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Brain noradrenaline, depression and antidepressant drugs: facts and hypothesis
TIPS -December 1981
314 I
I
Brain noradrenaline, depression and antidepressant drugs: f a c t s and h y p o t h e s i s Wojciech Kostowski Department o f Pharmacology and Physiology' c~flhe N(,rvol£~Sy,~tem, Psychcmeurological bL~titute, Warszawa 02.057, Poland.
Most studies conce-ning the mechanism of affective disorders implicate a dysfunction in noradrenaline (NE) and serotonin (5-HT) neurons in the brain. The theories that implicate simply one neurotransmitter in the mechanism of depression and mania are currently being re-evaluated on the basis of new experimental and clinical findings. Complications to the simple amine theories arise from studies on the complexity of functkmal interaction between various transmitter systems and from discrepancies between experimental and clinical findings. In this short study I try to support the noradrenergic theory of depression that seems, in our opinion, the most probable and attractive explanation of affective disorders as well as the mode of action of antidepressants. This theory, however, needs new comment and explanation. A great deal of evidence suggests.that brain NE plays an important role at least in some types of depression. Depressive patients show decreases in both cerebrospinal and urinary concentrations of 3met hoxy-4-hydroxyphenylgly¢~l (MHPG), the major brain NE metabolite'. DnJgs that either deplete brain catechoiamines (e.g. reserpine) or block postsynaptic catecholamine re,~ptors (e.g. neuroleptics) are known to worsen or even induce depressive states in humans and are commonly used as model substances producing laboratory animal models of depression. On the other hand, numerous antidepressant c~rugs are believed to inc~'ease transmission in NE synapses. All the data presented above contribute to the noradrenaline hypothesis of depression. This problem must be considered in the context of the complexity of noradrenergic interactions with other trans,~ El~g'ffNo,*'t h-Holland Biomedk:al Prcs~ I qg I 0165 - 6147/81/OtXg) - ~HNff$02.75
mitter systems and the high degree of morphological and functional suborganization of the brain NE system.
Two functionally opposite NE systems in the brain Several experiments provide evidence for the existence of two functiona¢ly opposite NE systems: the dorsal bund~,e (DB) and the ventral bundle (VB). The DB originates in the region of the locus coeruleus (LC) and innervates mostly cortical areas such as the neocortex, hippocampus and cerebellar cortex. The VB is the projection from disseminated pontine and medullary cell groups that innervate hypothalamus, amygdalar nuclei and other subcorticai areas". There is evidence that these NE systems play a different role in the regulation of behavior and operate differently on other transmitter systems. Electrolytic lesion of the LC has been reported
i normal
to reduce both locomotion and exploratory activity as well as decrea~ avoidance acquisition in rats. On the other hand, destruction of the VB increases locomotion and facilitates avoidance acquisition~. There is also evidence that lesions of the LC reduce activity of brain dopamine (DA) neurons whilst lesions of the VB ~ e m to produce the opF:,site effect. This supposition is based on the lesion effect upon behavioral actions of drugs that operate through dopaminergic mechanisms, such as neuroleptics (that block DA receptors) and psychostimulants (that may stimulate DA receptors directly or indirectly). The details of these s~udies are described elsewhere', but briefly, it was found that lesion of the LC markedly increased catalepsy in rats treated with neuroleptics while lesion of the Vii abolished the catalepsy. Destruction of the LC is supposed to increase activity of brain 5-HT neurons since it leads to increased brain 5-hydroxyindoleacetic acid (5-HIAA) concentrations in both cats and rats ~,'. On the other hand, lesion of the VB produced no change in brain 5-HIAA'. However, it may be speculated that at least in some conditions this ~esion is associated with decreased 5-HT function. This supposition is based on the similarity between behavioral effects of VB and 5-HT nuclei lesions. Like destruction of the VB the latter produce behavioral excitation, facilitation of avoidance acquisition and reduction in cataleptogenic action of neuroleptics7''~'. On the basis of these findings one
l
I
LC lesion
OAf
VB lesion
Fig. !. Tire proposed model showing ,m interaction between brain NE systems, tire 5.HT neurons and dw DA neurons. The NA system o f the LC ~i.e. the DB) inhibiL~"the 5-HT neurons (dashed lines) an~i stimulates the DA neurons (solid line) while tire NA system ofthe VB exerts an opposite effect. The normal stale represents an equilibrium between excitatory and inhibitory in]iuences, lesion o f the LC leads to the funcl, onal prevalence o f 5-HT neurons while lesion o f the VB leads to dw prevalence o f D A neuroPL~. Both these states may occur during affeclive disorders -depression and ~,,,i;~ qee eext for details).
