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the cardiovascular complications of thermal injury might well lead to a fall in arterial pressure, which should respond readily to infusion of colloidal solutions to fill the expanded vascular compartment. Thus, one could predict improvements in cardiac output, renal function, and skin blood flow. Careful study of complex clinical events often yields treat

inexplicable data, thereby posing more questions about the underlying pathophysiology; the results described by Crum et al are no exception. The normal initial plasma angiotensin II values, which increased four-fold in 3 days, and the three-fold rise in plasma atrial natriuretic peptide despite very slight changes in central venous pressure are two examples in this study. Unravelling such complexities of the stress mechanisms in major thermal trauma may eventually lead to rational therapeutic strategies to reduce the mortality and morbidity of bum injury. 1.

Frayn KN. Hormonal control of metabolism in trauma and sepsis. Clin Endocrinol 1986; 24: 577-99.

EA. The effects of stress on salt and water balance. Clin Endocrinol Metab 1987; 1: 375-90. 3. Alberti KGMM, Batstone GF, Foster KJ, et al. Relative role of various hormones in mediating the metabolic response to injury. J Parenteral Enteral Nutr 1980; 4: 141-46. 4. Vaughan GM, Becker RA, Allen JP, Goodwin CW, Pruitt BA, Mason AD. Cortisol and corticotropin in burned patients. J Trauma 1982; 22:

2. Espiner

263-73. 5. Dolecek R, Adamkova M, Sotornikova T. Endocrine response after burn. Scand J Plast Reconstr Surg 1979; 13: 9-16. 6. Brizio-Molteni L, Molteni A, Warpeha RL, Angelats J, Lewis N, Fors EM. Prolactin, corticotropin, and gonadotrophin concentrations following thermal injury in adults. J Trauma 1984; 24: 1-7. 7. Becker RA, Wilmore DW, Goodwin CW, et al. Free T4, free T3 and reverse T3 in critically ill, thermally injured patients. J Trauma 1980; 20: 713-19. 8. Vaughan GM, Mason AD, McManus WF, Pruitt BA. Alterations of mental status and thyroid hormones after thermal injury. J Clin Endocrinol Metab 1985; 60: 1221-25. 9. Demling RH, Kramer G, Harms B. Role of thermal injury-induced hypoproteinemia on fluid flux and protein permeability in burned and non-burned tissue. Surgery 1984; 95: 136-43. 10. Aulick LH, Wilmore DW, Mason AD, Pruitt BA. Influence of the burn wound on peripheral circulation in thermally injured patients. Am J Physiol 1977; 233: H520-26. 11. Griffiths RW, Millar JGB, Albano J, Shakespeare PG. Observations on the activity of the renin-angiotensin-aldosterone (RAA) system after low volume colloid resuscitation for burn injury. Ann R Coll Surg 1983; 65: 212-15. 12. Shirani KZ, Vaughan GM, Robertson GL, et al. Inappropriate vasopressin secretion (SIADH) in burned patients. J Trauma 1983; 23: 217-24. 13. Becker RA, Vaughan GM, Goodwin CW. Plasma norepinephrine, epinephrine and thyroid hormone interactions in severely burned patients. Arch Surg 1980; 115: 439-43. 14. Crum RL, Dominic W, Hansbrough JF, Shackford SR, Brown MR. Cardiovascular and neurohumoral responses following burn injury. Arch Surg 1990; 125: 1065-69. 15. Cowley AW, Liard JF, Skelton MM, Quillen EW, Osborn JW, Webb RL. Vasopressin-neural interactions in the control of cardiovascular function. In: Schrier RW, ed. Vasopressin. New York: Raven, 1985: 1-10. 16. Ebert TJ, Cowley AW, Skelton MM, Smith JJ. Physiologic vasopressin infusion in man alters resting hemodynamics and reflex responses to low level lower body negative pressure. Fed Proc 1984; 43: 896. 17. Cowley AW, Barber BJ. Vasopressin vasculature and reflex effects—a theoretical analysis. Prog Brain Res 1983; 60: 415-24. 18. Burnier M, Waeber B, Nussberger J, Nicod P, Brunner HR. Cardiovascular effects of vascular antagonists (V1) to the action of vasopressin in health and disease. In: Cowley AW, Liard J-F, Ausiello DA, eds. Vasopressin: cellular and integrative functions. New York: Raven, 1988: 473-85.

NOW WE UNDERSTAND ANTIPSYCHOTICS?

