- Email: [email protected]
This and that: on method and muricide
TiPS - March 1987 fVol.81
87
is
temporally offset correlation was found beb teen dopamine release and rotational rate, the peak of dopamine release occurring 40 min before maximum rotational behavior*. Other studies have revealed that glutamine is the most abundant extracellular amino acid3 and the high intracellular to extracel1uh.r ratios of neuroactive amino acids. The ratio for GABA is 9000 : 1 (Ref. 5). Fiber dialysis can also be used in reverse, to deliver chemicals to the brain. Thus, changes in amino acid content of extracellular fluid in response to perfusion of depolarizing concentrations of potassium have been examined. Findings have been quite different from those found in similar experiments on brain slices7. There are marked increases in taurine and phosphoethanolamine efflux in hippocampus perfused in vivo with potassil;m. Only moderate increases are seen in glutamate and GABA efflux. With hippocampal slices, however, potassium depolarization leads to marked increases in glutamate and GABA efflux and little change in the efflux of other amino acids. These differences are presumably ascribable to the greater cellular damage found in slices and the relative anoxia of cells in the interior of the slice.
HYPOTHESES BY DEFINITION are experimentally testable. Their construction is, th.erefore, limited by the available methodology. Thus, a symbiotic relationship exists in science betwee!? the abstraction of thought in office and library (or other places) and the arduous reality of the laboratory bench. This is the scientist’s version of duality; the separateness yet indivisibility of soul and body, theory and practice; the impossibility of the one without the other. Great advances have been made in science in the wake of new theories and hypotheses. Great advances have also been made in the wake of new methods and technologies. In the brain, cell talks to cell not in the dialysate is a function not only of its concentration in extraonly through the specificity cellular fluid but also of the flow of neural connection, but via rate of buffer through the fiber and the changing composition of the rate constants of diffusion. For the extracellular fluid which example, Ungerstedt et n1.l report bathes them. Chemicals - transthat under a given set of conditions mitters, modulators, intermediin vitro, recovery of amino acids is ates, metabolites, substrates only 28%. Thus, the concentraand waste - are continually tions reported in experiments with being released into and taken thesle fibers may not accurately up from this slowly stirring represent concentrations in extrasoup. Both the composition and cellular space, but changes in perfusate concentration do reflect temporal change in composichanges in extracell Jar composition of extracellular fluid contion. Various types of mathetain detailed information on malical analyses have been apcellular behavior. Not surprisplied to dialysis data3”. ingly, scientists have attempted The first application of the to access this information by method was to examine the neuromeans of cortical cups, intrachemical correlates of behavior. cerebral fluid sampling and Rats rotate in response to unipush-pull cannulas. lateral lesioning of dopaminergic The difficulties and drawpathways. Using fiber dialysis, a backs of these methods are many. Recently, a quantum leap forward has been achieved by means of microdi?lysis of extracellular fluid through implanted semipermeable fibers (Ref. 1). Hollow fibers, of 0.3 mm diameter or less, are implanted in various brain areas, and buffer “pumped slowly through th zrn. Dialysable substances enter the fiber, the perfusate c&&d, and analysed by HFLC. Fibers of various sizes have been used, ranging from 5000 to 50 000 Da. As the sample sizes are so small, the development of this new method depended on the availability of another fairly new method, HPLC, for sample an,alysis. Following the initial report, modifications of the fiber Fig. 1. Sagittalsection through posterior hyporhalamus of rat with an intrahypolhalmic dialysis method were quickly oialysis loop implanted (x 200). The section showspartof the dialysis tube (D) which has e WaIdiameter of about3W mm and the lumen of the fube (1) 8 hours after impfantafion. published by other groups”. There is no damage lo fhe braintissueapartfrom a small area immediately surrounding A review of methodology has fhe lube. Photograph kindly supplied by C. Routledge and C. A. Mawden. University of recently appeared’. Nottingham Medical School, UK. The concentration of a substanlze
-@ 1987,
Elsevier
Publications.
