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Tricyclic antidepressant drugs induce antinociceptive effect and suggest that their analgesic action could be related to the monoaminergic activity of the drugs. The analgesic activity of amitriptyline was observed in mouse models of acute pain. Mice were divided into different groups and were given amitriptyline in different doses alone and in combination with morphine. Reaction time in Hot-Plate and Tail-Flick tests was observed. Results showed that amitriptyline had antinociceptive effect in acute pain state in experimental models. Amitriptyline in combination with morphine had better analgesic effect than the morphine alone in Hot-Plate test.

EuMil, is a herbal formulation comprising the standardised extracts of Withania somnifera (L) Dunal, Ocimum sanctum L, Asparagus racemosus Willd and Emblica officinalis Gaertn., all of which are classified in Ayurveda as rasayanas to promote physical and mental health, improve defense mechanisms of the body and enhance longevity. These attributes are similar to the modern concept of adaptogenic agents, which are, known to afford protection to the human physiological system against diverse stressors. The present study was undertaken to investigate the adaptogenic and antistress activity of EuMil against chronic unpredictable, but mild, footshock stress-induced perturbations in behaviour (depression), glucose metabolism, suppressed male sexual behaviour, immunosuppression and cognitive dysfunction in CF strain albino rats. Panex ginseng (PG) was used for comparison. Gastric ulceration, plasma corticosterone levels, serum lipid, hepatic and renal functions were used as the stress indices. These effects were attenuated by EuMil (dose 100 mg/kg, p.o.) and PG (100 mg/kg. p.o.), administered once daily over a period of 14 days, the period of stress induction period. Further, chronic stress also induced glucose intolerance, suppressed male sexual behaviour, induced behavioural despair and cognitive dysfunction and immunosuppression. All these chronic stress-induced perturbations were attenuated, in a dose dependent manner by EuMil and PG. Thus, the results indicate that EuMil has significant adaptogenic and anti-stress, activity, qualitatively comparable to PG, against a variety of behavioural, biochemical and physiological perturbations, induced by unpredictable stress, which has been proposed to be a better indicator of clinical stress than acute stress. The likely contribution of the individual constituents of EuMil in the observed adaptogenic action of the polyherbal formulation, has been discussed.

EuMil, a polyherbal formulation consisting of standardised extracts of Withania somnifera (L) Dunal, Ocimum sanctum L, Asparagus racemosus Wilid and Emblica officinalis Gaertn., is used as an anti-stress agent to attenuate the various aspects of stress related disorders. In the present study, the neurochemical mechanisms underlying the anti-stress activity of EuMil were evaluated by measuring the rat brain monoamine neurotransmitter levels and tribulin activity. Chronic electroshock stress (14 days) significantly decreased the nor-adrenaline (NA) and dopamine (DA) levels in frontal Cortex, pons-medulla, hypothalamus, hippocampus and striatal, hypothalamal region, respectively, and increased the 5-hydroxytryptamine (5HT) level in frontal cortex, pons medulla, hypothalamus and hippocampus. Chronic stress, also increased the rat brain tribulin activity. EuMil (100 mg/kg, p.o., 14 days) treatment normalized the perturbed regional NA, DA, 5HT concentrations, induced by chronic stress. EuMil also significantly attenuated the stress-induced increase in the rat brain tribulin activity. The amelioration of chronic stress-induced neurochemical perturbations by EuMil explains the neurochemical mechanisms underlying the observed putative anti-stress activity of the product.

Effect of tannoid principles emblicanin A, emblicanin B, punigluconin, and pedunculagin of E. officinalis was assessed on chronic unpredictable footshock-induced stress-induced perturbations in oxidative free radical scavanging enzymes in rat brain frontal cortex and striatum. Chronic stress, administered over a period of 21 days, induced significant increase in rat brain frontal cortical and striatal superoxide dismutase (SOD) activity, concomitant with significant reduction in catalase (CAT) and glutathione peroxidase (GPX) activity. The changes in the enzyme activities was accompanied by an increase in lipid peroxidation, in terms of augmented thiobarbituric acid-reactive products. Administration of Emblica tannoids (10 and 20 mg, po) for 21 days, concomitant with the stress procedure, induced a dose-related alteration in the stress effects. Thus, a tendency towards normalization of the activities of SOD, CAT and GPX was noted in both the brain areas, together, with reduction in lipid peroxidation. The results indicate that the reported antistress rasayana activity of E. officinalis may be, at least partly due to its tendency to normalize stress-induced perturbations in oxidative free radical scavenging activity, in view of the postulate that several stress-induced diseases, including the process of aging, may be related to accumulation of oxidative free radicals in different tissues.

Nine extracts of H. perforatum, containing hyperforin in conjugated forms, but devoid of free hyperforin and adhyperforin, were subjected to antidepressant screening using the forced swim test (FST). The observed activity was compared with that of SJW extracts containing hyperforin and adhyperforin (in free form). Results indicate that hyperforin conjugates exhibit significant antidepressant activity as evidenced by the reduced immobility period in the FST in rats.

A standardised 50% aqueous ethanolic extract of the Indian variety of Hypericum perforatum (IHp) was examined for its putative anti-inflammatory and analgesic activity at the doses of 100 and 200 mg/kg, po. The experimental paradigms used were carrageenan induced pedal edema and cotton pellet induced granuloma for anti-inflammatory activity, whereas the tail flick, hot plate and acetic acid induced writhing methods were used to asses analgesic activity. Indomethacin (20 mg/kg, ip) was used as the standard anti-inflammatory drug. Pentazocine (10 mg/kg, ip) and aspirin (25 mg/kg, ip), both clinically used analgesics, were used as standard analgesics for comparison. IHp extract showed significant anti-inflammatory and analgesic activity at both dose levels, in all the paradigms used. Additionally, IHp potentiated the anti-inflammatory activity of indomethacin and analgesic activities of pentazocine and aspirin.