TIPS
- December
1981
may suppo.~ that decreased function of the L(" is associated with hypoactivity of brain DA neurons and with overactivily of 5-FIT neurons. Conversely. decrea,~d function of the VB leads to enhanced activity of brain DA neurons and decreased activity of 5-HT neurons. I , conclusion, from the data outlined above, a picture emerges where 'primary' NE deficiency is associated with diametrically different alteralions in transmitter balance and with extremely different behavioral patterns. The question arises therefore, as to whether these phenomena are involved with the m e c h a n i s m of affective disorders.
Towards a noradrenery,k: theory of depression.
it seems that primary dysfunction in NE neurons is responsible for a mosaic of fun.,-t i o n a l changes that implicate at least two other transmitter systems, the 5-HT aqd DA systems. Both 5-HT and DA are commonly believed to be intimately involved in mechanisms of affcctive disorders. Brain 5-HT dysfunction is associated with the so-called serotonin subgroup of depressionz'~. In view of findings in certain depressions, it appears that 5 - l - I T mechanisms may be overactive and not, as previously suggested, underactiveL Such findings are in line with the present knowledge of the role of 5-I-IT in behavioral processes. Also, numerous experimental and clinical data indicate that D A deficiency is conducive to depression, while excessive activity of DA neurons occurs in mania*. The evidence just reviewed led us to advance the hypothesis that functional deficiency of the two main NE systems represents the primary functional defect in depression and mania*. I now wish to discuss two model situations (see Fig. l ). l'he first is the situation in which deficiency of the DB prevails. This state is characterized by decrea~d function of DA neurons and hyperactivity of 5-HT neurons. Functional changes therefore reflect these monoamine disturbances and are characterized by decreased locomotion, reduced motivation and learning capacity. Other changes such as the sleep disturbance and hormonal disorders frequently reported in depression, may also be associated with this monoamine dysfunction. The second 'model' situation is the NE deficiency which involves mainly the VB. The symptoms in this state depend mainly upon the overactivity of DA neurons and, possibly, upon decreased function of 5-HT neurons. In this state locomotor and psychomotor excitation may appear; the symptoms characteristic for mania and agitated de-
315 pression. The advantage of our hypothesis. called by us the "noradrenergic-interaction hypothesis' is that it provides a chance to explain why two extreme behavioral states. depression and mania (in other words. behavioral inhibition and e xcilation) might coexist wilh the common primar)' deficiency in NE systems. CIonidiee model o f The function of NE neurons is controlled by complex physiological mechanisms. First of all. the release of NE may be regulated by both inhibitory, and excitato~, receptors Iocaled presynaptically, i.e. in nerve terminals. Some of the~ presynaptie receptors are autoreceptors, i.e. are seh:clively ~nsitive to NE and other adrenergic agonists and antagonists. The most commonly accepted are presynaptic a-receptors belonging to the so-called a, group of adrenoceptors. These are selectively sensitive In clonidine, amethyl-noradrenaline and relatively less sensitive to NE than post-synaptic (~adrenoceptors ~. Stimulation of a=adrenoceptors leads to decrease in release of NE. These receptors are. therefore. involved in an inhibitor)' feedback mechanism that regulates the function of adrenergic neurons. Other autoreceptors of the a~ type are located on the cell bodies of NE neurons (e.g. on the NE cells of the LC). These receptors are responsible for inhibiting the activity of the neuron '~,':.
