Neuronal Uptake Of Serotonin Research Articles

Quantitative and histological evaluations for the potentiality of pilocarpine on tramadol induced xerostomia and structural alterations in Rats parotid gland

Tramadol is a centrally acting analgesic with weak opioid agonist properties, which also has monoaminergic activity, exerted via inhibition of neuronal uptake of serotonin and norepinephrine. Tramadol is generally well tolerated and the most common adverse events are nausea, dizziness, drowsiness, sweating, vomiting and dry mouth. The effect of intraperitoneal injection of tramadol and pilocarpine were studied in rats on the flow of saliva, histological and histochemical change in the parotid salivary gland. The rats were divided into three groups, first group, rats received saline and used as control. The second group treated with 10 mg tramadol hydrochloride for three days. The third group treated with tramadol hydrochloride for three days followed with 1 mg pilocarpine. The rats were sacrificed at the fourth day after the end of experimental procedure. The administration of tramadol caused decreased in salivary flow rate by approximately 60 %. The parotid histopathological changes include vacuolation and atrophy of acini and excessive widening of the interstitial tissue area which are replaced by extensive fibrosis fibrosis mostly associated with the degenerated ducts and acini and their replaced by inflammatory cells.

New Serotonin-Norepinephrine Reuptake Inhibitors and Their Anesthetic and Analgesic Considerations.

Serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibit the presynaptic neuronal uptake of serotonin and norepinephrine and prolong the effects of the monoamines in the synaptic cleft within the central nervous system, leading to increased postsynaptic receptor activation and neuronal activities. Serotonin-norepinephrine reuptake inhibitors can have multiple clinical indications, including as the first-line agents for the management of depression and anxiety, and as analgesics in the treatment of chronic pain. The effects of reuptake inhibition of norepinephrine and serotonin are often dose-dependent and agent-dependent. There are five FDA-approved serotonin-norepinephrine reuptake inhibitors (desvenlafaxine, duloxetine, levomilnacipran, milnacipran and sibutramine) currently being marketed in the United States. As the COVID-19 pandemic significantly increased the incidence and prevalence of anxiety and depression across the country, there are significantly increased prescriptions of these medications perioperatively. Thus, anesthesiologists are more likely than ever to have patients administered with these agents and scheduled for elective or emergency surgical procedures. A thorough understanding of these commonly prescribed serotonin-norepinephrine reuptake inhibitors and their interactions with commonly utilized anesthetic agents is paramount. There are two potentially increased risks related to the continuation of SNRIs through the perioperative period: intraoperative bleeding and serotonin syndrome. SNRIs have some off-label uses, more new indications, and ever-increasing new applications in perioperative practice. This article aims to review the commonly prescribed serotonin-norepinephrine reuptake inhibitors and the current clinical evidence regarding their considerations in perioperative anesthesia and analgesia.

Synthesis and pharmacological evaluation of new (indol-3-yl)alkylamides and alkylamines acting as potential serotonin uptake inhibitors.

A series of new indolylalkylamides 3-18 and alkylamines 19-26 has been prepared in the search of novel 5-hydroxytryptamine (5-HT) uptake inhibitors. Synthesis of N-2,3 or 4-pyridinyl-(indol-3-yl) acetamides and propionamides 3-10 was achieved starting from the corresponding Ph3P/BrCCl3 or DCC-activated acids. Reduction of the pyridine nucleus led to the N-piperidinylalkylamides 15-18 via the tetrahydropyridinyl derivatives 11-14, and LiAlH4 reduction afforded the desired amines 19-26. The affinity of these compounds for 5-HT and also dopamine (DA) and noradrenaline (NA) uptake sites was measured. Among the 16 studied amides only N-(methylpiperidin-3-yl)-(indol-3-yl) propionamide 16 exhibited a moderate 5-HT uptake inhibitory effect: 38% at 10 mu mol/l. In contrast the N-pyridinyl-(indol-3-yl)alkylamines 19-26 exerted high inhibition at this concentration and two of them, 23 and 24, remained very efficient at 0.1 mu mol/l. Optimal activity was observed in the 4-pyridinyl subseries and was compatible with variation (n = 1, 2) of the length of the interspacing alkylamino chain. Although 23 and 24 were about 17-fold less active than indalpine as 5-HT uptake inhibitors, they demonstrated, like indalpine, excellent selectivity for the 5-HT uptake site versus the DA uptake site. Both amines inhibited tetrabenazine-induced hypothermia and potentiated 5-HTP-induced behavioural effects in mice. The absence of 3,4-dioxyphenylalanine (dopa)-induced behavioural effects with compound 24 suggests possible antidepressant activity through selective inhibition of central neuronal serotonin uptake and/or increased monoamine release.