Cambridge
0165 - 6147/R71502JJ@
TlPS - March 1987 [Vol. 81
SS Brain dialysis has also been used to examine basal and stimulated release of preloaded (radiolabelled) substances. It has been shown by this means that genetically, seizure susceptible rats hzve a
much higher rate of o-aspartate (a efflux analog) ncuroexcitatory from the hippocampus on depolarization than do seizure resistant rats6. There is no reason why the use
THE NEUROCHEMISTRY OF AGGRESSION is not a fashionable topic, but who can doubt the significance of an understanding of the mechanisms precipitating aggression? Surely the factors that lead one man to strike out at another are also involved in the problematic relationships between sovereign states in this overcrowded and overmilitarized globe. In a succinct phrase, aggressiveness is a threat to the existence of humanity*. Many have commented on the disparity between the evolution of human technology and the lack of a corresponding evolution in the ability nmn+inn4ity. Is ag*gression ‘hard-wired’ in the to control primiti;, x n bII.V..U. _ _ human brain, so much a part of the essence of being human that it can be modified only at the expense of our individual and species identity? In the same manner tha t a solitary existence is integral to the petrel and communalitv to the ant? A first problem in the study of 2.3% of Wistars and 3% of August the neurochemistry of aggresratss. sion is the defining of the Muricidal rats show a number of neurochemical alterations, includphenomenon under investigaing decreased levels of GABA in tion. Mandel et al., while the olfactory bulb, decreased tumadmitting the difficulty of defiover of 5-HT in the raphe area, and nition, Suggest that, ‘d dggresincreased choline acetyltransferase sive display is an attempt to activity in the amygdala. Mandel et endanger the integrity of the a1.9 hypothesiz, that inhibitory opponent”. If integrity refers to circuits from the olfactory bulb psychic as well as physical suppress muricidal behavior. In state, then two humans can support of this, ablation of the hardly come together without olfactory bulb produces muricidal such a display. behavior in 60% of otherwise In selected modeis of aggression, normai ratsi3, and injections of it is to be hoped that aggression GABA, GABA agonists, inhibitors and its modulation could be of GABA reuptake, or GABA transexplained in terms of molecular aminase inhibitors all increase mechanisms. One important findGABA levels in the olfactory bulb ing with animals is that aggression and all block spontaneous muriis not necessarily a male trait, nor tidal behavior14. Killing is also necessarily linked with male sex abolished by lesioning of the hormones. Widely used models amygdala or the lateral hypoinclude the aggressive behavior thalamus. The suppression of of females towards lactating f:amouse-killing behavior is not due mdes*‘, and aggression produced to anosmia per se, as sectioning of In both sexes by isolation and sociothe olfacto? nerve, removal of environmental deprivation1’*‘2. nasal mucoja, or isolating mice The muricidal rat, the so-called behind a teflon sheet does not ‘killer’ rat, has been another modify the behavior. Hyperacwidely used model13. Such a rat tivity appears to be associated will quickly dispatch a mouse with muricidal behavior. Bulplaced in its cage. The behavior is bectomized rats are hyperactive stereotyped, including chase, capand lesioning of the dorsal or ture and neck biting sequences. medial raphe nucleus increases Significantly, the behavior is not both locomotor activity and killing learned and is exhibited without behavior. previous experience. Nonkiller Taurine, another inhibitory IX-, rats, even when raised with kil!ers, w-amino aci.d, also blocks murishow no interest in mice. There is a tidal behavior, although other genetic component to mouse-killamino acids are without effect. The ing behavior, in that 70% of wild action of taurine is synergistic Norwegian rats are muricidal, as with that of valproate (a transcompared to 58% of Long-Evans, aminase inhibitor), suggesting
of such a convenient method as fiber dialysis should be limited to the brain. One obvious application for pharmacologists would be the study of regional drug metabolism in the liver. that these compounds act at different sites. Lipophilic analogs of taurine are effective ‘antimuritides’ when given by mouth, allowing the predictions of lsiah 11:6 and 65:25 to be achieved. Thus, taltrimide, glanced upon in
Fig. 2. In&a species aggression in mice. Photograph kindly supplied by P. F. Brain, Dept. Zoology, University College of Swansea, Swansea, UK.
