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The present study was taken up to see the effect of chicoric acid (CA) on behavioral and biochemical alterations induced by chronic restraint stress in experimental Swiss albino mice. CA at 1mg/kg dose level exhibited considerable antidepressant activity as shown by significant decrease in immobility period in the Porsolt's swim stress-induced behavioral despair test and escape failures in Learned "helplessness test". The antidepressant activity shown by CA can be attributed to its modulating effect on nor-adrenaline (NA), dopamine (DA) and 5- hydroxy tryptamine (5-HT) as shown by their quantification in CA treated chronically stressed mice. Further, a significant antioxidant effect was exhibited by CA as shown by estimation of lipid peroxidation, glutathione (GSH) and glycogen in liver of chronically stressed mice. It also normalized altered values of serum glucose, triglycerides, aspartate aminotransferase (AST) alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in a dose dependent manner. The stress busting potential of CA was further confirmed by its regulating effect on raised plasma corticosterone levels and significant attenuation of the depleted ascorbic acid, cholesterol and corticosterone levels in adrenal glands. Thus, our results suggest that CA possesses considerable stress busting potential, and that anti-oxidation may be one of the mechanisms underlying its antistress action., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Curcumin, a yellow pigment extracted from rhizomes of the plant Curcuma longa (turmeric), has been widely used as food additive and also as a herbal medicine throughout Asia. The present study was designed to study the pharmacological, biochemical and neurochemical effects of daily administration of curcumin to rats subjected to chronic unpredictable stress. Curcumin treatment (20 and 40 mg/kg, i.p., 21 days) significantly reversed the chronic unpredictable stress-induced behavioral (increase immobility period), biochemical (increase monoamine oxidase activity) and neurochemical (depletion of brain monoamine levels) alterations. The combination of piperine (2.5 mg/kg, i.p., 21 days), a bioavailability enhancer, with curcumin (20 and 40 mg/kg, i.p., 21 days) showed significant potentiation of its anti-immobility, neurotransmitter enhancing (serotonin and dopamine) and monoamine oxidase inhibitory (MAO-A) effects as compared to curcumin effect per se. This study provided a scientific rationale for the use of curcumin and its co-administration with piperine in the treatment of depressive disorders.

Broadband white noise exposure (100 dB) in wistar strain male albino rats significantly increased the levels of dopamine (DA), serotonin (5-HT) and 5-HT turnover in many of the discrete brain regions (cerebral cortex, cerebellum, hypothalamus, hippocampus, pons-medulla and corpus striatum) during sub-chronic noise exposure (4 h daily for 15 days). In acute (4 h for 1 day) and chronic noise exposures (4 h daily for 30 days) the levels were significantly altered only in certain regions. The turnover study of serotonin clearly indicates that neurotransmitter level alone cannot be an indicator, as in some brain regions the rate of synthesis matched with the degradation in order to maintain the normal levels. The intraperitoneal administration of 70% ethanolic extract of Ocimum sanctum(OS) at the dosage of 100 mg/kg body weight to animals subjected to noise exposure has prevented the noise induced increase in neurotransmitter levels without affecting the normal levels. This indicates that OS can be a probable herbal remedy for noise induced biogenic amine alterations.

Previous pharmacological studies have implicated serotonergic brain systems in opiate withdrawal. To test the hypothesis that serotonin (5-HT) has a critical role in the development of opiate withdrawal, we have employed a near-total brain 5-HT system lesion technique (90% depletion) using 5,7-dihydroxytryptamine combined with induction of opiate dependence by implantation of morphine pellets or by repeated injections of increasing doses of morphine. The effects of serotonergic neuron lesion were examined on spontaneous opiate withdrawal (changes in circadian locomotor activity) and naloxone-precipitated opiate withdrawal syndrome (the somatic aspect). The antiwithdrawal properties of clonidine, an alpha(2)-adrenoceptor agonist currently used for clinical treatment for the somatic signs of opiate withdrawal, were tested also in the lesioned rats. Our findings show that serotonergic lesions in morphine-dependent rats did not alter either the spontaneous or the naloxone-induced withdrawal syndrome (with exception of jumping behavior). Moreover, clonidine alleviated the naloxone-induced withdrawal syndrome in lesioned as well as in sham-operated morphine-dependent rats. These results demonstrate that 5-HT systems are not directly responsible for the development of the somatic opiate withdrawal syndrome in morphine-dependent rats.

The Bennett and Xie model of peripheral nerve injury was used to study the effects of aging on the onset and progression of sciatic nerve ligation (SNL)-induced thermal hyperalgesia and tactile-evoked allodynia in young, mature, and aged Fischer 344 FBNF1 male rats (4-6, 14-16, and 24-26 months old, respectively). A plantar analgesia meter and calibrated von Frey pressure filaments were employed as the analgesiometric assays. In the absence of nerve injury, aged rats were found to be more sensitive than younger animals to noxious thermal stimuli. Following the SNL surgery, thermal hyperalgesia was observed in all three age groups within 3 days. On post-SNL day 35, the paw-withdrawal latency values of the young and mature animals returned to presurgical baseline levels, while the aged rats continued to exhibit thermal hyperalgesia. Tactile-evoked allodynia was apparent within 3 days following peripheral nerve injury in the oldest cohort, but was delayed in the younger animals. On post-SNL days 0 (control), 3, 21, and 35, young, mature, and aged rats were sacrificed and high-performance liquid chromatography and electrochemical detection (HPLC/ECD) methods were used for neurochemical analyses of spinal serotonin (5-HT), norepinephrine (NE), and 5-hydroxyindoleacetic acid (5-HIAA). Spinal 5-HT and NE levels were not significantly altered by the aging process, nor were they affected by peripheral nerve injury. However, spinal 5-HT turnover from the aged animals was greater than that detected in spinal tissue from the younger counterparts. Differences in spinal 5-HT turnover may contribute to age-related variability in spinal nociceptive processing.