Venlafaxine-associated tinnitus

Venlafaxine, an antidepressant currently indicated for major depressive disorder, generalized anxiety disorder, panic disorder, and social anxiety disorder, inhibits neuronal uptake of serotonin, norepinephrine, and dopamine.[1][1] In 18- to 65-year-old patients, the most common adverse effects

Abnormal Bleeding after an Oral Surgical Procedure Leading to Airway Compromise in a Patient Taking a Selective Serotonin Reuptake Inhibitor and a Nonsteroidal Antiinflammatory Drug

SELECTIVE serotonin reuptake inhibitors block the uptake of serotonin into thrombocytes. One of the functions of serotonin in thrombocytes is to promote platelet aggregation. When serotonin levels are depleted after several weeks of treatment, the altered platelet function leads to prolonged bleeding time, thereby increasing the risk of abnormal bleeding. Selective serotonin reuptake inhibitors may contribute substantially to the burden of abnormal bleeding after surgical procedures in the general population, due to the large number of users of selective serotonin reuptake inhibitors. In patients taking the combination of selective serotonin reuptake inhibitors and nonsteroidal antiinflammatory drugs, the risk of abnormal bleeding is thought to be even higher. We report a case of abnormal bleeding after an oral surgical procedure leading to airway compromise in a patient taking a selective serotonin reuptake inhibitor and a nonsteroidal antiinflammatory drug.

Effects of bupropion on oxidation metabolism catalyzed by human cytochrome P450 isoenzymes (CYP3A4, CYP2A6, CYP2C19 and CYP2D6)

Background: Bupropion is an antidepressant and a non-nicotine aid used in smoking cessation. It blocks the neuronal uptake of serotonin and norepinephrine and inhibits the neuronal reuptake of dopamine. Although several in vitro study demonstrated that CYP2D6 activity was inhibited by bupropion, there is no in vitro study that directly reports the inhibitory effects of bupropion on human major CYP isoforms. In the present study, we investigated the inhibitory effects and mechanism-based inactivation potencies of bupropion for human CYP2C19, CYP2D6, CYP2A6 and CYP3A4 activities. Methods: In vitro study was performed using microsomes from baculovirus-infected insect cells expressing specific human CYP isoforms. The specific activities for human CYP isoforms included in this study were S-mephenytoin 4'-hydroxylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6), testosterone 6-hydroxylation (CYP3A4), and coumarin 7-hydroxylation (CYP2A6). Results: Bupropion competitively inhibited S-mephenytoin 4'-hydroxylase (Ki = 1.631±0.544 μM) and bufuralol 1'-hydroxylase (Ki = 1.017±0.284 μM). The IC50 values for inhibition of CYP2C19 (coumarin, 1 μM) and CYP2D6 (bufuralol, 1 μM) index reaction by bupropion were 3.36 μM and 6.45 μM, respectively. CYP3A4 and CYP2A6 activities were not significantly inhibited by bupropion. Furthermore, bupropion did not reveal a mechanism-based inactivation of CYP2C19 and CYP2D6. It was clearly shown that CYP2C19 and CYP2D6 were not inactivated by bupropion in a time and concentration dependent manner. Conclusions: Bupropion showed inhibitory effects on CYP2C19 and CYP2D6 activities. These results suggest that bupropion would affect the pharmacokinetics of clinically used drugs that are metabolized by CYP2C19 and CYP2D6.