The effect of acute administration of 50% standardised ethanolic extract of Indian Hypericum perforatum (IHp) was studied on the rat brain concentrations of monoamines and their metabolites in five different brain regions, viz. hypothalamus, hippocampus, striatum, pons-medulla and frontal cortex by a HPLC technique. IHp extract was administered at the doses of 50 and 200 mg/kg, p.o. and the brain monoamines were assayed after 30 min of the treatment. IHp treatment significantly decreased the levels of serotonin (5-HT) and its metabolite 5-hydroxy indole acetic acid (5-HIAA) and 5-HT turnover in all the brain regions assayed. On the other hand, IHp treatment significantly augmented the levels of norepinephrine (NE) and its metabolite methylhydroxy phenyl glycol (MHPG) and NE turnover in all the brain regions studied. Similarly, the levels of dopamine (DA) were also significantly augmented in the hypothalamus, striatum and frontal cortex. Likewise, the levels of dihydroxyphenyl acetic acid (DOPAC), the major metabolite of DA, were also increased in these brain areas. Pharmacological studies with IHp extract have shown two major behavioural actions, namely, anxiolytic and antidepressant effects. The present findings tend to rationalise these observations, reduced 5-HT activity being consonant with anxiolytic and increased NA and DA activity being consonant with antidepressant action.

Indian Hypericum perforatum (IHp) was investigated on a 14-day mild, unpredictable and inescapable foot shock stress (FSS) induced perturbations in behaviour (depression), suppressed male sexual behaviour and cognitive dysfunction in albino rats. Gastric ulceration, and adrenal gland and spleen weights, were also used as the stress indices. Panax ginseng (PG) was used as the standard adaptogenic agent for comparison. FSS induced marked gastric ulceration, significant increase in adrenal gland weight with concomitant decrease in spleen weight. Chronic stress also suppressed male sexual behaviour, induced behavioural depression (Porsolt's swim despair test and learned helplessness test) and cognitive dysfunction (attenuated retention of learning in active and passive avoidance tests). All these FSS induced perturbations were attenuated dose dependently by IHp (100 and 200 mg/kg, po) and PG (100 mg/kg, po). The results indicate that IHp has significant anti-stress activity, qualitatively comparable to PG, against a variety of behavioural and physiological perturbations induced by chronic stress, which has been proposed to be a better indicator of clinical stress than acute stress, and may indicate adaptogenic activity.

Hypericum perforatum (HP), better known as St. John's Wort, has been used clinically for centuries. Modern usage is still quite diverse and includes kidney and lung ailments, insomnia and depression. Standardised extracts of HP are widely used in the treatment of psychovegetative disorders and especially for mild forms of depression. Several bioactive constituents of this plant may play important role in its well-known antidepressant activity, which are discussed in the present article. Furthermore, emphasis is also given on its botany, chemistry, pharmacology and clinical efficacy.

The putative anxiolytic activity of 50% ethanolic extract of Indian Hypericum perforatum (IHp) was investigated in rats using various experimental paradigms of anxiety viz. open field exploratory behaviour (OFB), elevated plus maze (EPM), elevated zero maze (EZM), novelty induced suppressed feeding latency (FL) and social interaction (SI) tests. Pilot studies indicated that single dose administration of IHp had little to no acute behavioural effects, hence the extract of IHp was administered orally at different dose levels once daily for three consecutive days, while lorazepam (LR) (0.5 mg/kg, i.p.) was administered acutely. IHp extract (100 and 200 mg/kg, p.o.) showed significant anxiolytic effects on all the paradigms of anxiety. The results indicate that IHp and LR induced a significant increase in open field ambulation and slight increase in rearings and activity in centre, whereas grooming and fecal droppings remain unchanged. In EPM, significant augmentation of open arm entries, open arm/closed arm entries ratio and time spent on open arms was noted in IHp treated rats. In EZM test, significant increase in time spent on open arms and entries in open arms were observed, whereas slight increase in head dips and stretched attend postures were also observed. IHp and LR significantly attenuated the novelty induced increase in feeding latency. IHp treated rats also showed significant increase in social interaction in the novel environment. The IHp extracts showed consistent and significant anxiolytic activity in all the tests. The effects induced by 50% ethanolic extract of IHp were less marked than those of lorazepam were.

Putative anxiolytic activity of ethanolic extract of Indian A. pindrow Royle leaf was investigated in rats using various experimental paradigms of anxiety viz. open field exploratory behaviour, elevated plus maze (EPM) and elevated zero maze (EZM) tests. Pilot studies indicated that single dose administration of extract had little to no acute behavioural effects, hence the extract was administered orally at different dose levels once daily for three consecutive days, while lorazepam (LR) (0.5 mg/kg, i.p.) was administered acutely. Ethanolic extract of A. pindrow (AP) leaves (50 and 100 mg/kg, p.o.) showed significant anxiolytic effects on all the paradigms of anxiety. The results indicate that AP and LR induced a significant increase in open field ambulation and slight increase in rearings and activity in center, whereas grooming and faecal droppings remain unchanged. In EPM, significant augmentation of open arm entries, and time spent on open arms was noted in AP treated rats. In EZM test, significant increase in time spent on open arms and entries in open arms was observed, whereas slight increase in head dips and stretched attend postures was also observed. The AP extract showed consistent and significant anxiolytic activity in all the tests. The effects induced by ethanolic extract of AP were less marked than those of lorazepam were.

Siotone (ST) is a herbal formulation comprising of Withania somnifera, Ocimum sanctum, Asparagus racemosus, Tribulus terristris and shilajit, all of which are classified in Ayurveda as rasayanas which are reputed to promote physical and mental health, improve defence mechanisms of the body and enhance longevity. These attributes are similar to the modern concept of adaptogenic agents, which are, known to afford protection of the human physiological system against diverse stressors. The present study was undertaken to investigate the adaptogenic activity of ST against chronic unpredictable, but mild, footshock stress induced perturbations in behaviour (depression), glucose metabolism, suppressed male sexual behaviour, immunosuppression and cognitive dysfunction in CF strain albino rats. Gastric ulceration, adrenal gland and spleen weights, ascorbic acid and corticosterone concentrations of adrenal cortex, and plasma corticosterone levels, were used as the stress indices. Panax ginseng (PG) was used as the standard adaptogenic agent for comparison. Additionally, rat brain levels of tribulin, an endogenous endocoid postulated to be involved in stress, were also assessed in terms of endogenous monoamine oxidase (MAO) A and MAOB inhibitory activity. Chronic unpredictable footshock induced marked gastric ulceration, significant increase in adrenal gland weight and plasma corticosterone levels, with concomitant decreases in spleen weight, and concentrations of adrenal gland ascorbic acid and corticosterone. These effects were attenuated by ST (50 and 100 mg/kg, p.o.) and PG (100 mg/kg, p.o.), administered once daily over a period of 14 days, the period of stress induction. Chronic stress also induced glucose intolerance, suppressed male sexual behaviour, induced behavioural depression (Porsolt's swim despair test and learned helplessness test) and cognitive dysfunction (attenuated retention of learning in active and passive avoidance tests), and immunosuppression (leucocyte migration inhibition and sheep RBC challenged increase in paw oedema in sensitized rats). All these chronic stress-induced perturbations were attenuated, dose-dependently by ST (50 and 100 mg/kg, p.o.) and PG (100 mg/kg, p.o.). Chronic stress-induced increase in rat brain tribulin activity was also reversed by these doses of ST and by PG. The results indicate that ST has significant adaptogenic activity, qualitatively comparable to PG, against a variety of behavioural, biochemical and physiological perturbations induced by unpredictable stress, which has been proposed to be a better indicator of clinical stress than acute stress parameters. The likely contribution of the individual constituents of ST in the observed adaptogenic action of the polyherbal formulation, have been discussed.