The purpose of the present study was to examine the effect of subchronic treatment (24 days) with antidepressants displaying differential effects on noradrenaline and serotonin reuptake, on behavior, neurochemistry, and hypothalamic-pituitary-adrenal (HPA) axis activity following FST exposure in the rat. Desipramine (7.5 mg/kg, IP) significantly decreased immobility in the FST, whilst paroxetine (7.5 mg/kg IP) and venlafaxine (10 mg/kg, IP) were without effect. Nonetheless, treatment with all three antidepressants significantly attenuated stress-related increases in amygdaloid and cortical serotonin turnover. Of the three antidepressants examined, only desipramine attenuated the stress-associated elevation in serum corticosterone. In conclusion, although FST-induced increases in serotonin turnover in the frontal cortex and amygdala were attenuated following treatment with all three antidepressants, FST-induced behavioral changes and increased HPA axis activity were normalized only following desipramine treatment. In addition, these results suggest that neurochemical mechanisms independent of increased serotonergic activity subserve the normalization of behavior and HPA axis responses in the FST. These data also add to our understanding of the interactions between antidepressants and stress-induced behavioral, neurochemical, and endocrine alterations, and illustrates important differences between classes of antidepressants.

Influence of a naloxone (an opioid receptor antagonist) challenge (5 mg/kg, IP) on levels of biogenic amines and their metabolites in various brain regions of rats infused continuously with butorphanol (a mu/delta/kappa mixed opioid receptor agonist; 26 nmol/microliter/h) or morphine (a mu-opioid receptor agonist; 26 nmol/microliter/h) was investigated using high-performance liquid chromatography with electrochemical detection (HPLC-ED). Naloxone precipitated a withdrawal syndrome and decreased the levels of: dopamine (DA) in the cortex and striatum, 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum, homovanilic acid (HVA) in the striatum, limbic, midbrain, and pons/medulla regions in butorphanol-dependent rats. However, the levels of norepinephrine (NE), serotonin (5-hydroxytryptamine; 5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in the regions studied were not affected by naloxone-precipitated withdrawal. In addition, naloxone increased the HVA/DA ratio in the cortex, while this ratio was reduced in the limbic, midbrain, and pons/medulla. The reduction of 5-HIAA/5-HT ratio was also detected in the limbic area. In the animals rendered dependent on morphine, the results obtained were similar to those of butorphanol-dependent rats except for changes of 5-HIAA levels in some brain regions. These results suggest that an alteration of dopaminergic neuron activity following a reduction of DA and its metabolites in specific brain regions (e.g., striatum, limbic, midbrain, and pons/medulla) play an important role in the expression of the opioid withdrawal syndrome.

(+/-)3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy"), an increasingly popular recreational drug, is known to damage brain serotonin (5-hydroxytryptamine [5-HT]) neurons, whilst also having a less pronounced effect on the dopaminergic system. Treatment with MDMA results in an increased locomotor activity, elevated basal serum corticosterone concentrations, decreased exploratory activity, and changes in body temperature. The aim of this study was to examine the dose related effects of subacute administration of MDMA (5, 10, and 20 mg/kg IP twice daily for 4 days) on home cage locomotor activity, "open field" and "step-down passive avoidance" behaviours, changes due to an 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) challenge, and on plasma corticosterone and brain neurotransmitter concentrations. Total locomotor activity counts were significantly increased by both 10 and 20 mg/kg MDMA for the 4 days of drug administration. There were no significant differences seen in the "open field" or "step down passive avoidance" behaviour, in the 8-OH-DPAT induced hypothermia, or in basal serum corticosterone concentrations. MDMA caused a significant depletion of both 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortex and amygdala and a significant elevation of dopamine and noradrenaline in the hippocampus. Apart from the increase in locomotor activity following subacute administration, the observed behaviour of the MDMA treated rats would not appear to reflect the substantial changes in brain biogenic amine neurotransmitters.

Exposure to HBO causes hypothermia, bradycardia, head weaving, resting tremor, piloerection, and straub tail in rats. These physiological and behavioral responses can also be evoked by selective activation of serotonin1A (5-HT1A) receptors. The purpose of the current study was to determine if hypothermia caused by HBO is due to increased activation of 5-HT1A receptors. The levels of brain biogenic amines were measured in brain regions of Sprague-Dawley (SD) rats exposed to HBO. Exposure to HBO caused an increase in the levels of 5-hydroxyindoleacetic acid (5-HIAA) in the striatum (92%, p < 0.05) and occipital-temporal cortex (116%, p < 0.05), but not in other brain regions. Exposure to HBO did not change the levels of tryptophan, serotonin (5-HT), other biogenic amines, or their metabolites. It is hypothesized that the Fawn Hood (FH) rat, which is reported to be resistant to hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), has an abnormality of 5-HT1A receptor activity. Although the FH rat was more resistant to hypothermia induced by HBO than the SD rat, we were not able to confirm that this rat was resistant to hypothermia induced by 8-OH-DPAT. The 5-HT receptor antagonists, 1-(1H-Indol-4-yloxy)-3-[(1-methylethyl)amino]-2-propanol (Pindolol), 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide (NAN-190), and methysergide, did not block hypothermia induced by HBO in SD rats. A series of control experiments were used to confirm that the antagonists blocked hypothermia induced by serotonin agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of cocaine on defensive withdrawal behavior in rats and elevated plus-maze behavior in mice were investigated. Cocaine (20 mg/kg IP) injected daily for 7 or 14 days induced defensive withdrawal; that is, the latency to emerge from a small chamber in an open field and the mean time in the chamber were both significantly increased. Acute cocaine administration also induced defensive withdrawal, and this effect was prevented by prior treatment with chlordiazepoxide (5 mg/kg IP). Both acute and chronic cocaine treatments significantly increased plasma concentrations of corticosterone and reduced the ratios of 3,4-dihydroxyphenylacetic acid to dopamine and 5-hydroxyindoleacetic acid to serotonin in several brain regions. Further evidence for an acute anxiogenic effect of cocaine was obtained from mice studied in the elevated plus-maze. Acute cocaine administration decreased both the number of entries into and the time spent in the open arms of the maze. These results taken together strongly support an anxiogenic action of acute and chronic cocaine administration.