TIPS - March 1987 [r/s!. 81 an earlier column as an antiepileptic agent”, given by mouth in a dose of 1.6 mmol kg-l, quickly reduces muricidal behavior to 20% of control. 2-Benzamidoethanesulfon-N-t- bu’:;lamide is even more effr-_:_-:a Another model of aggression is the light-deprived hamsteP. Male hamsters exposed to less than 12.5 h of light per day show an increase in aggressiveness. The interesting aspect of this model is the removal of the macho factor, or the normal masculine elements that are associated with aggression. Hamsters are sexually dimorphic, the males being smaller and less aggressive than the females. When deprived of light, the testicles decrease in size and plasma levels of various hormones, including testosterone, falll’. There is an inverse relationship between testosterone levels and aggressiveness. On re-exposure to long-day photoperiods, these changes reverse to normal. Although this report should not be taken as encouragement for male pharmacologists to sleep with the light on, this association of light deprivation with aggression does lead me to wonder if long hours in poorly lit offices have any connection with the ferocity of intraoffice politics. There is a huge literature on violence, but studies of neurochemistry and molecular mechanisms are negligible. This is a strange lacuna considering how violence shapes and constrains our A few score people societies. suffering from Legionnaire’s disease, a few thousand dying of acquired immunodeficiency, and society responds by an outpouring of funds to research cause and cure. But the telescope is at the blind eye when it comes to the violence that is as integral as language to the human state. Mandel et al.‘have shown that in experimental animals aggressive behaviors are selectively modifiable. There would appear to be no need to lobotomize away the esthetic appreciations that give life its finer shadings in order to control aggression. However, how relevant are these animal studies to the complexities of our world? Are the particular models good? For those who question the relevance of the killer r-! to the myriad corporate and individual forms in which aggression is expressed by
89 humans, I ask them to consider carefully the following statement from an admirable man and a great scientist: ‘In view of the moral responsibility of a scientist to the society that provides the opportunity to do research, we should bear in mind any potential clinical usefulness of such investigations on aggressive behavior. There is littie doubt that the natural history, motivation and consciousness that underlie human aggressive behavior show it to differ profoundly from our animal models of aggressive behavior. However, the basic phenomena of communication among brain circuits and of final expression of behavioral patterns are strongly b0un.d to netuotransmitter mechanisms, which are fairly similar in different species. Thus one might expect that a knowledge of the molecular mechanisms governing aggressive behavior in experimental animals would, in time, guide us toward the control of some basic molecular mechanisms of human aggressive behavior’s. In the muricidal rat, aggressiveness is due to the loss or suppression of an inhibitory pathway. Mandel et aL9 quote Lorenz to the effect that all the well-armed carnivores have inhibitions that operate with enough security to avoid self-destruction of the species. The crow and wolf would long since have disappeared, if sure and proven inhibitions were not present. Is Homo sapiens to be the species to invalidate this rule? Cl
cl
q
For those puzzled by the last sentence of my November 1986, column, Trinity Site, New Mexico, was the location at which the first explosion of an atomic bomb occurred (July 16, 1945). B. MAX