Recently' the existence of other reet'ptors located pres.~napticall~ on N t~ neur~,ns ha~ been postulated b~ re,nee authors ~ m e ol t b e ~ receptors are responsible for inhibilion of NE release, e.g. chohnergic muscanine (M ) receptors, histamlne l h receptors and opiate rec~ph}rs. ~hile other~ :ue responsible hw stimulation of transmitter relea~, eg /l-ad enocet,aors and angiolensin-Ii receptors. I do not intend , , reva:w the literature regarding the problem of presynaptic receptors (see Ret i 5 ) but in general, it can be concluded thal most studies implicate the pres)naptic ,~+adrenoceptors in regulation ol NE relent. and turnover in this connection it seems o| parlicular interest to investigate bcha~u)ral and biochemical phenomena asst~.'iated with stimulation and bhs:kade ol this receptor group, it ma~ appear rea~mable that drugs that stimulate ,~-adrenoceptors could provide a ne~ approach to finding improved laborator)" models of depression. Although few investigations have been performed, there are ~ m e report,, v, hich suggest that clonidine ma~' be suitable for use as a drug thal induces depressionlike symptoms. This hypotensi~e compound is a powerful and selective agonist ot c~radrenoceptors and bx ~irtue of stimulation of t h e ~ receptor~ it suppresses the release of NE from ner~e terminals '~. Clonidine i,, al.~) knos+n to inhibit the firing of LC neurons, probably due to stimulation of a=-adrentg:eptors located on cell ~+dies ~; The reduction of NE turnoxer ~s
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3! 6
TIPS
manifested by a fall in MHPG concenr~'ations in the brain following administrahon of this drug. CIo,idine produces numerous symptoms of behavioral depression in laboratory animals. These include sedation and suppression of locomotion and exploratory behavior, inhibition of conditioned avoidance acquisition and suppression of self stimulation4.9. Almost all of the central effects of clonidine can be blocked by agonists of a2-adlenoceptors such as yohimbine and piperoxan. This finding strongly suggests that the depressive action ofclonidine is mediated through ,he t~-rcceptors4. Very recent studies rex eal that clonidine effects are antagonized by a[~tidepressant drugs. Desipramine, the secondary, amine tricyclic antidepressant, wa:, found to antagonize both clonidine-induced inhibition of NE release from cerebral cortex and clonidine-induced reduction in MHPG concentration in the brain Moreover desipramine, as well as other tricyclic and tetracyclic antidepressants, has been found to antagonize elonidine-induced sedation i,3 laboratory aaimalP.*.
Looking for an animal model of depression we have recently investigated the effect of clonidine on locomotion and exploration in the Mongolian gerbil (Meriones unguiculams ); the rodent recently accepted as a very suitable laboratory animal, especially for behavioral studies. We found that cionidine (0~05-0.1 mg kg -~ i.p.) strongly reduced both locomotion and explorato~, behavior, particularly the exploration of the "novel' object (i.e. the object that normally induced renewed interest fol-
-
December 1981
Tricyclic antidepressants possess significant anticholinergic activity and are known to block histamine Ha receptors*. Although the significance of these activities remains unclear, one may theoretically suppose that blockade of both M-cholinergic and I-h receptors located presynaptically on NE neurons leads to an increase in the liberation of NE. This problem remains to be investigated further. How do antidepressant drugs work? Certain antidepressants such as imiif we consider that depression is primar- pramine, nortriptyline, mianserin and ily related to reduced transmission through nomifensine possess 5-HT receptor blockNE synapses, the therapeutic efficacy of ing activity in doses near to those causing antidepressants could be interpreted as 5-HT or NE uptake inhibition's. Since increasing NE transmission, The analysis 5-HT neurons are suppo~d to exert an of possible mechanisms of action of antide- inhibitory influence upon NE neurons'.*, pressants belonging to various groups the anti-5-HT action o! antidepressants reveals that this facilitatory effect may be may be considered as 'reinforcing" their realized in several ways such as inhibition noradrenergic action. This problem is of transmitter uptake, action upon pre- briefly di;¢ussed below. synaptic receptors and autoreceptors and Considering the fact that antidepressants finally by antiserotonergic action. It is now increase NE concentration in the synaptic certain that il,hibition of neuronal uptake cleft it should be taken into account that of monoamines is essential for antidepres- this mechanism leads to adaptive changes sants belonging to the tricyclic group. Ter- in receptors, it is commonly believed that tiary amine antidepressants such as imi- receptors adapt to the degree of receptor pramine and amitriptyline are relatively stimulation by either increasing or decreasmore ix)tent inhibitors of 5-HT uptake ing their sensitivity. Interestingly, these than NE uptake. On the other hand, sec- adaptive processes develop in some recepondary amines such as de,:ipramine and tors whilst they are not seen in others, it nortriptyline mostly inhibit NE uptake n. was found that both acute and also chronic The second po~ible mechanism by which administration of these drugs decreases antidepressants increase NE transmission both the sensitivity and number of preis their ability to facilitate transmitter synaptie a2-adrenoceptorsae while producrelease due :o blocking presynaptic c~=- ing no change in post-synaptic madrenoceptors. Such an effect has been receptors. The changes in a,-receptor sendescribed for numerous tricyclic and tetra-" sitivity and number may lead to increased cyclic drugsa. NE liberation and consequently, may
lowing habituation to the environment). All the clonidine effects were markedly reduced in animals pretreated with yohimbine as well as tricyclic antidepressants such as dcsipramine, imipramine and clomipramine*. Further experiments are continuing in our laboratory to evaluate clonidine-induced sedation in animals as a useful laboratory model of depression.
