A comparative study of the effects of cinnarizine, sulpiride and thiethylperazine on vestibular nystagmus in rabbits

The effects of cinnarizine, sulpiride, thiethylperazine and a placebo on vestibular nystagmus in rabbits were investigated. The nystagmus was provoked by means of a torsion swing. A suppressive effect was shown by all drugs and not by the placebo. A fast and strong effect was seen after the administration of sulpiride, however this effect decreased after 1 h. The onset of the effect of cinnarizine was slower but the effect lasted longer. Thiethylperazine had a clear suppressive effect but less strong and shorter than that of the other two drugs.     

Pertussis toxin blocks the action of morphine, norepinephrine and clonidine on isolated guinea-pig ileum

Administration of pertussis toxin (60 μg/kg i.p.) to guinea-pigs blocked the ability of morphine, norepinephrine and clonidine to inhibit electrically stimulated contractions in the isolated ileum. The toxin reached its maximum effect 6 days after its administration. The effect of the toxin was reversible; a slow but full recovery of the response to morphine was observed in ilea from guinea-pigs treated with toxin 18 days before the experiment. It is suggested, based on the known action of pertussis toxin, that inhibition of adenylate cyclase through Ni (guanine-nucleotide regulatory protein) is involved in the acute action of morphine, norepinephrine and clonidine in the motoneurons of the myenteric plexus of the ileum.     

S(−)DP-5,6-ADTN as an in vivo dopamine receptor ligand: Relation between displacement by dopamine agonists and their pharmacological effects

Summary The use of (–)DP-5,6-ADTN as a non-radio-actively labeled ligand for an in vivo DA receptor assay is described and compared with racemic DP-5,6-ADTN, previously used for that purpose. The effects of four DA agonists (NPA, bromocriptine, DP-7-OH-ATN and 3-PPP) on the specific (–)DP-5,6-ADTN binding are related to their potencies to decrease striatal HVA concentrations and to induce stereotypy in rats. NPA and DP-7-OH-ATN caused a maximal decrease in HVA levels, when only a fraction of the receptors were occupied, while the occurrence of stereotypy was associated with a high receptor occupation, reflecting the higher affinity of these agonists for presynaptic than for postsynaptic receptors. Bromocriptine did not show this effect, as the dose-response relationships for HVA decrease, for induction of stereotypy and for the decrease in specific (–)DP-5,6-ADTN binding were all virtually equal to each other. While NPA and bromocriptine behaved as full postsynaptic agonists, in that maximal stereotyped behavior was observed after high doses, DP-7-OH-ATN was found to be a partial postsynaptic agonist, as it did not induce maximal stereotypy at a maximal receptor occupation. Racemic 3-PPP only caused a state of hypoactivity, but did neither affect specific (–)DP-5,6-ADTN binding nor striatal HVA levels. Our results are discussed in view of theories on the relation between receptor occupation and pharmacological effects and it is concluded that the in vivo receptor binding method using (–)DP-5,6-ADTN is a very useful tool for such investigations.     

Method for the rapid determination of norepinephrine,dopamine, and serotonin in the same brain region

A method is presented for the fluorometric analysis of norepinephrine, dopamine and serotonin. This procedure is a combination of an unpublished catecholamine assay developed by Hogans and of the o-phthaldialdehyde serotonin reaction reported by Maickel and Miller [9]. This procedure should greatly facilitate the correlation of neurotransmitter levels in brain regions with changes in behavior produced by experimental manipulations.     

Behavioral evidence implicating dopamine in sensorimotor arousal and norepinephrine in the sedative effects of antidepressant drugs

The effects of acute and chronic antidepressant treatment on acoustic startle were evaluated in three experiments. Administration of 2.5–10.0 mg/kg desipramine, amitriptyline, and nortriptyline depressed acoustic startle responding after repeated sensory stimulation. In contrast to the tricyclic drugs, the serotonin reuptake inhibitor zimelidine increased acoustic startle, and inhibition of dopamine reuptake following acute nomifensine and bupropion administration did not influence startle reactivity in the doses examined. The response reducing effects of desipramine and amitriptyline persisted following chronic exposure to these drugs, and these findings were discussed in relation to the inhibitory actions of the tricyclics on locus coeruleus neurons. A second major finding in this study was that animals challenged withd-amphetamine during desipramine and amitriptyline withdrawal showed a facilitated startle response. Enhanced startle reactivity to amphetamine was also observed following long-term exposure to iprindole, and a withdrawal hyperactivity of acoustic startle was evident after chronic treatment with amoxapine, bupropion, and nomifensine. These results agree with evidence that repeated administration of antidepressants increases dopamine neurotransmission which modulates sensorimotor arousal.     