Maternal hyperglycemic effect was studied on the offspring behaviour. Offspring were obtained from diabetic rats by mating a normal father with a diabetic mother (NFDM), diabetic father with normal mother (DFNM) and diabetic father with diabetic mother (DFDM). Rats were rendered diabetic by injecting streptozotocin (STZ, 50 mg/kg i.p.) in citrate buffer. Offspring were subjected to various anxiety parameters including open field exploratory behaviour, elevated plus maze and zero maze behaviours, and the social interaction tests at the age of 8 weeks. The results indicate that offspring of NFDM and DFDM showed anxiogenic activity on the elevated plus maze zero maze and the social interaction test. Offspring of NFDM and DFDM exhibited hyper and emotional activity in the open field behaviour test. The behavioural alterations observed in the offspring were comparable to the behavioural alterations noted in STZ diabetic rat as reported earlier. Further offspring of NFDM and DFDM exhibited mild hyperglycaemia. No significant behavioural alterations in the offspring of DFNM were observed. It may be concluded, that exposure of offspring to diabetic environment in their foetal life can lead to anxiogenic/emotional behaviours in adult life.

A standardised 50% aqueous ethanolic extract of Indian Hypericum perforatum (IHp) was investigated for its antidepressant activity on various experimental paradigms of depression, viz. behavioural despair (BD), learned helplessness (LH), tail suspension (TS) and reserpine-induced hypothermia (RIH) tests in rats and mice. Pilot studies indicated that single dose administration of IHp had very little or no acute behavioural effects, hence the IHp was administered orally at two dose levels (100 and 200 mg/kg, p.o.) once daily for three consecutive days, while imipramine (15 mg/kg, i.p.), a clinically used antidepressant agent, was administered acutely to rats (CF strain, 150 +/- 10 g) and mice (Wistar strain, 23 +/- 2 g) of either sex as the standard drug. Controls animals were treated similarly with equal volume of vehicle (0.3% carboxymethyl cellulose). Indian Hypericum perforatum extract showed significant antidepressant activity on all the paradigms of depression used. Thus IHp and imipramine treatments significantly reduced the immobility time in BD and TS tests. Significant reduction in escape failures was also observed in LH test. In RIH test IHp and imipramine inhibited reserpine induced hypothermia in a dose dependent manner. The observed antidepressant activity of IHp was qualitatively comparable to that induced by imipramine.

Rodent models of clinical depression are extensively used for the evaluation of putative antidepressants. In the present review, the available experimental methods which can be utilized by most laboratories involved in preclinical screening of antidepressants, have been discussed. The methods have been categorized on the basis of induction of the depressive state or on the assumption that monoamine deficiency leads to depression. These methods have been critically validated in terms of efficacy of standard antidepressants in these tests and, in some cases, by the neurochemical basis of depression, namely, the deficient monoaminergic theory of clinical depression.

Brain antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) levels were studied in the brains of early diabetic (72 hr) and long term diabetic (one month) rats. Diabetes was induced by injecting streptozotocin (50 mg/kg, i.p.) in citrate buffer. One group of diabetic rats was treated with insulin (1U/day/animal). The results indicate that early diabetic rats exhibit increased SOD and CAT activities with no alteration in the GPX activity. On the contrary, increased CAT decreased GPX activities with no alteration in the SOD activity, was noted in the long-term Diabetic rats. Insulin treatment reversed these alterations in both the groups. It can be concluded that, in diabetic condition antioxidant enzyme levels are elevated and insulin treatment attenuated these changes. Hence, diabetes mellitus, if left untreated, may initiate degenerative processes and other CNS complications due to accumulation of oxidative free radicals.

The antioxidant activity of tannoid active principles of E. officinalis consisting of emblicanin A (37%), emblicanin B (33%), punigluconin (12%) and pedunculagin (14%), was investigated on the basis of their effects on rat brain frontal cortical and striatal concentrations of the oxidative free radical scavenging enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), and lipid peroxidation, in terms of thiobarbituric acid-reactive products. The results were compared with effects induced by deprenyl, a selective monoamine oxidase (MAO) B inhibitor with well documented antioxidant activity. The active tannoids of E. officinalis (EOT), administered in the doses of 5 and 10 mg/kg, i.p., and deprenyl (2 mg/kg, i.p.), induced an increase in both frontal cortical and striatal SOD, CAT and GPX activity, with concomitant decrease in lipid peroxidation in these brain areas when administered once daily for 7 days. Acute single administration of EOT and deprenyl had insignificant effects. The results also indicate that the antioxidant activity of E. officinalis may reside in the tannoids of the fruits of the plant, which have vitamin C-like properties, rather than vitamin C itself.

Different groups of pregnant rats were treated with diazepam (10 mg/kg), phenobarbital (10 mg/kg), haloperidol (0.1 mg/kg), fluoxetine (10 mg/kg) and vehicle (normal saline) intraperitoneally once a day during gestation days 13 to 21. After birth these pups were culled to 8 pups/dam and foster-nursed by lactating mothers for 3 weeks and were reared in colony cages thereafter. Sex and weight matched pairs of rat offsprings were subjected to foot shock induced aggression test at 8 weeks of age. Two parameters of aggressive behaviour were recorded namely, the latency to fight and total number of fighting bouts. The results indicate that prenatal exposure to diazepam, phenobarbital, haloperidol and fluoxetine caused significantly enhanced aggression in terms of number of fighting bouts.