AntiserotonergiCaction ] ' Presynapticreceptor blockade:a.. H2
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Changedsensitivity anddensityof ~x~adrenoceptors i
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DEPRESSION SYMPTOMS . , l
T I P S - D e c e m b e r 1981
increase NE neurotransmission. The possible role of prcsynaptic #-adrenoceptors in th,: action of antidepressants has recently been discussed by some authors. As mentioned previously, stimulation of these receptors may produce the increased liberation of neurotransmitter. Interestingly, some agonists of ~-adrenoceptors (e.g. salbutamol) have been reported recently to produce antidepressive effects. A rom of presynaptic //-receptors in the actkm of mianserin has also been postulated. Fig. 2 shows possible sites of action of antidepressants, At present it is difficult to explain why increased concentration of HE in the synaptic cleft attenuates the depression symptoms, it is probable that increased activity of HE neurons by interaction with other transmitter systems induces a mosaic of changes in neuronal mechanisms that finally compensates pathological processes and consequently, attenuates depression. Another important mechanism recently discussed is related to adaptive receptor changes. Recently, Sulser and I',is colleagues proposed the interesting hypothesis that reduced sensitivity of post-synaptic //-adrenoceptors is responsible for antidepressant action. They found that chronic administration of antidepressants belonging to various groups dramatically reduced the activity of the //-adrenoceptor
~l
5-HT neuronsexerl an inhibitor) influence utxm both 5-HT and D A neumm,. Locomotor activity a.~well ;is slereotypk.-s pr;~luced by I~+lh amphetamine ;end ai~wmorphine are enhanced in animals with lesioned brain 5-HT neurons and lrcalcd with p-chlorophenylalanine, the 5-11"1" depictor ~. Lesions of raphe nuclei, t l~,:area containing 5-H'l" cell Ix~l~s, prcKlucc a ,,ignificanl increa~ in brain M H P G conccnIrations ~. These data indicate thai decreased function of 5-HT neurons i~ associated with overactivity of i ~ l h DA and NE neurons. Destruction of brain 5-HT neurons produces locomotor agitation in animals. This effect is at least partially duc Io overaclivily of catccholamine neurons sincc it may easily be bh~cked by (,-methyll)-tyrosin~:. the inhibitor of tyrosine hydroxyla~L Other excitato~* effects such as facilitation ot avoidance acquisition, incrca~d aggressi~,ity and permanent desynchronization in the conical EEG pattern can be obscrved after destruction of 5-HT neurons TM. Animals with destroyed 5-1-1"i"neurons are also less susceptible to depressive action of neuroleptics ~. Interestingly enough, depressive action of donidine is antagoniz,:d by destruction of 5-HT neurons '°. Therefore, if the central cltonidine effects might be regarded as depression-like symptoms, the anti-5-HT action could be considered as a potent anti-depressant mechanism. It may be concluded that anti-5-HT action of antidepressants is of particular importance in their therapeutic efficacy. It is ,~)mewhat disturbing to find that 5-hydroxyt~'ptophan (5-HTP). the precursor of 5-HT, is u,~ful in tream~ent of ~-~me types of depression. It is. hosteler, highly probable that this amino ilcid illav not act in a ph)siological manner, ~ince it leads to 5-HT production in I~th 5-ttT and catecholamine neurons, it ~as found that high d o ~ s of 5-HTP displace the DA in dopaminergic neurons and induce DA rclea~L It is therefore difficult to interpret the results obtained with 5-1tlP a, "~rotonergic'.