THC is the major psychoactive constituent of marijuana and is known to produce psychopharmacological effects in humans. These studies were designed to determine whether acute or chronic exposure to marijuana smoke or THC produces in vitro or in vivo neurochemical alterations in rat or monkey brain. For the in vitro study, THC was added (1-100 nM) to membranes prepared from different regions of the rat brain and muscarinic cholinergic (MCh) receptor binding was measured. For the acute in vivo study, rats were injected IP with vehicle, 1, 3, 10, or 30 mg THC/kg and sacrificed 2 h later. For the chronic study, rats were gavaged with vehicle or 10 or 20 mg THC/kg daily, 5 days/week for 90 days and sacrificed either 24 h or 2 months later. Rhesus monkeys were exposed to the smoke of a single 2.6% THC cigarette once a day, 2 or 7 days a week for 1 year. Approximately 7 months after the last exposure, animals were sacrificed by overdose with pentobarbital for neurochemical analyses. In vitro exposure to THC produced a dose-dependent inhibition of MCh receptor binding in several brain areas. This inhibition of MCh receptor binding, however, was also observed with two other nonpsychoactive derivatives of marijuana, cannabidiol and cannabinol. In the rat in vivo study, we found no significant changes in MCh or other neurotransmitter receptor binding in hippocampus, frontal cortex or caudate nucleus after acute or chronic exposure to THC. In the monkey brain, we found no alterations in the concentration of neurotransmitters in caudate nucleus, frontal cortex, hypothalamus or brain stem.(ABSTRACT TRUNCATED AT 250 WORDS)

Performances of male rats of the Roman High- (RHA), Roman Control- (RCA) and Roman Low- (RLA) Avoidance strains were compared in two working memory tests, a spatial one, the radial maze, and a nonspatial one, an object recognition test. The same rats were subjected to measures of emotional reactivity and of different forms of motor activity and finally to measures of cholinergic and aminergic activities in the hippocampus, frontal cortex and striatum. Compared to RHA, RLA performed better in the two working memory tests, displayed "anxiety" and had also lower levels of exploratory locomotor activity. Hippocampal ChAT activity was higher in RLA than in RHA. Levels of DA and DOPAC in the striatum were higher in RLA compared to RHA, whereas in the frontal cortex they were lower. For most of these measures, RCA were intermediate between RLA and RHA. These results confirm and extend the finding that the Roman strains are not only a genetic model for two-way avoidance conditioning but also for working memory.

To assess the potential involvement of metabolism of 3,4-methylenedioxymethamphetamine (MDMA) to the catechol alpha-methylepinine in producing serotonergic neurotoxicity, we attempted to correlate aspects of this reaction with the neurotoxicity profile of MDMA. In contrast to the stereoselectivity of S-(+)-MDMA in causing persistent declines in rat brain 5-hydroxyindole levels, no stereochemical component to the metabolic reaction was apparent. Rat liver microsomes generated a significantly greater amount of alpha-methylepinine than did mouse microsomes, but similar amounts of metabolite were produced by brain microsomes from the two species. Formation of alpha-methylepinine by hepatic, but not brain, microsomes was inhibited by SKF 525A and induced by phenobarbital, possibly indicating a tissue specificity in cytochrome P-450-dependent metabolism of MDMA. To directly assess whether alpha-methylepine is a likely mediator of MDMA neurotoxicity, the compound was administered intracerebroventricularly. No persistent declines in biogenic amines or their metabolites were observed one week following treatment. These data suggest that alpha-methylepinine alone is not responsible for the neurotoxic effects of MDMA.

Exposure to inescapable footshock provoked region-specific alterations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) activity across six strains of mice (A/J, BALB/cByJ, C3H/HeJ, C57BL/6J, DBA/2J and CD-1). The stressor provoked reductions of hypothalamic NE and increased MHPG accumulation in all strains. In contrast, the effects of the stressor on NE activity in the hippocampus and locus coeruleus varied appreciably across strains. In the mesocortex and nucleus accumbens shock induced an increase of DOPAC accumulation and pronounced reductions of DA in some strains, while in others these variations were less pronounced or entirely absent. Stressor-provoked alterations of 5-HT and 5-HIAA were most evident in the mesocortex. Strain-specific neurochemical alterations following footshock are discussed relative to stressor-induced behavioral disturbances and animal models of depression.

The present study in mice demonstrated the TRH when administered over 5 days remained active in the Everett Dopamine Potentiation Test. No evidence of tolerance was observed. In fact, an accumulative effect of TRH appeared to take place. Ablation of the adrenals, ovaries, testes, pineal, spleen, parathyroid, one kidney, or thymus did disrupt this behavioral potentiation of dopamine by TRH. TRH was found to potentiate the effects of imipramine. T3, T4, and TSH were found to be active in the DOPA potentiating test. No overt toxicity was observed between TRH and pargyline or between TRH and DOPA. Toxicity was seen only when all three agents were used together. TRH was found active in young and old mice. TRH was also found active in potentiating the central effects of serotonin. Biogenic amine brain levels in mice were not altered by TRH when administered for five days. Alpha-methyl-p-tyrosine reduced the activity of TRH in the dopamine potentiation test, suggesting dopaminergic mechanisms are involved by a direct receptor interaction.

Post-decapitation seizures (PDR) are a spinal reflex which seems regulated by some monoaminergic neurons present in the spinal cord (S.C.). In order to better characterize the role of dopaminergic neurons in PDR, we studied the effect of treatment with opiates, which are known to increase dopamine (DA) and serotonin (5HT) metabolism in the brain, on the duration of PDR and on the metabolism of DA and 5HT in S.C. Morphine, given either IP or ICV, reduced the duration of PDR and increased DA metabolism. Both effects were more evident after systemic administration. [D-Ala2]Met5 enkephalin amide acted similarly to ICV administered morphine. Biochemical and behavioral effects were significantly correlated.

The effects of morphine administered to pregnant Sprague-Dawley rats on the schedule-controlled behavior of the offspring were examined. It was observed that both male and female adult rats exposed prenatally to morphine were tolerant to the disruptive effects of morphine on fixed-interval responding compared to age-matched controls. These morphine-treated rats, however, were neither tolerant nor supersensitive to the disruptive effects of the catecholaminergic agonist, amphetamine, and did not exhibit any alteration in their steady state levels of central monoamines. These observations are discussed in relation to the effects of prenatal morphine exposure on unconditioned behaviors.