Fu?!colour reprints of the
Weferences 1 Ungerstedt, U., Herrera-Marschitz,
M., Jungnehus, V., Stahle, L., Tossman, U. and Zetterstrom, 1. (1982) in Advances in Dopamine Research, (Kohsaka, M., Shohmori, T., Tsukada, Y. and Woodruff, G. N., eds), Pp. 219-231 Pergamon Press 2 Hamberger, A., Berthold, C-H., Kadsson, Et., Lehmann, A. and Nystrom, B. (1983) Neuroi. Neurobiol. 7,473-492 3 Lerma, I., Herranz, A. S., Herreras, O., Abraira, V. and de1 Rio, R. M. (1986) Brain Res. 384, 145-155 4 Vezzani, A., Ungerstedt, U., French, E. D. and Schwartz, R. (1985) J. Neurochem. 45,335-344 5 Hamberger, A., Berthold, C-H., Jacobson, I., Karlsson. B.. Lehmann. A.. Nystrom, 8. and Sandberg, M. (1985) in ?n Viva Perfusion and Release of Neuroacfive Substances’, (Bayon, A. and Drucker-Cohn, R., eds), pp, 119-139, Academic Press 6 Lehmann, A., Sandbere. M. and Httxtable, R. J. .(1986) Neu&hem. Znf. 8, 513-520 7 Lehmann,A., Hagberg, H.,Nystrcm, B., Sandberg, M. and Hamberger, A. (1985) in Taurine: Biolo,&al Actions and Clinica Perspectives, (Gja, S. S., Ahtee, L., Kontro, P. and Paasonen, M., eds), pp. 289-311, Liss 8 Mandel. P.. Mack. G. and Kemof. E. (1979) in Psy~ko~?;armacolo& of Aggression, (Sandler, M., ed.). pp. 95-110, Raven Press 9 Mandel, P., Gupta, R. C., Bourguignon, J. J., Wermuth, C. G., Molina, V, Gbbaille. S.. Ciesielski. L. and Simler, S. (1985) in T~un’ne: Biol&cal Acfions and Gnical Perspectives (O& S. S., Ahtee, L., Kontro, P. 6nd Paasonen, M., eds), pp. 449-458, Liss 10 Haug, M. and Mandel, 1’. (1978) Nezrrosci. Left. 7, 235-238 11 Valzelli, L. (1973) Psyc’ropharmacologia 31,305-320 12 Valzelli, L. and Garattini, S. (1972) Neurophamracolo~y 11, 17-22 13 Karli, P., Vergnes, M. and Didiergeorges, F. (1969) in Aggressive Beknvior, (Garattini, S. and Sigg, E. B., eds), pp. 47-55, Excerpta Medica 14 Mandel, P., Kempf, E., Simler, S.. Puglisi, L., Ciesielski, L. and Mack, G. (1983) in CNS Receptors-From Molecular Pkarmacology to Bejmoior, (Mandel, I’. and DeFeudis, F. V., eds), pp. 149, Raven 15 Max, 8. (1984) TiPS 5,256-257 16 Garrett, J. W. and Campbell, C. S. (1980) Norm. Behnv. 14,303-318 17 Turek, F. W., Elliot, J., Alvis. J. and Menaker. M. (1975) Bzo). Reprod. 13. 475-481
arher m Tips are available:
Peptides,reaipton5,antagonists Priceper5 copies IS fII6.00(+ 15% VAT in UK.) or US. $9.00 (incl. p. & p). Larger orders (lOO+) available at 15% discount. 0xdernfrom: Ekevier publications Cambridge,
68 Hills Road, Cambridge
CB2 ILA, UK.
87
is
temporally offset correlation was found beb teen dopamine release and rotational rate, the peak of dopamine release occurring 40 min before maximum rotational behavior*. Other studies have revealed that glutamine is the most abundant extracellular amino acid3 and the high intracellular to extracel1uh.r ratios of neuroactive amino acids. The ratio for GABA is 9000 : 1 (Ref. 5). Fiber dialysis can also be used in reverse, to deliver chemicals to the brain. Thus, changes in amino acid content of extracellular fluid in response to perfusion of depolarizing concentrations of potassium have been examined. Findings have been quite different from those found in similar experiments on brain slices7. There are marked increases in taurine and phosphoethanolamine efflux in hippocampus perfused in vivo with potassil;m. Only moderate increases are seen in glutamate and GABA efflux. With hippocampal slices, however, potassium depolarization leads to marked increases in glutamate and GABA efflux and little change in the efflux of other amino acids. These differences are presumably ascribable to the greater cellular damage found in slices and the relative anoxia of cells in the interior of the slice.