Many antipsychotic drugs act by blocking brain receptors for the neurotransmitter dopamine. In common with most neurotransmitters there are multiple receptors for dopamine; physiological, pharmacological, and biochemical studies have provided evidence’ for two receptor subclasses, D1 and Dz. Dz receptors are blocked by the antipsychotic drugs in eliciting their clinical effects-there are excellent correlations between the affinities of such drugs for Dz receptors and the average daily dose used to treat

schizophrenia.z,3 Dz receptors are found in several regions of the brain and it is believed that blockade of receptors in limbic and cortical is responsible for the antipsychotic effects of the drugs. Many antipsychotic agents are also associated with adverse reactions, especially with extrapyramidal (parkinsonian) motor side-effects that are thought to result from blockade of D receptors in the striatum (a typical motor region of the basal ganglia). Some antipsychotic drugs-the so-called atypical antipsychotics such as clozapine, sulpiride, and thioridazine-are less likely to induce extrapyramidal sideeffects, whereas typical antipsychotics such as haloperidol and spiperone are more often associated with such complications. This difference has been explained in several ways: the atypical drugs may preferentially block limbic! cortical Dz receptors;4they may penetrate more effectively into limbic/cortical brain regions;4or they may have a stronger blocking action on muscarinic acetylcholine receptors,thereby suppressing the side-effects. None of these explanations is entirely satisfactory. The discovery of a third dopamine receptor, by means of gene cloning techniques,6 has provided new insights into the typical atypical dichotomy and also into the mechanisms of the antipsychotic effect. In the past five years gene cloning techniques have considerably advanced the study of neurotransmitter receptors. Isolation of the genes encoding several receptors shown that has pharmacological studies have underestimated receptor diversity. Availability of cloned gene sequences for receptors has also opened the way for localisation of these receptor subclasses to be achieved by in-situ hybridisation. By expressing a unique receptor gene in a clonal animal cell line, highly specific screening systems for new drugs are now available. The D1 and Dz receptors have been cloned ;7,8 these receptors, when expressed, have properties that were predicted from earlier pharmacological studies. However, cloning of a third receptor, D3,6showed that it had properties unlike those of the D1 or Dz receptors. Pharmacologically and structurally the D3 receptor more closely resembles the Dz than the D1 receptor. Most dopamine antagonists, including antipsychotic drugs, have high affinities for the D3 receptor, although the affmities are generally lower than their corresponding affinities for the Dz receptor. By contrast, affinities of dopamine agonists are often higher at D3 than Dz receptors. Of special interest is that typical antipsychotic drugs show a 10-20-fold preference for Dz over D3 receptors whereas the atypical antipsychotics show only a 2-3-fold preference. Localisation of the D3 and Dz receptors also differs-the Dz receptor is found in motor (striatal), limbic, and cortical brain regions whereas the D3 receptor is largely confined to limbic and cortical regions. These regions of the brain are typically associated with the antipsychotic effect of these drugs, so it is of great interest to find a pharmacologically different areas

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dopamine receptor here. In addition, the lactotroph cells of the anterior pituitary gland, rich in Dz receptors, lack D3 receptors. The discovery of the D receptor has important implications for basic and clinical science. First, most dopaminergic drugs have affinities for both Dz and D3 receptors which are sufficiently high that results of previous studies on Dz receptors will also have included D3 receptors. Thus earlier biochemical, pharmacological, behavioural, and clinical studies will need to be re-evaluated for the effects of the drugs on the two receptor species. For