The acute and chronic effects of the "serotonergic anorectics" quipazine and dl-fenfluramine were examined in rats with substantial and specific depletions of brain 5-hydroxytryptamine (5-HT) induced by 5,7-dihydroxytryptamine (5,7-DHT). A "dessert" test which did not involve food deprivation was used to assess anorexia. Markedly increased sensitivity to the L-5-HTP-induced behavioral syndrome in 5,7-DHT-lesioned rats indicated postsynaptic 5-HT receptor supersensitivity. We found low (2 mg/kg) and intermediate (5 mg/kg) doses of fenfluramine, a putative presynaptic agent, were more effective in producing anorexia in lesion rats versus controls. A higher dose of fenfluramine (10 mg/kg) was less effective in lesion rats, suggesting that high dose and low dose fenfluramine anorexia are mediated by different mechanisms. We found quipazine, a putative 5-HT postsynaptic agonist, in a dose range of 2-10 mg/kg, to be no more effective in producing anorexia in lesion rats compared to controls. The development of tolerance to both fenfluramine and quipazine anorexia was similar for lesion and control rats showing that an intact brain 5-HT system is not necessary for tolerance. Tolerance to the "behavioral syndrome" induced by high doses of these agents developed rapidly in controls but not at all in lesion rats. This suggests that the behavioral syndrome and anorexia are independent effects of fenfluramine and quipazine. These results also challenge the popular notion that the primary anorectic action of fenfluramine is via brain serotonin.

Pregnant rats were subjected to once daily stress treatments consisting of handling and a saline injection. The offspring showed region-specific changes in brain 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) levels in infancy but only the hypothalamus still showed significant changes at 60 days of age. In a reaction-to-stress test 23-day-old offspring in the prenatal stress group showed a greater elevation in plasma corticosterone level but smaller changes in hypothalamic NE and 5-HIAA levels than control offspring suggesting that prenatal stress may have altered the functioning of the hypothalamic-pituitary-adrenal axis. It is suggested that changes in the development of specific monoamine-containing neurons may be associated with the reported behavioral deficits in offspring of female rats stressed during pregnancy.

Maternal exposure to delta 9-tetrahydrocannabinol (THC), the major psychoactive component in marihuana, or to the non-psychoactive cannabinol (CBN) or cannabidiol (CBD) alters male reproductive functions and brain biogenic amines in male and female offspring. Postnatal exposure to THC or CBN reduced body weights, while testicular weights were lower in CBD-exposed mice. Testicular testosterone (T) levels were also lower in CBN- and CBD-exposed animals. Postnatal cannabinoid exposure reduced plasma luteinizing hormone (LH) levels in intact and castrated adults. Although basal T production in vitro was not affected by postnatal cannabinoid exposure, testes from CBD-exposed males were more responsive to gonadotropin stimulation. In contrast, in vivo responsiveness to intratesticular human chorionic gonadotropin (hCG) administration was significantly reduced in THC- and CBD-exposed males. Pituitary weights and their basal LH production in vitro was higher in THC- or CBN-exposed mice. Pituitaries from cannabinoid-exposed males were less responsive to LH releasing hormone (RH) stimulation, however, hypothalamic LHRH content was significantly higher in the THC-exposed males. Hypothalamic dopamine (DA) levels were significantly lower in CBN-exposed castrated mice, compared to castrated controls. The reduction in hypothalmic norepinephrine (NE) in THC- and CBN-exposed castrates after alpha-methylparatyrosine (alpha-MPT) was significantly less than that observed in control castrates. Hypothalamic DA levels were depleted to a greater extent in CBD-exposed males. Brain levels of serotonin (5-HT) and 5-HIAA were significantly higher in castrated, than in intact THC-exposed males. In ovariectomized CBN-exposed females, hypothalamic NE levels were lower, while the alpha-MPT-induced depletion of NE was less in CBD-exposed, compared to control females. Levels of 5-HT were lower only in THC-exposed females. Plasma levels of LH were significantly higher in CBN-exposed, while plasma levels of FSH were reduced in THC- and CBD females. Maternal exposure to psychoactive or non-psychoactive cannabinoids on the day of parturition results in long term alterations in neuroendocrine function in male and female offspring. It is possible that the observed alterations in biogenic amines may mediate the effects of cannabinoids on pituitary and gonadal function.

This study investigated modification of the tonic convulsive threshold to maximum electroshock in 15- and 30 day old rats treated with drugs which reduce steady-state concentrations of monoamines. On postnatal day 15, reduction of central catecholamine concentrations by 6-hydroxydopamine or of central serotonin concentrations by 5,7-dihydroxytryptamine or p-chloroamphetamine did not alter the tonic convulsive threshold. However, simultaneous depletion of catecholamines and serotonin by tetrabenazine was associated with a significant decrease in the tonic threshold. This effect could be reversed partially by simultaneous administration of the catecholamine and serotonin precursors, L-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively. On postnatal day 30, reduction of brain serotonin concentration, but not catecholamine concentrations, was associated with a significant decrease of the tonic convulsive threshold. In a previous study, in which 7-8 day old rats were used, a tetrabenazine-induced decrease in the tonic convulsive threshold prevented by L-dihydroxyphenylalanine but not 5-hydroxytryptophan. Furthermore, intracisternal 6-hydroxydopamine, but not 5,7-dihydroxyhyptamine, decreased the threshold on postnatal day 8. Therefore, the results of the present day study involving 15- and 30 day old rats, together with the earlier findings in 7-8 day old rats, [28] suggest an apparent developmental transition from catecholaminergic to serotonergic dominance in regulation of the tonic convulsive threshold during the first postnatal month.

Rats subjected to electrolytic lesions of the ventral medial tegmentum (VMT) showed long-lasting increased locomotor activity in the open field compared to sham-operated controls. In addition to severe depletion of mesolimbic dopamine, the lesions also caused significant depletions of striatal dopamine, mesolimbic and striatal norepinephrine and striatal and hippocampal serotonin. Administration of d-amphetamine sulfate produced similar dose-response functions for locomotor activity in both VMT-lesioned and sham-operated rats despite the extensive depletion of dopamine in the VMT-lesioned rats. These results suggest that the mesolimbic dopamine pathway is not the sole substrate for amphetamine-stimulated locomotor activity. Electrolytic lesions of the VMT interrupt several neurotransmitter pathways which may produce complex and antagonistic effects on behavior.