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314 I
I
Brain noradrenaline, depression and antidepressant drugs: f a c t s and h y p o t h e s i s Wojciech Kostowski Department o f Pharmacology and Physiology' c~flhe N(,rvol£~Sy,~tem, Psychcmeurological bL~titute, Warszawa 02.057, Poland.
Most studies conce-ning the mechanism of affective disorders implicate a dysfunction in noradrenaline (NE) and serotonin (5-HT) neurons in the brain. The theories that implicate simply one neurotransmitter in the mechanism of depression and mania are currently being re-evaluated on the basis of new experimental and clinical findings. Complications to the simple amine theories arise from studies on the complexity of functkmal interaction between various transmitter systems and from discrepancies between experimental and clinical findings. In this short study I try to support the noradrenergic theory of depression that seems, in our opinion, the most probable and attractive explanation of affective disorders as well as the mode of action of antidepressants. This theory, however, needs new comment and explanation. A great deal of evidence suggests.that brain NE plays an important role at least in some types of depression. Depressive patients show decreases in both cerebrospinal and urinary concentrations of 3met hoxy-4-hydroxyphenylgly¢~l (MHPG), the major brain NE metabolite'. DnJgs that either deplete brain catechoiamines (e.g. reserpine) or block postsynaptic catecholamine re,~ptors (e.g. neuroleptics) are known to worsen or even induce depressive states in humans and are commonly used as model substances producing laboratory animal models of depression. On the other hand, numerous antidepressant c~rugs are believed to inc~'ease transmission in NE synapses. All the data presented above contribute to the noradrenaline hypothesis of depression. This problem must be considered in the context of the complexity of noradrenergic interactions with other trans,~ El~g'ffNo,*'t h-Holland Biomedk:al Prcs~ I qg I 0165 - 6147/81/OtXg) - ~HNff$02.75
mitter systems and the high degree of morphological and functional suborganization of the brain NE system.
Two functionally opposite NE systems in the brain Several experiments provide evidence for the existence of two functiona¢ly opposite NE systems: the dorsal bund~,e (DB) and the ventral bundle (VB). The DB originates in the region of the locus coeruleus (LC) and innervates mostly cortical areas such as the neocortex, hippocampus and cerebellar cortex. The VB is the projection from disseminated pontine and medullary cell groups that innervate hypothalamus, amygdalar nuclei and other subcorticai areas". There is evidence that these NE systems play a different role in the regulation of behavior and operate differently on other transmitter systems. Electrolytic lesion of the LC has been reported
i normal
to reduce both locomotion and exploratory activity as well as decrea~ avoidance acquisition in rats. On the other hand, destruction of the VB increases locomotion and facilitates avoidance acquisition~. There is also evidence that lesions of the LC reduce activity of brain dopamine (DA) neurons whilst lesions of the VB ~ e m to produce the opF:,site effect. This supposition is based on the lesion effect upon behavioral actions of drugs that operate through dopaminergic mechanisms, such as neuroleptics (that block DA receptors) and psychostimulants (that may stimulate DA receptors directly or indirectly). The details of these s~udies are described elsewhere', but briefly, it was found that lesion of the LC markedly increased catalepsy in rats treated with neuroleptics while lesion of the Vii abolished the catalepsy. Destruction of the LC is supposed to increase activity of brain 5-HT neurons since it leads to increased brain 5-hydroxyindoleacetic acid (5-HIAA) concentrations in both cats and rats ~,'. On the other hand, lesion of the VB produced no change in brain 5-HIAA'. However, it may be speculated that at least in some conditions this ~esion is associated with decreased 5-HT function. This supposition is based on the similarity between behavioral effects of VB and 5-HT nuclei lesions. Like destruction of the VB the latter produce behavioral excitation, facilitation of avoidance acquisition and reduction in cataleptogenic action of neuroleptics7''~'. On the basis of these findings one
l
I
LC lesion
OAf
VB lesion
Fig. !. Tire proposed model showing ,m interaction between brain NE systems, tire 5.HT neurons and dw DA neurons. The NA system o f the LC ~i.e. the DB) inhibiL~"the 5-HT neurons (dashed lines) an~i stimulates the DA neurons (solid line) while tire NA system ofthe VB exerts an opposite effect. The normal stale represents an equilibrium between excitatory and inhibitory in]iuences, lesion o f the LC leads to the funcl, onal prevalence o f 5-HT neurons while lesion o f the VB leads to dw prevalence o f D A neuroPL~. Both these states may occur during affeclive disorders -depression and ~,,,i;~ qee eext for details).