example, it had been thought that antipsychotic drugs exert their effects via blockade of Dz receptors in limbic/cortical brain regions, but this view must now be modified to include blockade of both Dz and D3 receptors. The relative importance of the two receptors in antipsychotic action will need to be determined and this research will be aided by the design of more selective compounds. That atypical antipsychotics have closer affinities for Dz andD3 receptors than do the typical antipsychotics led to the suggestion6 that the lower frequency of extrapyramidal side-effects seen with the atypical drugs could result from this difference. However, all antipsychotics have greater affinities for Dz receptors, which are found at high concentrations in typical dopamine motor areas of brain where Dz receptor blockade is thought to lead to side-effects, so perhaps it is the particular mix of Dz and D3 receptor blockade that contributes to the atypical profile. Second, compounds that are selective for D3 receptors, or have D1 or Dz receptor activity but reduced activity at D3 receptors, may be of use clinically. D3 receptors are found at high concentrations in limbic and cortical regions of brain, regions that are typically associated with control of motivation, mood, emotion, and more complex behaviour; some of these functions are disturbed in the positive psychotic symptoms of schizophrenia. A drug that selectively blocked D3 receptors might therefore be beneficial in psychosis; the lack of Dz receptor blockade would also mean that the drug would have fewer extrapyramidal side-effects and would not alter prolactin secretion since pituitary lactotrophs lack D3 receptors. Alternatively, some Dz receptor blockade may be required for the antipsychotic effect. A D1/DZ receptor agonist with reduced D3 receptor activity might be useful in the treatment of Parkinson’s disease. Such a drug should help to restore dopaminergic control of basal ganglia function, but with fewer psychotomimetic effects if these complications are due to D33 receptor interactions. Dz receptor agonists with reduced D1 and D3 receptor potency should control excess pituitary prolactin secretion and therefore be useful for therapy of prolactin-secreting tumours. 1. Kebabian JW, Calne DB. Multiple receptors for dopamine. Nature 1979; 277: 93-96. 2. Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976; 192: 481-83. 3. Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 1976; 261: 717-19. 4. Strange PG. Subtypes of the D2 dopamine receptor. Trends Pharmacol Sci 1990; 11: 357. 5. Miller RJ, Hiley CR. Antimuscarinic properties of neuroleptic drugs and drug induced parkinsonism. Nature 1974; 248: 596-97. 6. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC. Molecular cloning and characterisation of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 1990; 347: 146-51. 7. Strange PG. Aspects of the structure of the D2 dopamine receptors. Trends Neurosci 1990; 13: 373-78.

8.

Dearry A, Gingrich JA, Falardeau P, Fremeau RT, Bates MD, Caron MG. Molecular cloning and expression of the gene for a human D1 dopamine receptor. Nature 1990; 347: 72-76.

ALCOHOL AND VIOLENCE There is considerable circumstantial evidence that alcohol consumption is closely associated with violence. For example, screening of patients in accident and emergency departments has shown that up to 86% of those involved in assaults are intoxicated at the time of injury. In relation to offenders, studies have shown that 63% of Scottish young offenders in one large institution were intoxicated at the time of their offence, as were 80% of offenders found guilty of breaches of the peace and 88% of those guilty of causing criminal damaged Alcohol had been consumed by either or both parties in 60% of murders in half of twenty-eight published studies, and in more than 30% in all but three;3 murders committed by relatives, friends, or acquaintances seem more likely to be linked to alcohol consumption.4 However, it is dangerous to draw conclusions from analyses confined to aggregate data. Moreover, in the absence of controlled clinical investigations (eg, those that have incriminated alcohol as a cause of road accidents), arguments that alcohol may not contribute to violent behaviour can be persuasive.s Thus it has been suggested that it is not alcohol which makes people violent but the proximity of large numbers of men for long periods in licensed premises, and even that alcohol merely makes offenders less able to avoid arrest than sober individuals.6 Violence and intoxication may have the same root-cause (eg, certain personality traits), or the circumstances and environment where violence occurs may be more important than alcohol consumption itself. In relation to young males who have been injured in brawls and assaults-by far the most important group numerically-the few case-control studies that have been conducted have shown that when more than about eight units of alcohol were consumed in a city-centre bar, the risk of involvement increased sharply. With consumption of fewer units or of more than about sixteen, the risk of injury was no greater than for age and sex matched control individuals with the same socioeconomic background who had been present in the same bar.s Severity and numbers of injuries sustained are linked with degree of intoxication in assault patients. Another controlled study showed that injured participants in violence can be differentiated from age and sex matched non-participants on the basis of habitual weekly alcohol consumption only in people over 25 years of age;6 this increased progressively with age so that, in patients over the age of 40, the link between heavy alcohol consumption and being injured in a violent incident was

especially pronounced. Not all those who drink alcohol become violent, but there is some evidence that alcohol consumption by a stressed individual predisposes to violent behaviour.8 Different expectations of the effects of alcohol are important determinants of behaviour at different ages and in different cultures.9 A link between paranoia and violence was found in a controlled study of alcoholic men. to There is also evidence that defence activity, developed to deal with anxietyprovoking events or behaviour, is increased by alcohol so that violence becomes more likely." Alcohol consumption by young males increases the likelihood that the behaviour of others will be perceived as insulting or challenging.12 For young men, the behaviour of fathers, mothers, and peers is the most important predictor of alcohol consumption habits