Hyperforin mediates neurite outgrowth via TRPC6 channels in PC12 cells

Hyperforin, a bicyclic polyprenylated acylphloroglucinol derivative, is the main active principle of St. John's wort extract responsible for its antidepressive profile. Hyperforin inhibits the neuronal uptake of serotonin and norepinephrine comparable to synthetic antidepressants. Whereas synthetic antidepressants directly block neuronal amine uptake, hyperforin increases synaptic serotonin and norepinephrine concentrations by an indirect and yet unknown mechanism. We identified TRPC6 as the molecular target of hyperforin. The hyperforin-induced non-selective cation entry e.g. sodium and calcium was highly specific and related to TRPC6. Sodium currents and the subsequent breakdown of the membrane sodium gradients may be the rationale for the inhibition of neuronal amine uptake. In cells expressing a dominant negative mutant of TRPC6 or cells treated with anti-TRPC6 siRNA hyperforin induced calcium influx was strongly diminished. In addition, hyperforin induces neuronal axonal sprouting like NGF in a TRPC6-dependent manner. In cells transfected with anti-TRPC6 siRNA or cells expressing a dominant negative mutant of TRPC6 hyperforin induced neurite outgrowth was strongly reduced. These findings identify hyperforin as the first selective pharmacological tool to study TRPC6 function. Furthermore, hyperforin integrates two important pharmacological activities the inhibition of neurotransmitter uptake and neurotrophic properties by the unique and specific activation of TRPC6.

The Neuro-Urological Connection

Urine storage and micturition are tightly controlled by the peripheral and central nervous systems. The parasympathetic pelvic nerves mediate signals for voiding, whereas the sympathetic hypogastric and the somatic pudendal nerves mediate signals for urine storage. Glutamate is a key transmitter of the descending neuronal pathways during the storage phase of the micturition cycle. Its effects on the activity of the hypogastric and pudendal nerves are modulated by serotonin and/or noradrenaline. Duloxetine inhibits the neuronal uptake of serotonin and noradrenaline and thereby enhances their effects in the central nervous system including the spinal nuclei responsible for urine storage. Thus, in a bladder irritation model in anaesthetised cats duloxetine dose-dependently restored bladder capacity and enhanced activity of the external urethral sphincter/rhabdosphincter. Such effects should prove beneficial in the treatment of patients with stress urinary incontinence.

The xerogenic potency and mechanism of action of tramadol inhibition of salivary secretion in rats

Tramadol is a centrally acting analgesic with weak opioid agonist properties, which also has monoaminergic activity, exerted via inhibition of neuronal uptake of serotonin and norepinephrine. Tramadol is generally well tolerated and the most common adverse events are nausea, dizziness, drowsiness, sweating, vomiting and dry mouth. Currently it was examined by which principal mechanism tramadol induces oral dryness. The effects of intravenous administration (+/-)-tramadol were studied in rats on the flow of saliva in response to a peripheral cholinergic stimulus or to reflex activation involving the relay of impulses in the central nervous system. In pentobarbitone-anaesthetized rats, the salivary secretion to acetylcholine (0.1-10 micromol/kg IV) was increased by up to 110% by tramadol (1-5 mg/kg IV) and the protein concentration therein by up to 400%. The administration alpha- and beta-adrenoceptor antagonists resulted in almost identical acetylcholine-evoked responses as in the absence of tramadol. The secretory response to the application of citric acid on the tongue of the rat was reduced by 38% and by 64%, respectively, at 5 and 10 mg/kg IV of tramadol (p < 0.05-0.01). Thus, tramadol exerts its principal xerogenic effect by activating inhibitory pathways in the central nervous system and has no anticholinergic effect on the salivary glands at dosages that may be clinically relevant. Furthermore, the tramadol-induced increase of the acetylcholine-evoked secretion occurred at a glandular level and depended most likely on a release of noradrenaline from glandular nerve terminals.

Role of Hyperforin in the Pharmacological Activities of St. John's Wort

The phloroglucinol derivative hyperforin has been recently shown to be a major antidepressant component in the extract of Hypericum perforatum. Experimental studies clearly demonstrated its activity in different behavioral models of depression. Moreover clinical studies linked the therapeutic efficacy of Hypericum extracts to their hyperforin content, in a dose-dependent manner. The molecular mechanism of action of hyperforin is still under investigation. Hyperforin has been shown to inhibit, like conventional antidepressants, the neuronal uptake of serotonin, norepinephrine and dopamine. However, hyperforin inhibits also the uptake of gamma-aminobutyric acid (GABA) and L-glutamate. The uptake inhibition by hyperforin does not involve specific binding sites at the transporter molecules; its mechanism of action seems to be related to sodium conductive pathways, leading to an elevation in intracellular Na(+) concentration. Other additional mechanisms of action of hyperforin, involving ionic conductances as well synaptosomal and vesicular function, have been suggested. In addition to its antidepressant activity, hyperforin has many other pharmacological effects in vivo (anxiolytic-like, cognition-enhancing effects) and in vitro (antioxidant, anticyclooxygenase-1, and anticarcinogenic effects). These effects could be of clinical importance. On the other hand, the role of hyperforin in the pharmacological interactions occurring during Hypericum extract therapy must be fully investigated. Hyperforin seems to be responsible for the induction of liver cytochrome oxidase enzymes and intestinal P-glycoprotein. Several pharmacokinetic studies performed in rats and humans demonstrated oral bioavailability of hyperforin from Hypericum extract. Only recently a new chromatographic method for detection of hyperforin in the brain tissue has been developed and validated. Taking into account the chemical instability of hyperforin, current efforts are directed to the synthesis of new neuroactive derivatives.