TIPS
- December
1981
may suppo.~ that decreased function of the L(" is associated with hypoactivity of brain DA neurons and with overactivily of 5-FIT neurons. Conversely. decrea,~d function of the VB leads to enhanced activity of brain DA neurons and decreased activity of 5-HT neurons. I , conclusion, from the data outlined above, a picture emerges where 'primary' NE deficiency is associated with diametrically different alteralions in transmitter balance and with extremely different behavioral patterns. The question arises therefore, as to whether these phenomena are involved with the m e c h a n i s m of affective disorders.
Towards a noradrenery,k: theory of depression.
it seems that primary dysfunction in NE neurons is responsible for a mosaic of fun.,-t i o n a l changes that implicate at least two other transmitter systems, the 5-HT aqd DA systems. Both 5-HT and DA are commonly believed to be intimately involved in mechanisms of affcctive disorders. Brain 5-HT dysfunction is associated with the so-called serotonin subgroup of depressionz'~. In view of findings in certain depressions, it appears that 5 - l - I T mechanisms may be overactive and not, as previously suggested, underactiveL Such findings are in line with the present knowledge of the role of 5-I-IT in behavioral processes. Also, numerous experimental and clinical data indicate that D A deficiency is conducive to depression, while excessive activity of DA neurons occurs in mania*. The evidence just reviewed led us to advance the hypothesis that functional deficiency of the two main NE systems represents the primary functional defect in depression and mania*. I now wish to discuss two model situations (see Fig. l ). l'he first is the situation in which deficiency of the DB prevails. This state is characterized by decrea~d function of DA neurons and hyperactivity of 5-HT neurons. Functional changes therefore reflect these monoamine disturbances and are characterized by decreased locomotion, reduced motivation and learning capacity. Other changes such as the sleep disturbance and hormonal disorders frequently reported in depression, may also be associated with this monoamine dysfunction. The second 'model' situation is the NE deficiency which involves mainly the VB. The symptoms in this state depend mainly upon the overactivity of DA neurons and, possibly, upon decreased function of 5-HT neurons. In this state locomotor and psychomotor excitation may appear; the symptoms characteristic for mania and agitated de-
315 pression. The advantage of our hypothesis. called by us the "noradrenergic-interaction hypothesis' is that it provides a chance to explain why two extreme behavioral states. depression and mania (in other words. behavioral inhibition and e xcilation) might coexist wilh the common primar)' deficiency in NE systems. CIonidiee model o f The function of NE neurons is controlled by complex physiological mechanisms. First of all. the release of NE may be regulated by both inhibitory, and excitato~, receptors Iocaled presynaptically, i.e. in nerve terminals. Some of the~ presynaptie receptors are autoreceptors, i.e. are seh:clively ~nsitive to NE and other adrenergic agonists and antagonists. The most commonly accepted are presynaptic a-receptors belonging to the so-called a, group of adrenoceptors. These are selectively sensitive In clonidine, amethyl-noradrenaline and relatively less sensitive to NE than post-synaptic (~adrenoceptors ~. Stimulation of a=adrenoceptors leads to decrease in release of NE. These receptors are. therefore. involved in an inhibitor)' feedback mechanism that regulates the function of adrenergic neurons. Other autoreceptors of the a~ type are located on the cell bodies of NE neurons (e.g. on the NE cells of the LC). These receptors are responsible for inhibiting the activity of the neuron '~,':.