Marked enhancement of tyrosine hydroxylase (TH) activity was observed in the rostral pons of Wistar albino rats, 3 days after a single injection of Oxotremorine. TH activity in other brain areas, and regional levels of norepinephrine, dopamine, serotonin and 5-hydroxyindoleacetic acid were unaffected. Enhancement of TH activity did not affect length or number of REM episodes, or the amount of REM occurring in 24 hr. REM occurrence did not, thus, vary in accordance with activity of the rate-limiting enzyme for catecholamine synthesis. These data suggest that, although REM may reflect neuronal protein synthesis, REM is not part of a mechanism regulating the activity of enzymes in the pontine CA synthesis pathway.

The function of dopaminergic innervations of the central medial nucleus accumbens in the processes maintaining intravenous morphine self-administration was assessed by lesioning with 6-OHDA and comparing drug intake with sham-vehicle treated littermates. Localized bilateral lesions of this structure resulted in significant increases in morphine intake shifting the dose-effect relationship to the right with twice the dose necessary to maintain prelesion rates of self-administration. Content of dopamine and dihydroxyphenylacetic acid was decreased in the nucleus accumbens after the lesion, but unchanged in the adjacent pyriform cortex and anterior caudate nucleus-putamen, while serotonin was significantly decreased in the pyriform cortex. High affinity uptake measurements also suggested nucleus accumbens dopaminergic and pyriform cortex serotonergic innervations to be affected by the lesion. The shift to the right in the dose effect relationship after the lesion suggests these neuronal systems to be excitatory to the processes mediating self-administration.

The seizure sensitive (WJL)UC) strain of Mongolian gerbils has been used to investigate the effects of drugs that modify central monoamine activity on spontaneous epileptiform seizures. Increasing central norepinephrine and dopamine levels significantly reduced the severity of the seizures and the importance of dopamine was further demonstrated by the protection from seizures after administration of the dopaminergic agonist apomorphine. These data indicate that a search for differences in regional levels, or turnover rates, of these amines between seizure sensitive and seizure resistant strains of gerbils might be profitable in determining the genetic deficit underlying the seizure phenomenon in these animals.

Progabide, a new antiepileptic GABA agonist of moderate affinity for GABA receptors, has been studied in a number of psychiatric disorders and the results compared with the action of this drug in animal models. In an animal model for anxiety (the aversive response to periaqueductal grey stimulation in the rat) progabide had a similar action to that of diazepam. However in clinical trials to date the effect of the GABA agonist was inferior to that of benzodiazepines. As progabide diminishes both the nigrostriatal dopamine neuron activity and the effects of striatal dopamine receptor activation, a trial in schizophrenic patients was undertaken. Progabide was devoid of any evident antipsychotic action. However a certain improvement in responsiveness to the environment and in social interactions was noticed in hebephrenic and schizoaffective syndromes. This lack of antipsychotic effect of progabide may be a reflection of the weak activity of GABA agonists on limbic dopamine neurons. In these various clinical trials a definite improvement of affect and mood was noted in those patients receiving progabide. In clinical trials in depressed patients progabide produces a significant reduction in depressive symptoms, an action similar to that of imipramine both for the global clinical rating and the HRSD. This antidepressant activity is reflected by the action of progabide in behavioural models of depression such as olfactory bulbectomy, learned helplessness and the sleep-wake cycle.

Reserpinized (1 mg/kg, IP-24 hr) and saline-pretreated male rats were subdivided into groups receiving p-chloroamphetamine (pCA, 5.2 mg/kg, IP), 1-fluoromethyl-2-p-chlorophenylethylamine (FpCA, 5.6 mg/kg, IP), or saline, 90 minutes before the testing of behavior in the open-field and 150 minutes before sacrifice for assay of brain levels of amines. FpCA and pCA produced identical investigative and social patterns of behavior in saline pretreated animals in spite of the fact that pCA reduced serotonin levels whereas FpCA did not. Both pCA and FpCA enhanced dopamine and noradrenaline levels compared to saline controls. The behavioral syndrome common to FpCA and pCA animals was one of increased sitting still, and decreased locomotion and self-grooming while alone, and decreased locomotion, and social behavior but increased sniffing of the environment while in the company of an untreated male rat. Reserpine pretreatment exacerbated this syndrome of inactivity in pCA more than in FpCA rats even though the reserpinized groups did not differ from each other in the concentrations of the three amines.

A retractable wire knife was used to transect medial or lateral components of the MFB or its lateral projections to the striatum and amygdaloid complex. All cuts produced significant depletions of NE, DA, and 5-HT from telencephalon and striatum but little or no effect on hypothalamic NE or 5-HT. Two of our cuts resulted in aphagia and adipsia, the third in hyperphagia and obesity. A detailed correlational analysis of the magnitude and direction of the behavioral and biochemical consequences of our cuts indicated that the ingestive behavior of all of our experimental animals (including animals which had been aphagic and adipsic after surgery as well as animals which were hyperphagic and obese) was positively correlated with the concentration of DA in striatum and telencephalon and negatively correlated with telencephalic 5-HT. Less consistent evidence for facilitatory noradrenergic influences on food intake was also obtained. Our results suggest that the regulation of food intake may be the result of an interaction between telencephalic serotonergic mechanisms and dopaminergic pathways which exert opposite effects on ingestive behavior.

Whole brain levels of 5-HT and NE in audiogenic seizure susceptible DBA mice were compared with those of the nonsusceptible C57BL/6 strain at different ages and in two separate laboratories that used different assay procedures. Contrary to previous reports, there were not significant differences between the susceptible and nonsusceptible animals in whole brain levels of either amine at the age of peak seizure susceptibility. Differential stress associated with capturing the susceptible mice had no effect on brain levels of NE. The data question the suggestion that deficits in brain monoamine transmission capable of being indexed by lower whole brain levels of NE and/or 5-HT play a role in genetically determined susceptibility to audiogenic seizures.

Pregnant HS/Ibg mice received 3 g/kg phenobarbital in their milled food; control dams received unadulterated milled food. Their offspring were tested on ages 22 and 50 days for norepinephrine (NE) and dopamine (DA) levels and DA turnover in the hypothalamus and striatum. Additional groups were tested on days 8, 22, and 50 for brain stem tryptophan hydroxylase (TPH) activity. Hypothalamic DA level among offspring with prenatal PhB exposure (B offspring) was 37% below control level on age 22 days and 61% below control on day 50 (p less than 0.001). Hypothalamic NE level of B offspring was reduced on age 50 days (52%, p less than 0.05) and not on day 22. DOPAC level and DA turnover did not differ among B and control groups. Prenatal exposure to PhB did not have a significant effect on TPH activity. The changes in catecholamines may mediate, at least in part, some of the early barbiturate induced neuromorphological and behavioral changes previously found in our laboratory.