Nefazodone in the treatment of patients with post-traumatic stress disorder

Post-traumatic stress disorder occurs in patients who have undergone a traumatic experience and manifests itself through a cluster of symptoms, including re-experiencing, avoidance and hyperarousal. Post-traumatic stress disorder is commonly found among veterans of war and victims of sexual trauma, natural disasters and accidents. Nefazodone is a medication that has an FDA-approved indication for treating depression. Nefazodone has also been reported to be efficacious in treating post-traumatic stress disorder. Despite recent reports of hepatotoxicity, when used appropriately, nefazodone is generally as well-tolerated as the medications currently FDA-indicated for post-traumatic stress disorder, the selective serotonin reuptake inhibitors. Through its mechanism inhibiting neuronal uptake of serotonin and norepinephrine and as a potent postsynaptic serotonergic antagonist, nefazodone has proven to be effective in treating post-traumatic stress disorder in several open-label trials. The results of such trials warrant its study in larger, double-blind, placebo-controlled clinical trials.

An eight-week, open-label, uncontrolled, multicenter, Phase IV study of remission rates in outpatients and inpatients with major depression treated with venlafaxine

Background: Venlafaxine is a structurally novel antidepressant that is believed to potentiate monoamine activity in the central nervous system. In preclinical studies, venlafaxine was shown to inhibit the neuronal uptake of serotonin and norepinephrine and, to a lesser degree, dopamine reuptake, but was without effect on monoamine oxidase (MAO) activity. Clinical trial results from ∼3000 patients suggest that venlafaxine is a safe and effective antidepressant with the potential to invoke an early onset of clinical activity. Objective: The purpose of this 8-week, open-label, uncontrolled, multicenter, Phase IV study was to examine the extent of remission and symptom relief in outpatients and inpatients with major depressive disorder treated with venlafaxine. Methods: This study was conducted at 12 centers across Belgium and Luxembourg. Consecutive, severely depressed inpatients and moderately depressed outpatients aged 18 to 70 years were eligible. Patients were administered open-label venlafaxine for 8 weeks. Dosing was initiated at venlafaxine 75 mg/d (37.5 mg BID), with dose adjustments made throughout the study, to a maximum daily dose of 375 mg for inpatients and 225 mg for outpatients. Results were measured using the Hamilton Depression (HAM-D) scale, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impression (CGI) scale. Results: A total of 149 consecutive patients (84 females, 65 males; mean age, 46.5 years; 88 outpatients, 61 inpatients) were enrolled; the intent-to-treat (ITT) population comprised 144 patients (84 outpatients, 60 inpatients); 111 patients (64 outpatients, 47 inpatients) completed the study. At the week 8 visit, 71.3% of patients (77/108) were considered to be responders according to the HAM-D scale; 73.8% (79/107) according to the MADRS; and 78.7% (85/108) according to the CGI scale. A sustained response was achieved in 33.3% of the ITT population (48/144), and at week 8, 50.8% of outpatients (32/63) and 37.8% of inpatients (17/45) were in remission according to the HAM-D scale. Venlafaxine was well tolerated at all doses, with the most frequently experienced adverse events (AEs) being nausea, sweating, and headache. Fewer inpatients than outpatients reported ≥1 AE (57.4% [35/61] and 73.9% [65/88], respectively), despite receiving a higher maximum daily dose of venlafaxine. Conclusion: The results of this study indicate that venlafaxine was a tolerable and effective antidepressant in both outpatients and inpatients, with a significant proportion of patients achieving remission.