Metoclopramide as pharmacological tool to assess vasopressinergic co-activation of the hypothalamus–pituitary–adrenal (HPA) axis: A study in healthy volunteers

The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus–pituitary–adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200 mg function test. Co-activation was investigated by administering metoclopramide 10 mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis.     

The effect of tricyclic antidepressants and neuroleptics on the peripheral and central action of norepinephrine in reserpine-treated mice

The effect of exogenous norepinephrine on the ptosis induced by reserpine and its modification by tricylic antidepressants and neuroleptics were studied in reserpine-pretreated mice.S.c. injection of norepinephrine (0.3–5 mg/kg) reversed dose-dependently the ptosis induced by reserpine. The maximal effect was obtained 15 min after norepinephrine administration. Tricyclic antidepressants (2.5 and 5 mg/kg i.p.) potentiated the effect of norepinephrine. In contrast neuroleptics (1 and 5 mg/kg i.p.) antagonized it.Intracerebral injection of norepinephrine (5–20 μg) also reversed dose-dependently the ptosis induced by reserpine, and the maximal effect was obtained within 5 min. Tricyclic antidepressants potentiated the effect of norepinephrine, but neuroleptics antagonized it.Among tricyclic antidepressants, the potentiating action of secondary amines was stronger than that of tertiary amines. Chlorpromazine blocked the action of norepinephrine more strongly than did the same dose of haloperidol.     

The role of brain norepinephrine in the anorexic effects of dextroamphetamine and monoamine oxidase inhibitors in the rat

The effects of d-amphetamine on food and water intake and brain monoamine concentrations in rats that had been deprived of food and water for 24 h were compared with those of two MAO inhibitors: tranylcypromine which has prominent amphetamine-like activity; and, pargyline which does not. All drugs produced dose-related depressions of food and water intake. The anorexic effects of the MAO inhibitors were correlated, over a 16-fold dose range, with elevated levels of norepinephrine, dopamine and serotonin. The anorexic effect of d-amphetamine was blocked by -methyltyrosine, an inhibitor of catecholamine synthesis. -Methyltyrosine failed to block the depression of food and water intake caused by the MAO inhibitors, although the rise in catecholamine levels was prevented. It was concluded that the mechanisms by which d-amphetamine produces anorexia may differ from those of the MAO inhibitors. Central adrenergic mediation appears to play a role in the anorexic activity of d-amphetamine, but may not be essential for the anorexic effect of tranylcypromine and pargyline.Publication No. 1023 of the Division of Basic Health Sciences of Emory University. This investigation was suported by NIMH Grant MH 12870-03.Postdoctoral trainee of NIH Graduate Pharmacology Training Grant GM-179 during part of this work.     

Clozapine: dopamine D1 receptor agonism in the prefrontal cortex as the code to decipher a Rosetta stone of antipsychotic drugs.

A large number of ligand binding studies have shown that clozapine has a number of receptor affinities, including those of the dopamine (DA) D1 and D2 receptor families. The study of intrinsic efficacy at these receptors is less straight-forward. In the experiments summarised here, evidence is presented that clozapine behaves as an agonist at DA D1 receptors. Thus, the hypothermia produced by clozapine (2.5 mg kg(-1)) in the rat is fully antagonised by either of the selective DA D1 receptor antagonists SCH-23390 (0.1 mg kg(-1)) or NNC-687 (4 mg kg(-1)). These results provide an intriguing explanation for the clinical profile of clozapine as an atypical antipsychotic drug. Thus, there are supporting clinical and laboratory observations implicating DA D1 receptors in the prefrontal cortex in cognitive functions. Finally, clozapine displays features with regard to extrapyramidal motor mechanisms, and seizure thresholds, that could be explained by its properties as a DA D1 receptor agonist.     