The literature describing the role of serotonin (5-HT) in the mediation of anxiety is a controversial one. Serotonergic involvement in the mechanism of action of two nonbenzodiazepine anxiolytics, buspirone and gepirone, supports a role for serotonin in anxiety. The anticonflict effect of both drugs is blocked by serotonin lesions, and gepirone induces the serotonin syndrome. A shift in the gepirone dose-response curve to the left in serotonin lesioned rats suggests that this may be 5-HT-receptor mediated. Both buspirone and gepirone enhance the acoustic startle response and gepirone's effect is attenuated in serotonin lesioned animals. While other components of buspirone's mechanism of action may suppress the behavioral expression of its serotonergic interactions, results from these studies suggest that serotonin agonist-like activity may be an important mechanism in the actions of a clinically proven nonbenzodiazepine anxiolytic (buspirone), and anxiolytic candidate (gepirone).

Previous reports suggesting that the behavioral response of the guinea pig to phencyclidine (PCP) administration is more similar to the effects of PCP observed in higher animals than those observed in mice and rats prompted us to investigate the effects of PC on spontaneous motor activity and brain biogenic amine levels in the guinea pig. Doses of 2.5 and 5.0 mg/kg PCP were found to significantly elevate spontaneous motor activity; however, 7.5 mg/kg PCP produced highly variable results which were not significantly different from control. The concentrations of tryptophan, serotonin, 5-hydroxyindoleacetic acid, and norepinephrine were measured in the forebrain and hindbrain of previously drug naive animals 30 min after administration of 5 mg/kg PCP. As compared to saline injected control animals, PCP was observed to have no effect on any of the neurochemical determinants measured. Contrary to previous reports, these data suggest that PCP produces behavioral effects in the guinea pig which are not unlike those observed in mice and rats. Furthermore, the effects which we report on spontaneous motor activity are not related to changes in the regional concentration of any of the neurochemical variables which were measured.

Previously, it had been shown that lesions of cerebral 5-hydroxytryptamine (5-HT)-containing neurons and injections of drugs affecting 5-HT synthesis or receptor mediated function would alter amphetamine self-administration in the rat. The present study sought to ascertain whether diets enriched in L-tryptophan (L-TRY), the amino acid precursor to 5-HT, would: elevate cerebral 5-HT concentrations and affect amphetamine self-administration behavior. Diets containing 2.0 and 4.0% L-TRY increased cerebral 5-HT concentrations above those of rats on normal rat chow (0.26% L-TRY). The 4.0% diet elevated brain 5-HT to the same degree in rats exposed to the diet for 1, 2 or 3 days. When normal diets were restored, brain 5-HT concentrations rapidly returned to normal. Animals trained to self-administer d-amphetamine, when given access to the L-TRY enriched diets, significantly reduced their daily amphetamine self-injection during exposure periods. When normal rat chow was restored a delay in recovery to pre-diet amphetamine self-administration was observed: 1 day with the 2.0% L-TRY diet and 2 days with the 4.0% L-TRY diet. The 4.0% L-TRY diet failed to alter saline-frustration responding indicating the diet did not produce decrements in motor performance. When animals were placed on the 4.0% L-TRY diet and allowed access to amphetamine for 1 day then exposed to saline, a profound decrease in saline-frustration responding was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Male Long-Evans rats were kindled via daily electrical stimulation of the left prepyriform cortex. The animals were then used in two experiments which examined the pharmacological basis of cocaine's effects on three mutually exclusive components of the kindled seizure, which were the following: (a) latency to clonus, (b) clonus duration, and (c) duration of AD outlasting clonus. The first experiment compared the effects produced by cocaine HCl (20 mg/kg, IP), lidocaine HCl (20 mg/kg, IP), and amphetamine sulfate (2.5 mg/kg, IP). The results indicated that both cocaine and lidocaine reduced the duration of kindled AD, latency to clonus, and duration of AD persisting beyond clonus, thus suggesting that these cocaine effects are mediated by local anesthetic mechanisms. Only cocaine reduced clonus duration, which suggests that this cocaine effect is not produced by a local anesthetic action. The second experiment examined the effects of cocaine following the administration of three dose levels of the monoamine antagonists haloperidol, prazosin, yohimbine, propranolol, or metergoline (selected for their ability to block dopamine, alpha-1-norepinephrine, alpha-2-norepinephrine, beta-norepinephrine, and serotonin receptors, respectively). The results of this experiment found no support for a monoaminergic contribution to cocaine's effect on clonus latency or AD after clonus. However, results for prazosin, which reduced clonus duration and exhibited an additive effect with cocaine on this variable, suggest that cocaine's norepinephrine action (especially on the alpha-norepinephrine systems) may modulate clonus duration.

Administration of gammahydroxybutyric acid (GHBA) to 4 days old animals caused a dose dependent decrease in locomotor activity. GHBA also induced a marked hypoventilation, irregular breathing and finally apnea, while heart rate was slightly increased. Changes in monoamine neurotransmitter turnover indicated an inhibition of dopamine (DA) neurotransmission. It is concluded that GHBA mechanisms in the neonatal rat brain are biochemically as well as functionally mature at an early age and that the effects on locomotor activity and respiratory regulation at least partly may involve interactions with central DA neurotransmission.

The neurotoxin, 6-hydroxydopamine (6-OHDA), has been used to selectively destroy dopamine containing neurons in discrete brain regions. Lesions of the nucleus accumbens with this neurotoxin decrease or eliminate cocaine and amphetamine self-administration and either increase or do not affect opiate self-administration in rats with unrestricted access to food and water. This study reports the effects of 6-OHDA lesions of the nucleus accumbens on responding maintained by food, water or morphine (3.3 mg/infusion). Six male rats with continuous access to three response levers were trained on a concurrent chained, fixed-ratio 1, fixed-ratio 9 schedule of reinforcer presentation. After stable patterns of responding were maintained by the three reinforcers, dose-effect curves for morphine were determined by substituting other doses of morphine or vehicle for 24-hour periods. Bilateral sham vehicle or 6-OHDA lesions of the nucleus accumbens were then completed and the effects of the lesion on food, water and morphine intake determined. Dose-effect evaluations were repeated after the lesion. The 6-OHDA lesions did not significantly affect responding maintained by food, water or morphine. The absence of an effect is most likely not the result of an insensitive baseline since other neurotoxin lesions produce long-term and selective decrements in morphine self-administration without affecting food and water responding. Like so many other manipulations, the magnitude of the effect that a neurotoxin lesion can exert on behavior may depend on the specific procedures that are used to maintain responding.