HYPOTHESES BY DEFINITION are experimentally testable. Their construction is, th.erefore, limited by the available methodology. Thus, a symbiotic relationship exists in science betwee!? the abstraction of thought in office and library (or other places) and the arduous reality of the laboratory bench. This is the scientist’s version of duality; the separateness yet indivisibility of soul and body, theory and practice; the impossibility of the one without the other. Great advances have been made in science in the wake of new theories and hypotheses. Great advances have also been made in the wake of new methods and technologies. In the brain, cell talks to cell not in the dialysate is a function not only of its concentration in extraonly through the specificity cellular fluid but also of the flow of neural connection, but via rate of buffer through the fiber and the changing composition of the rate constants of diffusion. For the extracellular fluid which example, Ungerstedt et n1.l report bathes them. Chemicals - transthat under a given set of conditions mitters, modulators, intermediin vitro, recovery of amino acids is ates, metabolites, substrates only 28%. Thus, the concentraand waste - are continually tions reported in experiments with being released into and taken thesle fibers may not accurately up from this slowly stirring represent concentrations in extrasoup. Both the composition and cellular space, but changes in perfusate concentration do reflect temporal change in composichanges in extracell Jar composition of extracellular fluid contion. Various types of mathetain detailed information on malical analyses have been apcellular behavior. Not surprisplied to dialysis data3”. ingly, scientists have attempted The first application of the to access this information by method was to examine the neuromeans of cortical cups, intrachemical correlates of behavior. cerebral fluid sampling and Rats rotate in response to unipush-pull cannulas. lateral lesioning of dopaminergic The difficulties and drawpathways. Using fiber dialysis, a backs of these methods are many. Recently, a quantum leap forward has been achieved by means of microdi?lysis of extracellular fluid through implanted semipermeable fibers (Ref. 1). Hollow fibers, of 0.3 mm diameter or less, are implanted in various brain areas, and buffer “pumped slowly through th zrn. Dialysable substances enter the fiber, the perfusate c&&d, and analysed by HFLC. Fibers of various sizes have been used, ranging from 5000 to 50 000 Da. As the sample sizes are so small, the development of this new method depended on the availability of another fairly new method, HPLC, for sample an,alysis. Following the initial report, modifications of the fiber Fig. 1. Sagittalsection through posterior hyporhalamus of rat with an intrahypolhalmic dialysis method were quickly oialysis loop implanted (x 200). The section showspartof the dialysis tube (D) which has e WaIdiameter of about3W mm and the lumen of the fube (1) 8 hours after impfantafion. published by other groups”. There is no damage lo fhe braintissueapartfrom a small area immediately surrounding A review of methodology has fhe lube. Photograph kindly supplied by C. Routledge and C. A. Mawden. University of recently appeared’. Nottingham Medical School, UK. The concentration of a substanlze
-@ 1987,
Elsevier
Publications.
Cambridge
0165 - 6147/R71502JJ@
TlPS - March 1987 [Vol. 81
SS Brain dialysis has also been used to examine basal and stimulated release of preloaded (radiolabelled) substances. It has been shown by this means that genetically, seizure susceptible rats hzve a
much higher rate of o-aspartate (a efflux analog) ncuroexcitatory from the hippocampus on depolarization than do seizure resistant rats6. There is no reason why the use
THE NEUROCHEMISTRY OF AGGRESSION is not a fashionable topic, but who can doubt the significance of an understanding of the mechanisms precipitating aggression? Surely the factors that lead one man to strike out at another are also involved in the problematic relationships between sovereign states in this overcrowded and overmilitarized globe. In a succinct phrase, aggressiveness is a threat to the existence of humanity*. Many have commented on the disparity between the evolution of human technology and the lack of a corresponding evolution in the ability nmn+inn4ity. Is ag*gression ‘hard-wired’ in the to control primiti;, x n bII.V..U. _ _ human brain, so much a part of the essence of being human that it can be modified only at the expense of our individual and species identity? In the same manner tha t a solitary existence is integral to the petrel and communalitv to the ant? A first problem in the study of 2.3% of Wistars and 3% of August the