Stress is often associated with water retention and its resolution with diuresis. The biological systems for the control of stress and water balance are very closely related. Corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) are co-localised in the hypothalamus and often act synergistically. Atrial natriuretic peptide (ANP) can exert a feedback control on the hypothalamic/pituitary/adrenal axis. ANP has been shown to be anxiolytic, whereas AVP may be anxiogenic. AVP and ANP levels have been found to be abnormal in a range of stress disorders and psychiatric illnesses. Isatin is an endogenous anxiogenic factor which is also a potent inhibitor of the ANP receptor. It may provide a link between the function of monoamines during stress, and the control of water balance by ANP.

Haloperidol (50 mg/kg, i.p.) treatment was given once to two different groups of pregnant Charles Foster rats on gestational day 9 and 14, these being respectively the critical periods of neural morphogenesis and rapid neural cell proliferation in this species. Pregnant control rats were similarly treated with equal volume of vehicle. The pups born were subjected to open-field exploratory behaviour and elevated plus-maze behaviour tests of anxiety and learned helplessness test of depression at 9 weeks of age. The results indicate that prenatal haloperidol treatment on gestational day 14 induces a significant increase in open-field ambulation and faecal droppings whereas haloperidol treatment on gestational day 9 caused significantly decreased rearing and unaltered ambulation in rat offsprings. Rat offsprings treated with haloperidol on gestational day 9 and 14 also displayed significant anxiogenic behaviour pattern on elevated plus-maze. Significantly increased number of escape failures were observed in learned helplessness tests indicating presence of depression in haloperidol treated rat offsprings. These behavioural alterations were found to be more marked in rat offsprings treated with haloperidol on gestational day 14. The results suggest that prenatal single exposure of high dose of haloperidol during critical period of neural cell proliferation leaves a lasting imprint on offsprings resulting in abnormal emotional state.

Petroleum ether (PE), benzene (BE), chloroform (CE), acetone (AE) and ethanolic (EE) extracts (50-200 or 200 mg/kg, i.p. or 200 mg/kg, p.o.) of dried Abies pindrow leaves, given 30-45 min before showed significant anti-inflammatory (both against acute and sub-acute models), analgesic, barbiturate hypnosis potentiation and anti-ulcerogenic acitivities in rats. All the extracts except EE decreased swim stress immobility in mice indicating some degree of anti-depressant activity. Only PE exhibited hypotension in dogs blocked by atropine. Chemically, extracts showed the presence of glycosides, steroids, terpenoids and flavonoids. They had no anti-bacterial effect. However, toxicity studies indicated that the extracts had an extended safety index. The investigations are consonant with some of the uses of this plant in Ayurveda.

GABA and baclofen (BAC), a GABA-mimetic agent, were investigated for antiulcerogenic activity. Orally administered GABA (100 mg/kg) and BAC (10 mg/kg) showed significant ulcer protection when given either alone for one day or for 4 days, or when given together with aspirin (ASP; 200 mg/kg x 3 days) in their 4 days treatment time in pylorus-ligated rats. Both the drugs showed a tendency to increase acid and decrease peptic output, and increased gastric mucus secretion in terms of total carbohydrate to protein ratio (TC:P) in both the above treatment groups. ASP tended to decrease acid and increase peptic output and significantly decreased TC:P ratio. Both GABA and BAC tended to reverse aspirin-induced effects, though they had little per se effect on TC:P ratio of gastric mucosal glycoproteins except an increase in sialic acid content both after one day or four days treatment. No, per se, effect on cell shedding (DNA and protein content of gastric juice) or cell proliferation (DNA/mg protein) was noted with GABA or BAC but the enhanced cell shedding induced by ASP was attenuated by them. ASP was found to enhance cell proliferation. However, neither of drug showed any effect on cell proliferation when given either alone or in combination with ASP. The antiulcerogenic effect of GABA and BAC may be due to their predominant effects on mucosal defensive factors like enhanced mucin secretion and decreased cell shedding or mucosal damage.

Haloperidol (0.1 mg/kg, i.p.) treatment was given from day 12 to 20 of gestation to pregnant rats, this being the critical period for neural development in this species. The pups born were subjected to open-field exploratory behaviour, tunnel-board exploratory behaviour, elevated zero-maze and elevated plus maze behaviour tests at 7-8 weeks of age. The results indicate that prenatal haloperidol treatment induces a significant increase in open-field ambulations and rearings, decrease in scratching and licking/washing behaviours whereas grooming and faecal droppings remain unchanged. Significantly reduced activity in the centre and increased activity in the periphery of the tunnel board was noted. These suggest presence of anxiety in these animals. Significant anxiogenic behavioural patterns were also observed on elevated zero-maze and plus-maze in the prenatally haloperidol treated offsprings. The results suggest that prenatal exposure of haloperidol leaves a lasting effect on offsprings resulting in hyper-emotional responsiveness and anxiety state.

Rodent models of clinical anxiety are extensively used for evaluating putative anxiolytic activity. In the present review, the available methods which can be utilized by most laboratories, have been discussed. These methods have been categorized as methods involving conditioning techniques and those not involving conditioning. In most cases, the methodology has been briefly discussed in terms of experimental use and efficacy of benzodiazepine and the newer non-benzodiazepine anxiolytics.

Diabetes mellitus was induced in male CF strain rats by streptozotocin (STZ) and hyperglycaemia and superoxide dismutase (SOD) activity of pancreatic islet cells was assessed on days 7, 14, 21 and 28. STZ induced significant hyperglycaemia and a concomitant decrease in islet cell SOD activity. Transina (TR), an Ayurvedic herbal formulation comprising of Withania somnifera, Tinospora cordifolia, Eclipta alba, Ocimum sanctum, Picrorrhiza kurroa and shilajit, had little per se effect on blood sugar concentrations and islet SOD activity in euglycaemic rats, in the doses of 100 and 200 mg/kg, p.o. administered once daily for 28 days. However, these doses of TR induced a dose- related decrease in STZ hyperglycaemia and attenuation of STZ induced decrease in islet SOD activity. The results indicate that the earlier reported anti-hyperglycaemic effect of TR may be due to pancreatic islet free radical scavenging activity, the hyperglycaemic activity of STZ being the consequence of decrease in islet SOD activity leading to the accumulation of degenerative oxidative free radicals in islet beta-cells.