Differential involvement of the norepinephrine, serotonin and dopamine reuptake transporter proteins in cocaine-induced taste aversion

Despite the impact of cocaine's aversive effects on its abuse potential, the neurochemical basis of these aversive effects remains poorly understood. By blocking the reuptake of the monoamine neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) into the presynaptic terminal, cocaine acts as a potent indirect agonist of each of these systems. The following studies attempted to assess the extent of monoaminergic mediation of cocaine's aversive effects using conditioned taste aversion (CTA) learning [Garcia, J., Kimeldorf, D.J., Koelling, R.A., Conditioned aversion to saccharin resulting from exposure to gamma radiation. Science 1955;122:157-158.]. Specifically, Experiment 1 assessed the ability of selective monoamine transporter inhibitors, e.g., DAT (vanoxerine), NET (nisoxetine) and SERT (fluoxetine), to induce taste aversions (relative to cocaine). Only the NET inhibitor approximated the aversive strength of cocaine. Experiment 2 compared the effects of pretreatment of each of these transport inhibitors on the development of a cocaine-induced CTA. Pretreatment with nisoxetine and fluoxetine both attenuated cocaine-induced aversions in a manner comparable to that produced by cocaine itself. The DAT inhibitor was without effect. Combined, the results of these investigations indicate little or no involvement of dopaminergic systems in cocaine's aversive effects while NE appears to contribute most substantially, with a possible modulatory involvement by serotonin.     

The noradrenergic cyclic AMP generating system in the limbic forebrain: pharmacological characterization in vitro and possible role of limbic noradrenergic mechanisms in the mode of action of antipsychotics.

The cyclic AMP generating system in slices of the rat limbic forebrain was investigated. In consists of: (u) A noradrenergic system which responds to norepinephrine (NE) and isoproterenol. Though the rise of the nucleotide elicited by isoproterenol is more rapid than that caused by NE, the maximal effect is less than half of that induced by NE; (2) an adenosine-dependent system. The noradrenergic cyclic AMP generating system in the limbic forebrain displays a number of properties of a central NE receptor: it develops supersensitivity to NE and isoproterenol following prolonged deprivation of NE at postsynaptic sites (chronic treatment with reserpine or chemosympathectomy with 6-hydroxydopamine). When noradrenergic terminals are protected from 6-hydroxydopamine by desmethylimipramine, the responses to NE are not enhanced. Responses to NE are blocked by both propranolol and phentolamine, while responses to isoproterenol are blocked by propranolol but not by phentolamine. The adenosine-dependent system does not develop supersensitivity after central chemosympathectomy and is not blocked by either alpha- or beta-antagonists. While not altering the basal level of the nucleotide, clinically effective antipsychotic drugs caused a dose-dependent inhibition of the limbic noradrenergic cyclic AMP response with clozapine and pimozide being particularly potent (IC50 0.06 and 0.08 muM, respectively). Antipsychotic drugs do, however, not affect cyclic AMP responses elicited by adenosine. The results are compatible with the view that the central NE receptor is closely related to or may be an integral part of an adenylate cyclase system and that its blockade in the limbic forebrain by antipsychotic drugs may contribute to their therapeutic action.     

Effect of an amnesic dose of reserpine, syrosingopine or guanethidine on the levels of whole brain dopamine and norepinephrine in the mouse

The effect of p-chlorophenylalanine (p-CPA) on testosterone (T) hypothalamic metabolism and on plasma levels of T, estradiol (E2) and corticosterone (B) was studied in male rats and rabbits: both were sacrificed 48 hours after the last injection. In both rats and rabbits a significant increase in T leads to E2 transformation (aromatization) was evident after p-CPA treatment. This increase could be responsible for the stimulatory effect on sexual behavior which has been described in literature following p-CPA administration. Moreover p-CPA caused a decrease of circulating T and E2 in both species.     

Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors

In the introductory section an overview is given of the strategies which have been proposed in the search for side-effect free antipsychotics. Special attention is paid to the role of predominant 5HT₂ receptor blockade over D₂ blockade. Whereas D₂ receptor blockade seems to be essential for the treatment of positive symptoms of schizophrenia, it also underlies the induction of extrapyramidal side effects (EPS). Predominant 5HT₂ receptor blockade may reduce the EPS liability and can ameliorate negative symptoms of schizophrenia. We further report a nearly complete list of neuroleptics that are on the European market and eight new antipsychotics that recently entered clinical trial, 5HT₂ and D₂ receptor binding affinity (K_i values) and the rank order in affinity for various neurotransmitter receptor subtypes are also discussed. For the eight new antipsychotics and for six reference compounds the complete receptor binding profile (including 33 radioligand receptor binding and neurotransmitter uptake models) is reported. Furthermore, for a series of 120 compounds the relative affinity for D₂ receptors and D₃ receptors (a recently cloned new dopamine receptor subtype) is compared. Finally, original findings are reported for the new antipsychotic risperidone and for haloperidol and clozapine on the in vivo occupation of neurotransmitter receptors in various brain areas after systemic treatment of rats or guinea pigs. The receptor occupation by the drugs was measured ex vivo by quantitative receptor autoradiography. The receptor occupancy was related to the motor activity effects of the test compounds (measurements were done in the same animals) and to the ability of the drugs to antagonize various 5HT₂ and D₂ receptor mediated effects. With risperidone a high degree of central 5HT₂ receptor occupation was achieved before other neurotransmitter receptors became occupied. This probably co-underlies the beneficial clinical properties of the drug. Antagonism of the various D₂ receptor-mediated effects was achieved at widely varying degrees of D₂ receptor occupancy, from just about 10% to more than 70%. For therapeutic application it may be of prime importance to carefully titrate drug dosages. Antipsychotic effects may be achieved at a relatively low degree of D₂ receptor occupancy at which motor disturbances are still minimal. With drugs such as risperidone that produce shallow log dose-effect curves, differentiation between the various D₂ receptor mediated effects may be made more easily, allowing EPS-free maintenance therapy of schizophrenic patients.     

Fish somatostatin sst3 receptor: comparison of radioligand and GTPgammaS binding, adenylate cyclase and phospholipase C activities reveals different agonist-dependent pharmacological signatures

