First to counteract the negative state associated with withdrawal thus showing that glucocorticoids have positive reinforcing effect that could at least partially substitute for that of drug. Second an increase glucocorticoid concentration during withdrawal could be to increase drug craving. As shown in animal models that injection of glucocorticoids can reinstate drug seeking behaviour.
During abstinence: A decrease in basal glucocorticoid secretion. Increase glucocorticoid negative feedback. A blunted response to stress. Drug vulnerable subjects have higher sensitivity to glucocorticoids.
Therapeutic implication – Two opposite therapeutic strategies could be foreseen. First strategy consists of using glucocorticoid agonist during withdrawal which could have double effect. These drugs by their positive reinforcing effect could help to reduce the negative state associated with withdrawal and at the same time bringing glucocorticoid level above the physiological range could reduce the drug craving. Second strategy consists of using glucocorticoid antagonist during abstinence. These antagonists could help in preventing relapse by two mechanisms – first they counteract the high sensitivity to glucocorticoids as observed in former drug abusers that probably contribute to their vulnerability to drugs. Second they could prevent relapse that seems to be prompted by an increase in glucocorticoid level.
Conclusion Current understanding of the role of neuropeptides in the pathophysiology of various psychiatric illnesses comes from animal models which may or may not accurately reflect the disorder. The ability to directly modulate the peptide receptor activity in human is a major setback to understand the role of neuropeptides in psychopathology. But recent development of nonpeptide agonist and antagonist of these peptides that can readily cross the BBB are the areas of clinical investigation that proves promising.
In addition to drug development and novel brain imaging tools, advances in psychiatric genetics are likely to reveal novel relationship between neuropeptide system and psychopatholgy. Finally psychopharmacogenetics which examine how genotype influences clinical response to drug may lead to individualised therapies targeting peptide system based on the patient’s genotype.
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