Recently' the existence of other reet'ptors located pres.~napticall~ on N t~ neur~,ns ha~ been postulated b~ re,nee authors ~ m e ol t b e ~ receptors are responsible for inhibilion of NE release, e.g. chohnergic muscanine (M ) receptors, histamlne l h receptors and opiate rec~ph}rs. ~hile other~ :ue responsible hw stimulation of transmitter relea~, eg /l-ad enocet,aors and angiolensin-Ii receptors. I do not intend , , reva:w the literature regarding the problem of presynaptic receptors (see Ret i 5 ) but in general, it can be concluded thal most studies implicate the pres)naptic ,~+adrenoceptors in regulation ol NE relent. and turnover in this connection it seems o| parlicular interest to investigate bcha~u)ral and biochemical phenomena asst~.'iated with stimulation and bhs:kade ol this receptor group, it ma~ appear rea~mable that drugs that stimulate ,~-adrenoceptors could provide a ne~ approach to finding improved laborator)" models of depression. Although few investigations have been performed, there are ~ m e report,, v, hich suggest that clonidine ma~' be suitable for use as a drug thal induces depressionlike symptoms. This hypotensi~e compound is a powerful and selective agonist ot c~radrenoceptors and bx ~irtue of stimulation of t h e ~ receptor~ it suppresses the release of NE from ner~e terminals '~. Clonidine i,, al.~) knos+n to inhibit the firing of LC neurons, probably due to stimulation of a=-adrentg:eptors located on cell ~+dies ~; The reduction of NE turnoxer ~s
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manifested by a fall in MHPG concenr~'ations in the brain following administrahon of this drug. CIo,idine produces numerous symptoms of behavioral depression in laboratory animals. These include sedation and suppression of locomotion and exploratory behavior, inhibition of conditioned avoidance acquisition and suppression of self stimulation4.9. Almost all of the central effects of clonidine can be blocked by agonists of a2-adlenoceptors such as yohimbine and piperoxan. This finding strongly suggests that the depressive action ofclonidine is mediated through ,he t~-rcceptors4. Very recent studies rex eal that clonidine effects are antagonized by a[~tidepressant drugs. Desipramine, the secondary, amine tricyclic antidepressant, wa:, found to antagonize both clonidine-induced inhibition of NE release from cerebral cortex and clonidine-induced reduction in MHPG concentration in the brain Moreover desipramine, as well as other tricyclic and tetracyclic antidepressants, has been found to antagonize elonidine-induced sedation i,3 laboratory aaimalP.*.
Looking for an animal model of depression we have recently investigated the effect of clonidine on locomotion and exploration in the Mongolian gerbil (Meriones unguiculams ); the rodent recently accepted as a very suitable laboratory animal, especially for behavioral studies. We found that cionidine (0~05-0.1 mg kg -~ i.p.) strongly reduced both locomotion and explorato~, behavior, particularly the exploration of the "novel' object (i.e. the object that normally induced renewed interest fol-
-
December 1981
Tricyclic antidepressants possess significant anticholinergic activity and are known to block histamine Ha receptors*. Although the significance of these activities remains unclear, one may theoretically suppose that blockade of both M-cholinergic and I-h receptors located presynaptically on NE neurons leads to an increase in the liberation of NE. This problem remains to be investigated further. How do antidepressant drugs work? Certain antidepressants such as imiif we consider that depression is primar- pramine, nortriptyline, mianserin and ily related to reduced transmission through nomifensine possess 5-HT receptor blockNE synapses, the therapeutic efficacy of ing activity in doses near to those causing antidepressants could be interpreted as 5-HT or NE uptake inhibition's. Since increasing NE transmission, The analysis 5-HT neurons are suppo~d to exert an of possible mechanisms of action of antide- inhibitory influence upon NE neurons'.*, pressants belonging to various groups the anti-5-HT action o! antidepressants reveals that this facilitatory effect may be may be considered as 'reinforcing" their realized in several ways such as inhibition noradrenergic action. This problem is of transmitter uptake, action upon pre- briefly di;¢ussed below. synaptic receptors and autoreceptors and Considering the fact that antidepressants finally by antiserotonergic action. It is now increase NE concentration in the synaptic certain that il,hibition of neuronal uptake cleft it should be taken into account that of monoamines is essential for antidepres- this mechanism leads to adaptive changes sants belonging to the tricyclic group. Ter- in receptors, it is commonly believed that tiary amine antidepressants such as imi- receptors adapt to the degree of receptor pramine and amitriptyline are relatively stimulation by either increasing or decreasmore ix)tent inhibitors of 5-HT uptake ing their sensitivity. Interestingly, these than NE uptake. On the other hand, sec- adaptive processes develop in some recepondary amines such as de,:ipramine and tors whilst they are not seen in others, it nortriptyline mostly inhibit NE uptake n. was found that both acute and also chronic The second po~ible mechanism by which administration of these drugs decreases antidepressants increase NE transmission both the sensitivity and number of preis their ability to facilitate transmitter synaptie a2-adrenoceptorsae while producrelease due :o blocking presynaptic c~=- ing no change in post-synaptic madrenoceptors. Such an effect has been receptors. The changes in a,-receptor sendescribed for numerous tricyclic and tetra-" sitivity and number may lead to increased cyclic drugsa. NE liberation and consequently, may
lowing habituation to the environment). All the clonidine effects were markedly reduced in animals pretreated with yohimbine as well as tricyclic antidepressants such as dcsipramine, imipramine and clomipramine*. Further experiments are continuing in our laboratory to evaluate clonidine-induced sedation in animals as a useful laboratory model of depression.