Antioxidant activity of active principles of Withania somnifera, consisting of equimolar concentrations of sitoindosides VII-X and withaferin A, was investigated for their effects on rat brain frontal cortical and striatal concentrations of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX). Results were compared with effects induced by deprenyl, an agent with well documented antioxidant activity. Active glycowithanolides of W. somnifera (WSG) (10 and 20 mg/kg, i.p.), administered once daily for 21 days, induced a dose-related increase in SOD, CAT and GPX activity in frontal cortex and striatum, which was statistically significant on days 14 and 21, except with the lower dose of WSG on GPX activity, where the effect was evident only on day 21. The data were comparable to those induced by deprenyl (2 mg/kg/day, i.p.) with respect to SOD, CAT and GPX activities, which were evident by day 14. These findings are consistent with the therapeutic use of W. somnifera as an Ayurvedic rasayana and medhyarasayana. Antioxidant effect of active principles of W. somnifera may explain, at least in part, the reported antistress, immunomodulatory, cognition-facilitating, anti-inflammatory and anti-aging effects produced by them in experimental animals, and in clinical situations.

Effects of pre- and post-natal undernutrition on anxiety and depression paradigms were studied in albino rats. Prenatal undernutrition was induced in rat pups by restricting the dam's daily food during the gestation period whereas postnatal undernutrition in rat pups was induced by rotating them between lactating and non-lactating maternalised females daily for 12 hr during suckling period from 2nd to 18th day after birth. At 2.5 to 3 months of age all the rat pups were subjected to (i) elevated plus maze behaviour, (ii) open-field behaviour, and (iii) swimming induced behavioural despair tests. The results indicate that postnatal undernutrition caused significantly increased anxiety in the elevated plus maze as well as in open-field behaviour tests. Whereas prenatal undernourishment caused lesser degree of anxiogenic behaviours in the elevated plus maze test. Prenatally undernourished rats showed increased anxiety in the open-field behaviour test. Both, pre- and post-natal undernutrition also lead to increased depressive behaviour in the behavioural despair test and postnatal undernourishment caused greater degree of behavioural despair.

Anxiogenic agents, yohimbine, pentylenetetrazole (PTZ), quinine, bufotenine, flumazenil and isatin were administered (ip) to rats at doses known to induce anxiety in this species. All the drugs exhibited anxiogenic response on the elevated plus-maze and induced a parallel increase in endogenous brain monoamine oxidase (MAO) inhibitory (tribulin) activity. The intensity of the drug-induced anxiety was fairly well correlated with the magnitude of increase in the MAO A inhibitory component of tribulin but not so with its MAO B inhibitory component. Thus, in the doses used, the degree of anxiogenic activity was PTZyohimbinebufoteninequinineisatinflumazenil, in terms of % entries on the open arms of the maze, whereas the magnitude of endogenous MAO A inhibition was PTZyohimbinebufoteninequinineflumazenilisatin. The results indicate that the MAO A inhibitory component of tribulin, rather than its MAO B inhibitory component, may be responsible for the postulated function of tribulin as an endogenous marker of anxiety.

Diazepam (10 mg/kg, ip) treatment was given from day 13 to 20 of gestation to pregnant rats, this being the critical period for neural development in this species. The pups born were subjected to open-field exploratory behaviour, tunnel-board exploratory behaviour, elevated zero maze behaviour and social interaction tests at 8-9 weeks of age. The results indicate that prenatal diazepam treatment induces a significant increase in open-field ambulation, grooming, scratching and licking/washing, whereas rearing and faecal dropping remain unchanged. Significant reduction in tunnel-board exploratory activity, activity on zero-maze and social interaction were also observed in the prenatally diazepam treated offsprings. The results suggests that prenatal interference in the form of diazepam leaves a lasting imprint on offsprings resulting in hyper-emotional responsiveness and anxiety state.

Continuous infusion of gamma- aminobutyric acid (GABA) and baclofen (BAC) on gastric acid and pepsin secretion in perfused rat stomach showed that GABA (25-100 mg/kg/hr, i.v.) and BAC (1 mg/kg/hr, i.v.) increased the acid output which was blocked by bicuculline (Bicc, 1 mg/kg, i.v.) when given 30 min before their infusion. However, lower dose of GABA (5 mg/kg/hr) and hig her doses of BAC (5 or 10 mg/kg/hr) did not show any significant effect on acid secretion. GABA (5 and 25 mg/kg/hr) inhibited peptic output and again Bicc in the above dose inhibited the inhibitory effect of 25 mg/kg/hr of GABA on peptic output. The result indicate dichotomy on the effects of GABA on acid and pepsin secretion. As both the effects were blocked by Bicc, involvement of GABAA receptor may be a possibility. The antiulcer effect of GABA and BAC could not be due to their effect on gastric acid secretion, but may be due to inhibition of pepsin secretion by GABA or effects of GABA or BAC on mucosal defensive factors.

Neurochemical effects of different fusarial toxins elaborated from F. moniliforme (FM) and F. oxysporum (FO) were investigated. FM showed significant nonspecific and irreversible monoamine oxidase (MAO) inhibition which was qualitatively comparable to that induced by nialamide, a nonselective MAO inhibitor. FO did not exhibit any significant MAO inhibitory effect. FM produced a dose related increase in monoamine concentrations (dopamine, noradrenaline and 5-hydroxytryptamine) in different rat brain areas namely, diencephalon-midbrain, caudate nucleus and pons-medulla. FO, on the contrary, produced marked increase in dopamine concentration in the caudate nucleus with concomitant reduction in noradrenaline levels in diencephalon-midbrain and pons-medulla with little effect on 5-HT concentration. The neurochemical effects of FM and FO are consonant with the earlier reports on the neuropharmacological profile of these toxins. Thus, FM was reported to have nialamide like activity, whereas FO actions were dopaminergic in nature.