Deshabituación tabáquica y bupropión: la ansiedad y la depresión como índices de eficacia terapéutica

Smoking and depression are related. Bupropion, the first non-nicotinic drug that is an effective treatment in smoking cessation, is a tricyclic antidepressant that inhibits neuronal uptake of serotonin, dopamine and norepinephrine in the thalamic nuclei. To assess if certain personality factors (anxiety or depression) might predict the efficacy of bupropion for smoking cessation. The study was carried out in two smoking cessation clinics in Madrid and Barcelona. Fifty patients (21 men) declaring the desire to quit smoking were enrolled. Their mean age was 43.6 years (SD 8.75). The patients were treated with 300 mg of bupropion per day for one month and expired CO was monitored for 6 months. Personality factors were assessed on a hospital anxiety and depression scale (HADS). We evaluated whether there was a significant difference in HADS scores for patients who were still not smoking after 6 months and those who had not managed to quit. The 50 patients were smokers of a mean 39 packs per year (SD 17.82) and had mean scores of 7.4 (SD 4.15) for anxiety and 5.8 (SD 3.93) for depression. Four patients (8%) were unable to complete the study. After one month, 28% of the patients smoked, after 3 months 56% smoked and after 6 months 58% still smoked. The patients who smoked during the first month had higher depression scores than did the non-smokers (p = 0.03). After 3 and 6 months the patients who had managed to continue not smoking were those who had higher anxiety scores than did those who still smoked (p = 0.0052 at 3 months and p = 0.017 at 6 months). Patients who responded better to treatment with bupropion after 6 months of follow-up were those with higher anxiety scores on the HADS. Depression levels influenced outcome only during the first month.

Hyperforin - Antidepressant Activity by a Novel Mechanism of Action

Hyperforin represents a major antidepressive constituent of St. John's wort (SJW) extract. It not only inhibits the neuronal uptake of serotonin, norepinephrine and dopamine like many other antidepressants, but also inhibits GABA and L-glutamate uptake. This broad-spectrum effect is obtained by an elevation of the intracellular Na+ concentration, probably due to activation of sodium conductive pathways not yet finally identified but most likely ionic channels. This makes hyperforin the first member of a new class of compounds with a preclinical antidepressant profile due to a completely novel mechanism of action.

Synthesis and in vivo evaluation (PIG) of the selective seretonin reuptake inhibitor [11C]NS 2456

AbstractWe evaluated a new selective serotonin reuptake inhibitor, NS 2456, to determine whether it is suited for use in PET. Racemic NS 2456 [(1RS, 5SR)‐8‐methyl‐3‐[4‐trifluoromethoxy phenyl]‐8‐azabicyclo [3.2.1]oct‐2‐ene] and its N‐demethylated analogue, racemic NS 2463, selectively inhibit serotonin uptake in rat brain synaptosomes. For uses in PET of the living porcine brain, racemic [11C]NS2463 as well as its radiolabelled enantiomers were used. The compounds crossed the blood‐brain‐barrier rapidly and accumulated preferentially in regions rich in serotonin uptake sites. However their binding potentials were relatively low and no stereoselectivity was found. Thus, neither [11C]NS 2456 nor [11C]‐labelled enantiomers are ideal for PET neuroimaging of neuronal serotonin uptake sites.

Synthesis and evaluation of racemic [ 11C]NS2456 and its enantiomers as selective serotonin reuptake radiotracers for PET

Positron emission tomography (PET) radiotracers are needed for quantifying serotonin uptake sites in the living brain. Therefore, we evaluated a new selective serotonin reuptake inhibitor, NS2456, to determine whether it is suited for use in PET. Racemic NS2456 [(1 RS,5 SR)-8-methyl-3-[4-trifluoromethoxyphenyl]-8-azabicyclo [3.2.1]oct-2-ene] and its N-demethylated analog, racemic NS2463, selectively inhibited serotonin uptake in rat brain synaptosomes; their IC 50 values were 3000-fold lower for [ 3H]serotonin than for either [ 3H]dopamine or [ 3H]noradrenaline. The enantiomers of NS2463 were also potent inhibitors of serotonin uptake in vitro, but they failed to show stereoselectivity. Racemic NS2463 as well as its enantiomers were radiolabelled by N-methylation with C-11, yielding [ 11C]NS2456 for use in PET of the living porcine brain. The compounds crossed the blood–brain barrier rapidly and accumulated preferentially in regions rich in serotonin uptake sites (e.g., brainstem, subthalamus and thalamus). However, their binding potentials were relatively low and no stereoselectivity was found. Thus, neither racemic [ 11C]NS2456 nor its [ 11C]-labelled enantiomers are ideal for PET neuroimaging of neuronal serotonin uptake sites.