1 The fish somatostatin receptor 3 (fsst3) is one of the few somatostatin (SRIF) receptors cloned from a non-mammalian species so far. Here we extended our earlier characterization of this receptor by investigating the guanine nucleotide sensitivity of agonist radioligand binding at the fsst3 receptor recombinantly expressed in CCL39 (Chinese hamster lung fibroblast) cells. Further, we measured somatostatin (SRIF) and cortistatin (CST) analogues stimulated GTPgammaS binding, inhibition of forskolin-stimulated adenylate cyclase (FSAC) and stimulation of phospholipase C (PLC) activities. The present transductional data were then compared with previous radioligand binding and/or second messenger features determined for fsst3 and/or human SRIF receptors (hsst2, hsst3 and hsst5). 2 The GTP analogue guanylylimidodiphosphate (GppNHp) inhibited binding of [125I]CGP 23996 and [125I][Tyr3octreotide by 72 and 83% suggesting preferential labelling of G-protein-coupled fsst3 receptors. By contrast, [125I]LTT-SRIF28 and [125I][Tyr10]CST14 binding was rather GppNHp insensitive (42 and 35% inhibition) suggesting labelling of both coupled and non-coupled receptor states. These results might explain the apparent higher receptor densities determined in saturation experiments with [125I]LTT-SRIF28 and [125I][Tyr10]CST14 (4470 and 4030 fmol mg(-1)) compared with [125I]CGP 23996 and [125I][Tyr3]octreotide (3420 and 1520 fmol mg(-1)). 3 SRIF14 (10 microm)-stimulated specific [35S]GTPgammaS binding by three-fold; SRIF28 and octreotide displayed full agonism, whereas most other ligands displayed 60-80% intrinsic activity compared with SRIF14. SRIF14 and SRIF28 inhibited forskolin-stimulated AC (FSAC) activity by 60%; all tested ligands except BIM 23056 inhibited FSAC with comparable high intrinsic activities. SRIF14 stimulated PLC activity five- to six-fold, as determined by measuring total [3H] IP(x) accumulation; it was rather insensitive to pertussis toxin (PTX, 100 ng ml(-1), 21% inhibition), which suggests the G(q)-family proteins couple to PLC activity. SRIF14, SRIF28 and [Tyr10]CST14 showed full agonism at PLC, whereas all other ligands behaved as partial agonists (20-70% intrinsic activity). BIM 23056, which showed weak partial or no agonism, antagonized SRIF14-induced total [3H]-IP(x) production (pK(B) = 6.83), but failed to block competitively agonist-stimulated [35S]GTPgammaS binding or agonist-induced inhibition of FSAC activity. 4 Comparison of the pharmacological profiles of fsst3 receptors established in GTPgammaS binding, FSAC inhibition and PLC stimulation resulted in low correlations (r = 0.410-0.594). Both rank orders of potency and rank orders of relative efficacy varied in the three second messenger experiments. Significant, although variable correlations were obtained comparing GTPgammaS binding and inhibition of FSAC activity with previously reported affinity profiles of [125I]LTT-SRIF28, [125I][Tyr10]CST14, [125I]CGP 23996, [125I][Tyr3]octreotide (r = 0.75-0.83; 0.68-0.89). By contrast, the PLC stimulation and radioligand-binding profiles did not correlate. 5 Comparison of the functional data (GTPgammaS binding, FSAC inhibition, PLC stimulation) of fsst3 receptors with those of human sst2, sst3, sst5 receptors expressed in CCL39 cells resulted in highest correlation with the hsst5 receptor (r = 0.94, 0.97, 0.49) > hsst2 (0.80, 0.50, n.d.) > hsst3 (0.25, 0.19, 0.17). 6 In summary, fsst3 receptors expressed in CCL39 cells are involved in signalling cascades similar to those reported for mammalian SRIF receptors, suggesting SRIF receptors to be highly conserved in evolution. Binding and functional data showed highest similarity of fsst3 receptors with the human sst5 receptor subtype. Different affinities, receptor densities and GppNHp-sensitivities determined with the four radioligands (agonists) are assumed to results from ligand-specific states of the fsst3-ligand complex. The differences in the rank orders of potency and relative efficacy in the various signalling cascades may be explained by agonist-induced receptor trafficking.     

The role of general pharmacological studies and pharmacokinetics in the evaluation of drugs (2): Pharmacokinetics

Pharmacokinetics studies are performed to clarify the absorption, distribution, metabolism, and excretion of drug candidates. The data are not only useful for the planning of animal toxicity studies and pharmacological studies but also required for establishing the efficacy and safety in humans by indicating the pharmacokinetically appropriate drug formulation and drug usage. Identification of the major metabolic enzymes related to the major metabolism of a drug is also essential for predicting pharmacokinetic drug interactions. Use of human tissues in drug metabolism studies becomes more and more important for rational and efficient drug development. It is necessary to establish an organization in Japan for supplying human tissues originating from the Japanese population.     

Distribution of 5-ht(1E) receptors in the mammalian brain and cerebral vasculature: an immunohistochemical and pharmacological study

BACKGROUND AND PURPOSE

The 5-ht_1E receptor is highly expressed in the human brain and its structure is conserved in humans, suggesting an important physiological role for 5-ht_1E receptors. However, neither the function nor the distribution of this receptor has been characterized in the mammalian brain.

EXPERIMENTAL APPROACH

Rats and mice lack the 5-ht_1E receptor gene; thus, we used guinea pig brain tissue and immunofluorescent staining techniques to provide the first specific localization of 5-ht_1E receptors in the mammalian brain.

KEY RESULTS

High levels of 5-ht_1E receptors are detected in olfactory bulb glomeruli as well as the molecular layer of the dentate gyrus (DG). In DG membranes, BRL54443, a 5-ht_1E/5-HT_1F agonist, selectively stimulated 5-ht_1E receptors and potently inhibited forskolin-dependent cAMP production (IC₅₀= 14 nM). The staining pattern of 5-ht_1E receptors in brain tissue suggests that this receptor is expressed predominantly in neurons rather than in glia. Additionally, 5-ht_1E receptors were detected in the adventitial layer of cerebral arteries but not in the microvasculature, venous tissue or other brain arteries.