The neuropharmacological activity profile of total fungal extract of F. oxysporum (FO) was investigated. FO enhanced spontaneous locomotor activity, exploratory behaviour and reduced pentobarbitone hypnosis. It had per se anticonvulsant action against maximal electroshock seizure (MES) and potentiated phenobarbitone and phenytoin in MES and also potentiated pentylenetetrazol (PTZ) convulsion. It antagonised morphine, tetrabenazine and haloperidol catalepsy. FO did not show per se analgesia or potentiation of morphine antinociception in mice, while both effects were present in rats. The effect of FO on body temperature was complex. It produced per se reduction in rectal temperature and potentiated the hypothermic responses of reserpine, apomorphine, PEA and I-dopa, and also the hyperthermic response of 5-HTP. The hyperthermic response of haloperidol was reversed by FO. It potentiated amphetamine and morphine lethality, amphetamine, PEA and apomorphine stereotypy, 5-HTP headtwitch response and post-swim grooming response. On swim-stress immobility, while the time of onset of immobility was reduced, FO did not modify the duration of immobility. On foot-shock induced aggression in paired rats, FO produced a decrease in the latency to onset of fighting behaviour and increased the total contact period and the cumulative aggressive score. FO potentiated clonidine automutilation. It has, thus, facilitated aggressive behaviour. The effects are likely to be due to the presence of fusaric acid in FO, which inhibits dopamine beta-hydroxylase and is known to have dopaminergic effects. This investigation has practical implications. since F. oxysporum is a common food contaminant.

The neuropharmacological profile of the total fungal extract of F. moniliforme (FM) has been investigated. FM produced dose related decrease in spontaneous motor activity (SMA) and exploratory activity, potentiated pentobarbitone hypnosis and the anticonvulsant actions of phenobarbitone and phenytoin against MES seizures, potentiated PTZ and tryptamine seizures, antagonised reserpine induced syndrome, attenuated tetrabenazine and morphine induced catalepsy and potentiated haloperidol catalepsy. FM showed per se antinociceptive activity and potentiated morphine analgesia. It increased rectal temperature, antagonised reserpine and apomorphine hypothermia and potentiated the hyperthermic response of haloperidol and 5-hydroxytryptophan (5-HTP) and hypothermic response of betaphenylethylamine (PEA) and L-dopa. FM had no per se effect on amphetamine lethality, but enhanced the lethality induced by morphine in aggregated animals. Stereotypy by amphetamine was potentiated while that of apomorphine was not affected. The behavioural response of 5-HTP and L-dopa was potentiated. FM had no effect on swim induced behavioural despair. The effect on aggressive behavior was complex, and while the cumulative aggressive score was reduced, the onset of fighting behaviour and contact period was increased. It also inhibited clonidine induced auto mutilation. Since earlier investigation had shown that FM, like nialamide, induced non-selective inhibition of monoamine oxidase (MAO), the results were compared with those induced by nialamide. A comparative profile of action reveals that the neuropharmacological action of FM are qualitatively similar to those induced by nialamide, and likely to be due to inhibition of MAO. The investigation has practical implications because F. moniliforme is a common contaminant of cereals and fruits.

Effects of prenatal undernutrition and phenobarbitone administration, individually and conjointly, was assessed on learning acquisition and subsequent retention of a black/white discrimination task and passive avoidance behaviour in rats. Undernutrition of the dams was induced by restricting food intake to half, throughout the period of gestation, whereas phenobarbitone sodium (2.5 mg/kg, ip) treatment was given from day 13 to 20 of gestation, this being the critical period for neural development in rats. The pups were subjected to brightness discrimination learning, retention of the learning acquisition in a single unit black/white T-maze and passive avoidance behaviour test at 8-9 weeks of age. The results indicate that prenatal undernutrition induces significant discrimination learning and retention deficits in the offsprings. Prenatal phenobarbitone treatment also caused significant learning acquisition and retention deficits in the discrimination test. Phenobarbitone augmented the learning and retention deficits induced by undernutrition. However, both prenatal undernutrition and phenobarbitone treatments did not affect the retention of the learned passive avoidance. The results indicate that the prenatal interference in the form of undernourishment and anticonvulsant barbiturates, may induce functional deficits resulting in perturbed cognition in the offsprings.

The effect of continuous infusion (iv) of graded doses of methysergide (0.1-50 microgram(s)/kg/hr) was studied on basal and pentagastrin (5 microgram(s)/kg/hr) stimulated gastric acid secretion in anaesthetised rats by the slow, continuous stomach perfusion method. Both basal and pentagastrin stimulated acid secretion indicated a biphasic response. Methysergide induced stimulation at a lower dose of 1 microgram(s)/kg/hr and inhibition at higher doses of 20-50 microgram(s)/kg/hr. The stimulatory effect may be due to postsynaptic receptor blockade while the inhibitory effect at higher dose may be due to blockade of presynaptic 5-HT autoreceptors, or due to a direct inhibitory effect of unknown basis.

Isatin (2,3-dioxoindole), one of the components of tribulin, which has been postulated to function as an endogenous marker of stress and anxiety, was shown to induce a dose-related attenuation of learning acquisition in an active avoidance test and inhibition of learning retention, or memory, in a step-down passive avoidance paradigm and transfer latency in an elevated plus-maze, in rats. Earlier studies have indicated that isatin functions as a 5-hydroxytryptamine (5-HT)3 receptor agonist in its anxiogenic activity in rats and is an antagonist at mammalian atrial natriuretic peptide (ANP) receptors. Since 5-HT3 receptor antagonists and centrally administered ANP have been shown to facilitate learning and memory, the observed memory dysfunction induced by isatin can be attributed to its receptor activity at 5-HT3 and ANP receptors. The investigation also indicates that anxiogenic agents are likely to disrupt memory functions.

Putative anxiolytic activity of leaf extract of A. indica, was investigated and compared with that of diazepam in rats using elevated plus maze and open field behaviour test paradigms of anxiety. Doses (10, 20, 50, 100, 200, 400 and 800 mg/kg) of freshly prepared leaf extract of A. indica and diazepam (1 mg/kg) were administered (po) once, 45 min prior to behavioural testing. Low doses (10, 20, 50, 100 and 200 mg/kg) of A. indica leaf extract produced significant antianxiety effects both in plus maze and open field test. However, the higher doses of leaf extract (400 and 800 mg/kg) did not show anxiolytic activity. The effects induced by low doses (10, 20, 50, 100, 200 mg/kg) of extract were comparable to those of induced by diazepam (1 mg/kg).