Inhibition of Synaptosomal Uptake of 3H-L-glutamate and 3H-GABA by Hyperforin, a Major Constituent of St. John's Wort The Role of Amiloride Sensitive Sodium Conductive Pathways

Extracts of St. John's Wort are widely used for the treatment of depressive disorders. The active principles have not yet been finally elucidated. We have recently shown that hyperforin, a major active constituent of St. John's Wort, not only inhibits the neuronal uptake of serotonin, norepinephrine and dopamine, but also that of L-glutamate and GABA. No other antidepressant compound exhibits a similar broad uptake inhibiting profile. To investigate this unique kind of property, kinetic analyses were performed regarding the uptake of 3H-L-glutamate and 3H-GABA into synaptosomal preparations of mouse brain. Michaelis-Menten kinetics revealed a reduction of Vmax (8.27 to 1.80 pmol/mg/min for 3H-L-glutamate, 2.76 to 0.77 pmol/mg/min for 3H-GABA) while Km was nearly unchanged in both cases, suggesting non-competitive inhibition. The unselective uptake inhibition by hyperforin could be mimicked by the Na+-ionophore monensin and by the Na+-K+-ATPase inhibitor ouabain. However, both mechanisms can be discarded for hyperforin. Several amiloride derivatives known to affect sodium conductance significantly enhance 3H-GABA and 3H-L-glutamate uptake and inhibit the uptake inhibition by hyperforin, while monensin or ouabain inhibition were not influenced. Selective concentrations of benzamil for amiloride sensitive Na+-channels and selective concentrations of 5'-ethylisopropylamiloride (EIPA) for the Na+-H+-exchangers both had an attenuating effect on the hyperforin inhibition of L-glutamate uptake, suggesting a possible role of amiloride sensitive Na+-channels and Na+-H+-exchangers in the mechanism of action of hyperforin.

Frontal-subcortical circuits in obsessive-compulsive disorder: Role of the dopamine D1receptor

Obsessive-Compulsive Disorder (OCD) is increasingly being recognized as a neurobiological disorder. Serotonergic mechanisms have been proposed on the basis of a partial response of patients to drugs which block the neuronal uptake of serotonin. Further evidence for a serotonergic abnormality is lacking. The major competing theory in the pathophysiology of OCD involves the neurotransmitter dopamine. OCD symptoms are frequently found in neuropsychiatric disorders involving the dopamine rich regions of the basal ganglia, dopamine agonists worsen OCD, peripheral models of central dopaminergic function are abnormal in OCD, urinary excretion of HVA is elevated and neurophysiological studies suggest dopamine-related gating abnormalities in OCD. The Dopamine D1 receptor is implicated in OCD following the finding of specific spatial working memory abnormalities in a series of neuropsychological studies. Spatial working memory is known to depend on the integrity of D1 receptor function in the Dorso-lateral Prefront...

ChemInform Abstract: Novel Tacrine Analogues for Potential Use Against Alzheimer′s Disease: Potent and Selective Acetylcholinesterase Inhibitors and 5‐HT Uptake Inhibitors.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Novel tacrine analogues for potential use against Alzheimer's disease: potent and selective acetylcholinesterase inhibitors and 5-HT uptake inhibitors.

Several novel analogues of tacrine have been synthesized and tested for their ability to inhibit acetylcholinesterase, butyrylcholinesterase, and neuronal uptake of 5-HT (serotonin) and noradrenaline. Changes in the size of the carbocyclic ring of tacrine produced modest potency against cholinesterase enzymes. Addition of a fourth ring resulted in compounds with marked selectivity for acetylcholinesterase (AChE) over butyrylcholinesterase (BChE): e.g. 6-amino-4,5-benzo-5H-cyclopenta[1,2-b]-quinoline (14a) had an IC50 of 0.35 microM against AChE and 3.1 microM against BChE. Some tetracyclic compounds are 100-400 times more active than tacrine as inhibitors of neuronal uptake of serotonin, in particular 13-amino-6,7-dihydro-5H-benzo-[3,4]cyclohepta[1,2-b]quinoline (18), which had an IC50 of 20 nM. These compounds would be expected to facilitate both cholinergic and monoaminergic transmission. They should be worth investigating in models of memory impairment.