It was found that in rats a gradient of retrograde amnesia for a passive avoidance response could be established when carbon dioxide (CO2) was used as the amnesic agent. The extent of passive avoidance increased as the period between application of a mild foot shock and CO2 treatment was increased. The amnesia gradient was found to cover a period of at least 60 min. Changes in hippocampal serotonin metabolism parallelled the amnesia gradient. Thus, the concent increased. The changes in hippocampal noradrenaline and dopamine did not correlate with the amnesia gradient.

Monoamine levels were measured by high performance liquid chromatography with electrochemical detection in seven brain regions of three models of experimentally-induced muricide (mouse-killing behavior) in rats (bilateral olfactory bulbectomized rats: OB rats, midbrain raphe nuclei lesioned rats: Raphe rats and nucleus accumbens lesioned rats: Acc rats). Noradrenaline (NA) levels in the lateral hypothalamus (LH) and ventromedial hypothalamus (VMH), 3,4-dihydroxyphenylacetic acid (DOPAC) levels in LH and homovanillic acid (HVA) levels in the frontal cortex (FC) were increased in all three muricide models. In LH, serotonin (5-HT) levels increased in Acc rats and the 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio was reduced in OB rats. But in VMH an increase in NA level was not accompanied by any changes of other amines in three muricide models except for 5-HT and 5-HIAA in Raphe rats. In the mamillary body (MB), NA level was increased and 5-HIAA/5-HT ratio was decreased in both OB and Acc rats. Monoamine changes in the amygdaloid nuclei were different in three muricide models, suggesting that the role of monoamines in various nuclei of the amygdala may be different in each muricide model. The present findings suggest that both noradrenergic (LH and VMH) and serotonergic function (LH and MB) may play an important role in exhibiting muricide of OB, Raphe and Acc rats, while dopaminergic function (LH and FC) may be related rather to hyperirritability elicited in these three muricide models.

Maternal exposure to delta 9-tetrahydrocannabinol (THC), the major psychoactive constituent in marihuana, or to the non-psychoactive cannabinol (CBN) or cannabidiol (CBD) alters endocrine functions and concentrations of brain biogenic amines in their male offspring. Prenatal CBN exposure on day 18 of gestation resulted in decreased plasma FSH levels, testicular testosterone (T) concentrations, and seminal vesicles weights, but increased plasma levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) post-castration in adulthood. Prenatal exposure to THC significantly enhanced the responsiveness of the testes to intratesticular LH injection in vivo and tended to increase human chorionic gonadotropin (hCG)-stimulated T production by decapsulated testes in vitro. In the CBN-exposed mice, hCG-stimulated T production was enhanced, while CBD exposure had no effect. Prenatal THC exposure altered the negative feedback effects of exogenous gonadal steroids in castrated adults, with lower plasma T and FSH levels after 20 micrograms T than in castrated controls. In contrast, CBD-exposed mice had higher levels of LH in plasma post-castration. In CBN-exposed adults, two weeks post-castration the concentration of norepinephrine (NE) and dopamine (DA) in hypothalamus and remaining brain were reduced, while levels of serotonin (5-HT) and its metabolite, 5-HIAA, were elevated compared to that in castrated OIL-controls. Prenatal CBD-exposure also reduced NE and elevated 5-HT and 5-HIAA, but did not affect DA levels post-castration. Concentrations of brain biogenic amines were not influenced by prenatal THC exposure in the present study. A single prenatal exposure to psychoactive or non-psychoactive components of marihuana results in long term alterations in the function of the hypothalamo-pituitary-gonadal axis. Changes in the concentrations of brain biogenic amines may be related to these effects of prenatal cannabinoids on endocrine function in adult male mice.

Rats will initiate self-administration of d-amphetamine and achieve a stable injection rate within 7-10 days. Animals injected intraventricularly with 5,7-dihydroxytryptamine, which selectively destroys 5-hydroxytryptamine-containing neurons, consistently self-injected larger amounts of d-amphetamine from the first day of training, but the acquisition of a stable rate of drug self-administration was not altered. Bilateral microinjection of 5,7-dihydroxytryptamine into nucleus accumbens failed to alter either the acquisition of d-amphetamine self-administration or the maintenance of a stable rate of injection.

Chlordiazepoxide (CDP; 0.4 mg/kg/day, per os) was administered to cats during either the acquisition (CDP 21-22 days) of a go-nogo successive discrimination task (SD) or the performance (CDP 10 days) of the previously learned SD task. Endogenous levels of serotonin, 5-hydroxyindoleacetic acid, noradrenaline and dopamine were assayed in 12 brain areas, in trained as well as in untrained cats. This study has shown that (1) CDP strongly impaired the acquisition but not performance of the SD task, revealing a dissociation of the effects of CDP on these two stages of training; (2) the CDP administration, as well as the SD training, produced regional changes in brain levels of biogenic amines, suggesting the involvement of particular monoaminergic neurons in the behavioral effects of CDP and in operant behavior; and (3) in particular brain areas, interactions were observed between the effects of the SD training and those of the CDP administration on monoamines, indicating that the behavioral state may interfere with the neurochemical effects of CDP.

The effects of papaverine on haloperidol-induced catalepsy and apomorphine-induced stereotypy as well as brain monoamines concentrations in rats were studied. Papaverine increased cataleptogenic effect of haloperidol whilst reduced stereotypy induced by apomorphine. Slight but significant decrease in brain dopamine concentration was observed in rats treated with papaverine. The present study indicates that papaverine has influences upon dopaminergic mechanisms in the brain.

The time course of amnesia for a one-trial passive avoidance response after treatment with carbon dioxide (CO2) was studied. Amnesia developed gradually over the first 4 hr following the amnesic treatment. Once established, amnesia remained during a 4 week test period. Previously, we reported that acquisition of the passive avoidance response was attended with a rise in the hippocampal concentration of serotonin 24 hr later and that this rise was not observed when acquisition was followed by amnesic treatment. In the present study, it was found that a rise in hippocampal serotonin parallelled the transient retention of the avoidance response 2 hr after amnesic treatment. However, 2 weeks after acquisition and amnesic treatment no changes in hippocampal monomine metabolism could be detected. Hippocampal noradrenaline did not correlate with avoidance and amnesia.