neurochemistry of aggresratss. sion is the defining of the Muricidal rats show a number of neurochemical alterations, includphenomenon under investigaing decreased levels of GABA in tion. Mandel et al., while the olfactory bulb, decreased tumadmitting the difficulty of defiover of 5-HT in the raphe area, and nition, Suggest that, ‘d dggresincreased choline acetyltransferase sive display is an attempt to activity in the amygdala. Mandel et endanger the integrity of the a1.9 hypothesiz, that inhibitory opponent”. If integrity refers to circuits from the olfactory bulb psychic as well as physical suppress muricidal behavior. In state, then two humans can support of this, ablation of the hardly come together without olfactory bulb produces muricidal such a display. behavior in 60% of otherwise In selected modeis of aggression, normai ratsi3, and injections of it is to be hoped that aggression GABA, GABA agonists, inhibitors and its modulation could be of GABA reuptake, or GABA transexplained in terms of molecular aminase inhibitors all increase mechanisms. One important findGABA levels in the olfactory bulb ing with animals is that aggression and all block spontaneous muriis not necessarily a male trait, nor tidal behavior14. Killing is also necessarily linked with male sex abolished by lesioning of the hormones. Widely used models amygdala or the lateral hypoinclude the aggressive behavior thalamus. The suppression of of females towards lactating f:amouse-killing behavior is not due mdes*‘, and aggression produced to anosmia per se, as sectioning of In both sexes by isolation and sociothe olfacto? nerve, removal of environmental deprivation1’*‘2. nasal mucoja, or isolating mice The muricidal rat, the so-called behind a teflon sheet does not ‘killer’ rat, has been another modify the behavior. Hyperacwidely used model13. Such a rat tivity appears to be associated will quickly dispatch a mouse with muricidal behavior. Bulplaced in its cage. The behavior is bectomized rats are hyperactive stereotyped, including chase, capand lesioning of the dorsal or ture and neck biting sequences. medial raphe nucleus increases Significantly, the behavior is not both locomotor activity and killing learned and is exhibited without behavior. previous experience. Nonkiller Taurine, another inhibitory IX-, rats, even when raised with kil!ers, w-amino aci.d, also blocks murishow no interest in mice. There is a tidal behavior, although other genetic component to mouse-killamino acids are without effect. The ing behavior, in that 70% of wild action of taurine is synergistic Norwegian rats are muricidal, as with that of valproate (a transcompared to 58% of Long-Evans, aminase inhibitor), suggesting
of such a convenient method as fiber dialysis should be limited to the brain. One obvious application for pharmacologists would be the study of regional drug metabolism in the liver. that these compounds act at different sites. Lipophilic analogs of taurine are effective ‘antimuritides’ when given by mouth, allowing the predictions of lsiah 11:6 and 65:25 to be achieved. Thus, taltrimide, glanced upon in
Fig. 2. In&a species aggression in mice. Photograph kindly supplied by P. F. Brain, Dept. Zoology, University College of Swansea, Swansea, UK.
TIPS - March 1987 [r/s!. 81 an earlier column as an antiepileptic agent”, given by mouth in a dose of 1.6 mmol kg-l, quickly reduces muricidal behavior to 20% of control. 2-Benzamidoethanesulfon-N-t- bu’:;lamide is even more effr-_:_-:a Another model of aggression is the light-deprived hamsteP. Male hamsters exposed to less than 12.5 h of light per day show an increase in aggressiveness. The interesting aspect of this model is the removal of the macho factor, or the normal masculine elements that are associated with aggression. Hamsters are sexually dimorphic, the males being smaller and less aggressive than the females. When deprived of light, the testicles decrease in size and plasma levels of various hormones, including testosterone, falll’. There is an inverse relationship between testosterone levels and aggressiveness. On re-exposure to long-day photoperiods, these changes reverse to normal. Although this report should not be taken as encouragement for male pharmacologists to sleep with the light on, this association of light deprivation with aggression does lead me to wonder if long hours in poorly lit offices have any connection with the ferocity of intraoffice politics. There is a huge literature on violence, but studies of neurochemistry and molecular mechanisms are negligible. This is a strange lacuna considering how violence shapes and constrains our A few score people societies. suffering from Legionnaire’s disease, a few thousand dying of acquired immunodeficiency, and society responds by an outpouring of funds to research cause and cure. But the telescope is at the blind eye when it comes to the violence that is as integral as language to the human state. Mandel et al.‘have shown that in experimental animals aggressive behaviors are selectively modifiable. There would appear to be no need to lobotomize away the esthetic appreciations that give life its finer shadings in order to control aggression. However, how relevant are these animal studies to the complexities of our world? Are the particular models good? For those who question the relevance of the killer r-! to the myriad corporate and individual forms in which aggression is expressed by