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DEPRESSION SYMPTOMS . , l
T I P S - D e c e m b e r 1981
increase NE neurotransmission. The possible role of prcsynaptic #-adrenoceptors in th,: action of antidepressants has recently been discussed by some authors. As mentioned previously, stimulation of these receptors may produce the increased liberation of neurotransmitter. Interestingly, some agonists of ~-adrenoceptors (e.g. salbutamol) have been reported recently to produce antidepressive effects. A rom of presynaptic //-receptors in the actkm of mianserin has also been postulated. Fig. 2 shows possible sites of action of antidepressants, At present it is difficult to explain why increased concentration of HE in the synaptic cleft attenuates the depression symptoms, it is probable that increased activity of HE neurons by interaction with other transmitter systems induces a mosaic of changes in neuronal mechanisms that finally compensates pathological processes and consequently, attenuates depression. Another important mechanism recently discussed is related to adaptive receptor changes. Recently, Sulser and I',is colleagues proposed the interesting hypothesis that reduced sensitivity of post-synaptic //-adrenoceptors is responsible for antidepressant action. They found that chronic administration of antidepressants belonging to various groups dramatically reduced the activity of the //-adrenoceptor
~l
5-HT neuronsexerl an inhibitor) influence utxm both 5-HT and D A neumm,. Locomotor activity a.~well ;is slereotypk.-s pr;~luced by I~+lh amphetamine ;end ai~wmorphine are enhanced in animals with lesioned brain 5-HT neurons and lrcalcd with p-chlorophenylalanine, the 5-11"1" depictor ~. Lesions of raphe nuclei, t l~,:area containing 5-H'l" cell Ix~l~s, prcKlucc a ,,ignificanl increa~ in brain M H P G conccnIrations ~. These data indicate thai decreased function of 5-HT neurons i~ associated with overactivity of i ~ l h DA and NE neurons. Destruction of brain 5-HT neurons produces locomotor agitation in animals. This effect is at least partially duc Io overaclivily of catccholamine neurons sincc it may easily be bh~cked by (,-methyll)-tyrosin~:. the inhibitor of tyrosine hydroxyla~L Other excitato~* effects such as facilitation ot avoidance acquisition, incrca~d aggressi~,ity and permanent desynchronization in the conical EEG pattern can be obscrved after destruction of 5-HT neurons TM. Animals with destroyed 5-1-1"i"neurons are also less susceptible to depressive action of neuroleptics ~. Interestingly enough, depressive action of donidine is antagoniz,:d by destruction of 5-HT neurons '°. Therefore, if the central cltonidine effects might be regarded as depression-like symptoms, the anti-5-HT action could be considered as a potent anti-depressant mechanism. It may be concluded that anti-5-HT action of antidepressants is of particular importance in their therapeutic efficacy. It is ,~)mewhat disturbing to find that 5-hydroxyt~'ptophan (5-HTP). the precursor of 5-HT, is u,~ful in tream~ent of ~-~me types of depression. It is. hosteler, highly probable that this amino ilcid illav not act in a ph)siological manner, ~ince it leads to 5-HT production in I~th 5-ttT and catecholamine neurons, it ~as found that high d o ~ s of 5-HTP displace the DA in dopaminergic neurons and induce DA rclea~L It is therefore difficult to interpret the results obtained with 5-1tlP a, "~rotonergic'.
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