Effects of prenatal undernutrition and chlordiazepoxide treatment on learning acquisition, and subsequent retention, of a black/white discrimination task, was assessed in the offspring. Undernutrition of the dams was induced by restricting food intake to half, throughout the period of gestation, whereas chlordiazepoxide (2.5 mg/kg, ip) treatment was given from day 13 to 20 of gestation, this being the critical period for neural development in this species. The pups born were subjected to brightness discrimination learning, and retention of the learning acquisition after an interval of one week, in a single unit black/white T-maze, at 8-9 weeks of age. The results indicate that prenatal undernutrition induces significant learning and retention deficits in the offspring. Prenatally administered chlordiazepoxide induced significant deficits in learning acquisition and subsequent retention of the discrimination problem. Chlordiazepoxide induced similar learning and retention deficits in the normal and undernourished rats, and exaggerated the learning and retention deficits induced by undernutrition. The results indicated that the prenatal insults in the form of undernourishment and anxiolytic benzodiazepine compounds, leave a lasting imprint on cognitive behaviour of the offspring.

The anxiolytic, antidepressant and anti-aggression activities of Mentat were investigated in rats and mice, using standard behavioural paradigms. Single acute administration of Mentat, up to a dose of 200 mg/kg, ip, induced insignificant behavioural effects on the test parameters. However, when Mentat was administered subchronically for 7 days at two dose levels (50 and 100 mg/kg, intragastrically), the drug induced dose-related behavioural effects. Thus, it exhibited anxiolytic effect, as assessed by paradigms like the open-field test and elevated plus-maze tests in mice, and the social interaction test and Vogel's drink conflict test in rats. Furthermore, Mentat attenuated the increase in rat brain tribulin, a putative endocoid marker of anxiety, levels induced by pentylenetetrazole (20 mg/kg, sc), a known anxiogenic agent. Mentat attenuated footshock-induced aggressive behaviour in paired rats but failed to affect clonidine-induced automutilative behaviour. The observed aggression-attenuating effect of Mentat may be related to its anxiolytic activity. Mentat exhibited significant antidepressant effect as indicated by its ability to reduce swim stress induced immobility in Porsolt's behavioural despair test, reduction in escape failures concomitant with an increase in avoidance response in the learned helplessness test, and attenuation of muricidal behaviour, in rats. The observed behavioural effects are consonant with the reported clinical utility of Mentat as an adjuvant in the treatment of anxiety and depression.

Subchronic administration of BR-16A (Mentat), a compound herbal formulation, and the nootropic agent, piracetam, augmented learning acquisition and retention of learning in normal rats, as well as in states of cognitive deficits induced by prenatal undernutrition, postnatal environmental impoverishment and sodium nitrite hypoxia. The test paradigms used were step-down latency in a passive avoidance test and transfer latency in elevated plus maze. The drugs were administered orally once daily for 7 days, behavioural testing being done 1 hr after the last administration on day 7. Post-trial performances of the rats at 24 hr and after another 7 days was assessed as indices of learning acquisition and retention of learning (memory), respectively. Mentat (100 mg/kg) and piracetam (100 mg/kg) induced statistically significant nootropic effect in all the test parameters. However, the lower dose (50 mg/kg) of Mentat did not significantly augment learning acquisition in normal rats and in induced states of cognitive deficits, but significantly improved retention of learning in normal rats and in animals with cognitive deficits. Acute single administration of either Mentat (100 mg/kg, orally) and piracetam (100 mg/kg, orally) did not exhibit any discernible nootropic effect in any of the paradigms or parameters investigated. The results indicate that Mentat, like piracetam, can facilitate learning and memory, and can be categorized as a nootropic agent. They also corroborate clinical reports on the memory-facilitative effect of Mentat and earlier experimental evidence of its nootropic activity in mice.

Piracetam (PIR), a cyclic GABA derivative without GABA-mimetic activity, is classified as a nootropic agent, a new class of psychotropic drugs which augment learning acquisition and retention of memory. The present study indicates that PIR has significant anxiolytic activity in rodents following subchronic, but not acute administration, when tested against several paradigms of experimental anxiety. Thus, PIR (250 and 500 mg/kg), administered orally for 7 and 14 days, exhibited anxiolytic activity in the open-field, elevated plus-maze and footshock-induced fighting in paired mice paradigms, as well as in the Vogel's conflict test in rats. In addition, PIR induced significant reduction in rat brain tribulin levels, a putative endocoid marker for anxiety, produced by pentylenetetrazole, an anxiogenic agent. On the contrary, single acute administration of PIR failed to induce any anxiolytic effect. The present study, thus, confirms clinical reports that PIR can induce a delayed antianxiety effect in psychogeriatric individuals and in chronic alcoholism.

Piracetam, a prototype of a new class of psychotropic agents, the nootropic agents, which improve learning ability and memory retention, was found to induce a dose-related prevention of disruption of acquisition of a passive avoidance response produced by electroshock application. The amnesia attenuating effect of piracetam was accompanied by prevention of the decrease in acetylcholine concentrations of rat brain induced by electroshock. The study indicates that the cognition enhancing effect of piracetam may be due to a facilitatory effect on cholinergic transmission.

Effects of prenatal undernutrition, stress and diazepam treatment on learning acquisition, and subsequent retention of a spatial discrimination task was assessed in the offsprings. Undernutrition of the dams was induced by restricting food intake to half, throughout the period of gestation, whereas footshock stress and diazepam (0.5 mg/kg, ip) treatment was given from day 13 to 20 of gestation, this being the critical period for neural development in this species. The pups born were subjected to spatial discrimination learning, and retention of the learning acquisition after an interval of one week, in a single unit black/white T-maze, at 8-9 weeks of age. The results indicate that prenatal undernutrition induces significant learning and retention deficits in the offspring, whereas the effect of prenatal stress was limited to only deficit in learning acquisition. Prenatally administered diazepam induced significant deficits in learning acquisition and subsequent retention of the discrimination task in pups culled from normally nourished dams. However, offsprings from diazepam administered undernourished dams exhibited less marked cognitive deficits, which may be attributable to the altered emotional reactivity of pups born to undernourished mothers. Prenatally administered diazepam also induced differential effects in stressed and non-stressed dam offsprings, though the effects were statistically insignificant. The results suggest that prenatal insults, in the form of undernourishment, stress and anxiolytic drugs, leave a lasting imprint on cognitive behaviour of the offspring. The final effect on this behaviour may be determined by the co-existence of these prenatal factors, particularly at a time when the foetus is vulnerable because of neural development and differentiation.