89 humans, I ask them to consider carefully the following statement from an admirable man and a great scientist: ‘In view of the moral responsibility of a scientist to the society that provides the opportunity to do research, we should bear in mind any potential clinical usefulness of such investigations on aggressive behavior. There is littie doubt that the natural history, motivation and consciousness that underlie human aggressive behavior show it to differ profoundly from our animal models of aggressive behavior. However, the basic phenomena of communication among brain circuits and of final expression of behavioral patterns are strongly b0un.d to netuotransmitter mechanisms, which are fairly similar in different species. Thus one might expect that a knowledge of the molecular mechanisms governing aggressive behavior in experimental animals would, in time, guide us toward the control of some basic molecular mechanisms of human aggressive behavior’s. In the muricidal rat, aggressiveness is due to the loss or suppression of an inhibitory pathway. Mandel et aL9 quote Lorenz to the effect that all the well-armed carnivores have inhibitions that operate with enough security to avoid self-destruction of the species. The crow and wolf would long since have disappeared, if sure and proven inhibitions were not present. Is Homo sapiens to be the species to invalidate this rule? Cl
cl
q
For those puzzled by the last sentence of my November 1986, column, Trinity Site, New Mexico, was the location at which the first explosion of an atomic bomb occurred (July 16, 1945). B. MAX
Fu?!colour reprints of the
Weferences 1 Ungerstedt, U., Herrera-Marschitz,
M., Jungnehus, V., Stahle, L., Tossman, U. and Zetterstrom, 1. (1982) in Advances in Dopamine Research, (Kohsaka, M., Shohmori, T., Tsukada, Y. and Woodruff, G. N., eds), Pp. 219-231 Pergamon Press 2 Hamberger, A., Berthold, C-H., Kadsson, Et., Lehmann, A. and Nystrom, B. (1983) Neuroi. Neurobiol. 7,473-492 3 Lerma, I., Herranz, A. S., Herreras, O., Abraira, V. and de1 Rio, R. M. (1986) Brain Res. 384, 145-155 4 Vezzani, A., Ungerstedt, U., French, E. D. and Schwartz, R. (1985) J. Neurochem. 45,335-344 5 Hamberger, A., Berthold, C-H., Jacobson, I., Karlsson. B.. Lehmann. A.. Nystrom, 8. and Sandberg, M. (1985) in ?n Viva Perfusion and Release of Neuroacfive Substances’, (Bayon, A. and Drucker-Cohn, R., eds), pp, 119-139, Academic Press 6 Lehmann, A., Sandbere. M. and Httxtable, R. J. .(1986) Neu&hem. Znf. 8, 513-520 7 Lehmann,A., Hagberg, H.,Nystrcm, B., Sandberg, M. and Hamberger, A. (1985) in Taurine: Biolo,&al Actions and Clinica Perspectives, (Gja, S. S., Ahtee, L., Kontro, P. and Paasonen, M., eds), pp. 289-311, Liss 8 Mandel. P.. Mack. G. and Kemof. E. (1979) in Psy~ko~?;armacolo& of Aggression, (Sandler, M., ed.). pp. 95-110, Raven Press 9 Mandel, P., Gupta, R. C., Bourguignon, J. J., Wermuth, C. G., Molina, V, Gbbaille. S.. Ciesielski. L. and Simler, S. (1985) in T~un’ne: Biol&cal Acfions and Gnical Perspectives (O& S. S., Ahtee, L., Kontro, P. 6nd Paasonen, M., eds), pp. 449-458, Liss 10 Haug, M. and Mandel, 1’. (1978) Nezrrosci. Left. 7, 235-238 11 Valzelli, L. (1973) Psyc’ropharmacologia 31,305-320 12 Valzelli, L. and Garattini, S. (1972) Neurophamracolo~y 11, 17-22 13 Karli, P., Vergnes, M. and Didiergeorges, F. (1969) in Aggressive Beknvior, (Garattini, S. and Sigg, E. B., eds), pp. 47-55, Excerpta Medica 14 Mandel, P., Kempf, E., Simler, S.. Puglisi, L., Ciesielski, L. and Mack, G. (1983) in CNS Receptors-From Molecular Pkarmacology to Bejmoior, (Mandel, I’. and DeFeudis, F. V., eds), pp. 149, Raven 15 Max, 8. (1984) TiPS 5,256-257 16 Garrett, J. W. and Campbell, C. S. (1980) Norm. Behnv. 14,303-318 17 Turek, F. W., Elliot, J., Alvis. J. and Menaker. M. (1975) Bzo). Reprod. 13. 475-481
arher m Tips are available:
Peptides,reaipton5,antagonists Priceper5 copies IS fII6.00(+ 15% VAT in UK.) or US. $9.00 (incl. p. & p). Larger orders (lOO+) available at 15% discount. 0xdernfrom: Ekevier publications Cambridge,
68 Hills Road, Cambridge
CB2 ILA, UK.