The effect of treatment with carbon dioxide (CO2) on the performance of rats 24 hr after receiving a foot shock in a passive avoidance task was studied. Foot shock induced avoidance. Carbon dioxide produced retrograde amnesia for the foot shock induced avoidance response. Changes in brain monoamine metabolism were studied in groups of rats which had been treated with CO2, foot shock or foot shock +CO2. The rats were killed 24 hr after treatment. Changes mainly occurred in the brain stem and hippocampus. In the rats which had received foot shock alone, brain stem and hippocampal serotonin concentration were raised. This rise was not observed when the foot shock was followed by CO2 treatment. Furthermore, it was found that there was an increased release of noradrenaline in those rats subjected to foot shock alone but a decreased release of this amine in the group which received foot shock followed by CO2. It is suggested that the amnesic effect of CO2 parallels changes in brain serotonin and noradrenaline metabolism.

The tritiated adrenergic antagonists prazosin ([3H]PRZ) and idazoxan ([3H]IDA, or RX-781094) bind specifically and with high affinity to alpha 1- and alpha 2-adrenoceptors respectively, and were used to measure adrenoceptors in membrane preparations obtained from the cerebral cortex of Jaculus orientalis. Membrane preparations were also obtained from a group of cold exposed animals, to determine whether these adrenoceptors could be modified by a thermic stress. The density of receptors (Bmax; maximum binding capacity) and the dissociation constant (Kd 25 degrees C) were estimated by iterative modelling, and by using the procedure of Hill. After acute cold exposure (16 hr, 5 degrees C) there was a decrease in the affinity of the alpha 1-adrenoceptors, as judged by the Kd 25 degrees C for [3H]PRZ, with no changes in the Bmax. The alpha 2-sites did not show any significant changes, as revealed by [3H]IDA binding. Pretreatment of the membrane preparations from control animals with the disulfide and sulfhydryl reactives DL-dithiothreitol, 5,5'-dithiobis-(2-nitrobenzoic acid) and N-ethylmaleimide decreased specific [3H]PRZ and [3H]IDA binding, with minor changes in non-specific counts, indicating that the fixation of these ligands was to the receptor proteins. The endogenous cortical monoamine contents were also determined in the frontal cerebral cortex of these same animals, using high performance liquid chromatography with electrochemical detection. The catecholamine levels and their major metabolites were found to be stable in the cortex after the acute thermic stress, but there was a marked reduction in serotonin with a normal content in 5-hydroxyindole-3-acetic acid.

The alteration of monoamines and their metabolites in the brain in response to hypothermia was studied using rats subjected to a cold and immobilization stress. The experiments were designed to compare the responses in the "hypothermal" rats with those in the "normothermal" ones which received the same stress except for the change in body temperature. It has been found that the contents of norepinephrine (NE) and 5-hydroxytryptamine (5-HT) in various cerebral regions were significantly decreased during hypothermia. These decreases were readily reversed by the rewarming of animals. Moreover, the increase in the content of 5-hydroxyindole-3-acetic acid (5-HIAA), the metabolite of 5-HT, was also detected in some cerebral regions where the decrease of 5-HT was observed. Although the dopamine (DA) contents in all cerebral regions examined were found to be unaltered, its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and/or homovanillic acid (HVA) contents in most regions in the brain showed a significant elevation during and/or after the occurrence of hypothermia. These results suggest that the metabolic turnovers of 5-HT and DA in various cerebral regions may be accelerated during hypothermia.

Application of footshock during the acquisition trial of a one-trial passive avoidance test is associated with a rise in the concentration of serotonin in the hippocampi of rats 24 hr after termination of the acquisition trial. Rats subjected to amnesic treatment with carbon dioxide (CO2) immediately after footshock do not show this rise in the hippocampal concentration of serotonin. The ACTH-analogues, ACTH 4-10 and ACTH 4-10 (7D-Phe), alleviate CO2-induced amnesia for the passive avoidance response when administered 1 hr before retrieval test 24 hr after acquisition. These peptides do not have anti-amnesic activity when given before acquistion. Another ACTH-analogue, ACTH 11-24 does not affect amnesia, given before either the acquisition or the retrieval test. The anti-amnesic effect of ACTH 4-10 AND ACTH 4-10 (7D-Phe), was correlated with a rise in the hippocampal serotonin concentration similar to that observed in non-amnesic animals. Pre-acquisition treatment with ACTH 4-10 or administration of ACTH 11-24 did not affect hippocampal serotonin concentrations. Changes in the hippocampal concentrations of noradrenaline, dopamine, tryptophan and tyrosine were not related to the behavioural activity of any of the peptides. It is suggested that alterations in hippocampal serotonin metabolism 24 hr after acquisition of a passive avoidance response are associated with the retrieveability of the passive avoidance response.

The acute effects of ethanol, barbital, and lorazepam on the synthesis and metabolism of brain monoamines were studied in the AT (Alcohol Tolerant) and ANT (Alcohol Nontolerant) lines of rats, which have been selected for differential motor impairment after ethanol administration. The ethanol-sensitive ANT rats are also more sensitive than the ethanol-insensitive AT rats to the motor impairment caused by barbital and lorazepam. Ethanol increased, whereas barbital and lorazepam decreased, the synthesis of catecholamines in several regions of the brain. Ethanol did not affect the formation of DOPAC, whereas barbital and lorazepam reduced it. Similarly, the accumulation of 5-HTP was increased after administration of ethanol, but was decreased after administration of barbital or lorazepam. Ethanol, barbital and lorazepam decreased the formation of 5-HIAA. The rat lines did not differ in any of these responses. Some differences could, however, be demonstrated between the AT and ANT rats in the effects of the three drugs on the levels of the brain monoamines. Although the importance of these differences in the differential sensitivity to these drugs between the two lines is difficult to determine, the role of central monoaminergic mechanisms cannot be excluded. These findings also suggest that the motor impairment induced by ethanol, barbiturates, and benzodiazepines is probably not primarily based on the monoaminergic systems.