Footshock induced aggression (FIA) was induced in weight matched paired rats and three paradigms of aggressive behaviour was recorded, namely, the latency to fight (LF), total period of physical contact (TPP) and cumulative aggression scores (CAS). Dopamine (DA), administered centrally, and peripherally administered L-dopa (with benserazide, a peripheral decarboxylase inhibitor), a DA precursor, and the postsynaptic D2 receptor agonists, apomorphine, N-n-propyl-norapomorphine (PNA), bromocriptine, lisuride and pergolide, induced a dose-related facilitation of FIA characterized by decrease in LF and increase in TPP and CAS. However, the DA presynaptic receptor agonist, BHT-920, induced a biphasic effect with inhibition of FIA being induced by a lower dose and facilitation of the aggressive behaviour produced by a higher dose. The postsynaptic D2 receptor antagonists, haloperidol, spiperone and pimozide, induced a dose-related attenuation of FIA, an effect not seen with domperidone, a peripheral DA receptor antagonist. The results indicate that central dopaminergic postsynaptic D2 receptors have a modulatory facilitative effect on FIA, while the presynaptic DA autoreceptors mitigate aggressive behaviour. However, the presynaptic DA receptor agonist, BHT-920, appears to lose its receptor specificity on dose increment. Long term administration of haloperidol, followed by withdrawal, or desipramine, induced per se augmentation of FIA and potentiated the aggression-facilitative effects of L-dopa, apomorphine and PNA. Since both these treatments are known to induce supersensitivity of central postsynaptic dopamine D2 receptors, the effects are likely to be related to augmented function of dopamine neurones. The findings, in conjunction with a recent report from this laboratory indicating an increase in rat brain DA levels in FIA, support the contention that the central DA system has a facilitative effect on FIA.

Quinine, a cinchona alkaloid, was investigated for putative anxiogenic activity in view of clinical reports suggesting that it induces anxiety and apprehension following its use in malaria. The experimental paradigms chosen to elucidate anxiogenic activity have been shown to stand the tests of reliability and validity. Yohimbine, which has been shown to induce anxiety both in animals and in man, was used for comparison. Quinine was found to elicit a complex behavioural profile of activity ranging from overt central stimulation to marked central depression on dose increment. The doses 10 and 20 mg/kg, ip, of quinine chosen to investigate anxiogenic activity were comparable to those induced by 2.5 and 5 mg/kg ip of yohimbine. Quinine induced a dose-related anxiogenic activity in the open-field and elevated plus-maze tests in mice, and the social interaction and thirst conflict tests in rats, similar to effects induced by yohimbine. In addition, both quinine and yohimbine attenuated the effects of diazepam, an anxiolytic agent, in the open-field and thirst conflict tests. The results indicate that quinine exerts significant anxiogenic effect at a particular dose range.

There is now conclusive evidence for the presence of insulin and insulin receptors in the mammalian CNS and it has been postulated that they can modulate peripheral glucose homeostasis. Since a number of central neurotransmitters are also known to influence glucose levels and it is likely that CNS insulin receptors act through neurotransmitter mediation, the present study was conducted to investigate the effect of intracerebroventricularly (icv) administered insulin on rat brain dopamine (DA), noradrenaline (NA), serotonin and acetylcholine (ACh) activity in normal and alloxan-induced hyperglycaemic animals. Insulin was administered in doses (50 and 100 microU) which induced minimal hypoglycaemia, so as to obviate the likely effects of hypoglycaemia on neurotransmitter function. DA was estimated in midbrain-diencephalon (MD) and caudate nucleus (CN), NA and serotonin in MD and pons-medulla (PM), while ACh was estimated in all the three areas, namely, MD, CN and PM. The regional brain concentrations of DA, NA and serotonin were more in the hyperglycaemic rats as compared to their euglycaemic counterparts. However, the reverse was noted in case of ACh. Insulin induced a decrease in rat brain DA and NA levels, which was more marked in the hyperglycaemic animals. Conversely, insulin induced an increase in rat brain serotonin concentration which was not significantly different in normal and hyperglycaemic rats. Insulin induced marked increase in rat brain ACh levels, which was accentuated in hyperglycaemic animals. The present study reports for the first time the likely interaction between CNS insulin receptors and brain monoamines, and ACh, in euglycaemic and hyperglycaemic states.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of alkaloidal fraction of aqueous extract of T. malabarica (Tm) was studied on humoral antibody responses in rats and guineapigs. The anti-SRBC haemagglutination titre was found to be enhanced in rats pretreated with Tm (2.5 mg/kg). Passive cutaneous anaphylaxis (PCA) in rats was also increased in Tm treated group. In vitro experiments with sensitized rat peritoneal mast cells showed a significant decrease in antigen-induced various spasmogens on isolated guineapig ileum.

Footshock induced aggression (FIA) was induced in paired rats and three paradigms of aggressive behaviour were recorded, namely, latency to fight (LF), total period of physical contact (TPP) and cumulative aggression scores (CAS). The effects of increasing or decreasing central serotonergic activity, by using a number of pharmacological agents with well defined effects on rat brain serotonin, were investigated on FIA and on FIA augmented by apomorphine, a dopamine receptor agonist. The results show that centrally administered serotonin, the serotonin precursor, 5-hydroxytryptophan administered with clorgyline, a selective MAO A inhibitor, quipazine, a serotonin receptor agonist, and fluoxetine, a selective inhibitor of neuronal re-uptake of serotonin, attenuated all paradigms of FIA and apomorphine induced potentiation of FIA. On the contrary, the other re-uptake inhibitor used, citalopram, appeared to have a dual effect and decreased LF and CAS, while increasing TPP. The serotonin synthesis inhibitor, p-chlorophenylalanine and the selective serotonin receptor (5-HT2) antagonist, ketanserin, augmented all paradigms of FIA per se and apomorphine induced augmentation of FIA. However, the other serotonin receptor antagonist used, metergoline, which blocks both 5-HT1 and 5-HT2 receptor subtypes, attenuated FIA per se but decreased only CAS in apomorphine induced increase in FIA. The data confirm the inhibitory effect of the central serotonergic system on aggressive behaviour and the inverse relationship existing between it and the central dopaminergic system in the modulation of FIA, as has also been confirmed in earlier biochemical investigations from this laboratory. The data has been discussed in the light of existing knowledge on serotonin receptor subtypes and the presence of modulatory serotonergic heteroreceptors on central dopaminergic neurones.