CONCLUSIONS AND IMPLICATIONS

These observations should help to predict clinical effects of 5-ht_1E-selective drugs. For example, the stimulation of 5-ht_1E receptors and subsequent inhibition of adenylate cyclase activity in the DG suggests that 5-ht_1E receptors may mediate regulation of hippocampal activity by 5-HT, making it a possible drug target for the treatment of neuropsychiatric disorders characterized by memory deficits (such as Alzheimer''s disease) or as a target for the treatment of temporal lobe epilepsy.     

The role of dopamine D3, 5-HT2A and 5-HT2C receptor variants as pharmacogenetic determinants in tardive dyskinesia in African-Caribbean patients under chronic antipsychotic treatment: Curacao extrapyramidal syndromes study IX

Tardive dyskinesia (TD) is associated with polymorphisms of the dopamine D(3), serotonin 2A and 2C receptors (DRD3, HTR2A and HTR2C, respectively). This study investigated the possible relationship between TD and the polymorphisms Ser9Gly (DRD3), 102T>C (HTR2A), -1438G>A(HTR2A) and Cys23Ser (HTR2C) in African-Caribbean inpatients. One hundred and twenty-six patients under chronic antipsychotic treatment were genotyped. The assessment of TD was carried out with the abnormal involuntary movement scale (AIMS). The relationships between the carriership of the least frequent alleles and the respective orofaciolingual dyskinesia (TDof) (sum of the items 1-4 of the AIMS), limb-truncal dyskinesia (TDlt) (sum of items 5-7 of the AIMS) and TD (sum of items 1-7 of the AIMS) were analyzed with ANCOVA, comparing means with age as a covariate and stratification for carriers and non-carriers of the mutations. In addition, we conducted pre-planned t-tests to compare AIMS values of carriers of the combinations of alleles versus the corresponding non-carriers. In the study population, females with 9Ser carriership exhibited higher AIMS values than non-carriers. Male subjects with 9Ser carriership in combination with 23Ser or -1438A carriership exhibited higher AIMS values. In male patients also, the combination of 23Ser and -1438A carriership increased TD. The study clearly shows that the African-Caribbean population differs from the Caucasian population with regard to the association of TD with the polymorphisms studied and suggests that the association of TD with the studied polymorphisms of the 5-HT(2C) and probably of the 5-HT(2A) receptor are the result of a changed susceptibility of the patients, independent of the action of the antipsychotics on these receptors.     

Extracellular dopamine, norepinephrine, and serotonin in the ventral tegmental area and nucleus accumbens of freely moving rats during intracerebral dialysis following systemic administration of cocaine and other uptake blockers

Extracellular levels of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) were measured by microdialysis in conscious rats equipped with dual probes, one in the ventral tegmental area (VTA) and another one in the contralateral nucleus accumbens (NACC). Dialysate content of all amines in both regions was essentially abolished by local infusion of tetrodotoxin (1 μM) or Ca²⁺-free buffer. Injection of the selective DA uptake blocker GBR 12935 (15 mg/kg IP) increased DA, as well as NE and, to a lesser extent, 5-HT in the VTA; it increased DA more than 5-HT in the NACC. The selective NE uptake blocker desipramine (10 mg/kg IP) increased NE but also 5-HT in the VTA and NACC; the DA level was persistently enhanced in the VTA, whereas in the NACC it initially rose and then fell below baseline value. The selective 5-HT uptake blocker citalopram (15 mg/kg IP) was generally more effective in elevating dialysate level of 5-HT than that of other amines in both regions. Cocaine (20 mg/kg IP) was non-selective in enhancing all three amines in both regions. There is considerable crosstalk between monoamine systems occurring upon systemic administration of uptake blockers, and the VTA and NACC are notably different in the time course of the DA effect (long-lasting versus transient). Received: 25 February 1997 /Final version: 2 June 1997