Andrew J. Greenshaw

Behavioural pharmacology of 5-HT3 receptor antagonists: a critical update on therapeutic potential

There has been tremendous interest in 5-HT3 receptor antagonists since their discovery and the subsequent identification of 5-HT3 receptors in the CNS. Based on the results of early behavioural tests with these compounds, there has been substantial interest in their potential use for the treatment of various CNS disorders. In this review, Andrew Greenshaw attempts to clarify the status of the therapeutic potential of these drugs, discussing inconsistencies in preclinical findings and identifying areas in need of clarification through future research. 5-HT3 receptor antagonists are claimed to be potentially useful in the treatment of nausea, inflammatory pain (migraine and irritable bowel syndrome), anxiety, depression, schizophrenia, dementia and drug abuse!

Effects of long-term administration of antidepressants and neuroleptics on receptors in the central nervous system

Summary1.A review of the effects of long-term administration of antidepressants and neuroleptics on receptors in the central nervous system is presented.2.The effects of antidepressants on adenylate cyclase activity and on receptor binding in brain tissue are discussed. Effects on a variety of receptor types are considered.3.The utilization of electrophysiological, behavioral, and neurochemical studies to assess receptor function after chronic antidepressant administration is discussed, as is the use of peripheral receptor estimations in clinical studies.4.Animal studies on the actions of chronic administration of neuroleptics on pre- and postsynaptic dopamine receptors are reviewed. Effects of these drugs on dopamine receptors in humans are considered from the following perspectives: postmortem andin vivo binding studies in schizophrenia, tardive dyskinesia, and central versus peripheral receptor estimation.

5-HT receptors and reward-related behaviour: A review

The brains serotonin (5-HT) system is key in the regulation of reward-related behaviours, from eating and drinking to sexual activity. The complexity of studying this system is due, in part, to the fact that 5-HT acts at many receptor subtypes throughout the brain. The recent development of drugs with greater selectivity for individual receptor subtypes has allowed for rapid advancements in our understanding of this system. Use of these drugs in combination with animal models entailing selective reward measures (i.e. intracranial self-stimulation, drug self-administration, conditioned place preference) have resulted in a greater understanding of the pharmacology of reward-related processing and behaviour (particularly regarding drugs of abuse). The putative roles of each 5-HT receptor subtype in the pharmacology of reward are outlined and discussed here. It is concluded that the actions of 5-HT in reward are receptor subtype-dependent (and thus should not be generalized) and that all studied subtypes appear to have a unique profile which is determined by content (e.g. receptor function, localization - both throughout the brain and within the synapse) and context (e.g. type of behavioural paradigm, type of drug). Given evidence of altered reward-related processing and serotonergic function in numerous neuropsychiatric disorders, such as depression, schizophrenia, and addiction, a clearer understanding of the role of 5-HT receptor subtypes in this context may lead to improved drug development and therapeutic approaches.

The Non-Antiemetic Uses of Serotonin 5-HT3 Receptor Antagonists Clinical Pharmacology and Therapeutic Applications

SummaryThe discovery of multiple subtypes of the serotonin 5-HT receptor has generated enormous interest over the past few years. Possibly the most exciting, in terms of psychiatric clinical practice, appeared to be the 5-HT3 receptor. Early animal studies suggested that the 5-HT3 receptor antagonists, in addition to their well recognised antiemetic use, might be clinically useful in a number of areas. These included anxiety disorders, psychotic disorders, drug and alcohol abuse disorders, depressive disorders, cognitive disorders, the treatment of pain and the treatment of irritable bowel syndrome. With the exception of antiemetic actions, this review examines these potential therapeutic areas carefully, paying particular attention not only to the animal literature, but to the clinical studies which have resulted from these initial findings. Unfortunately, studies in many of these therapeutic areas have not lived up to their initial promise. Indeed, no clinical studies have yet clearly demonstrated the usefulness of 5-HT3 receptor antagonists in the treatment of CNS disorders. Nonetheless, in view of the absence of published results from double-blind, placebo-controlled studies in many of these therapeutic areas, further research would be useful in confirming the effectiveness, or otherwise, of this group of compounds.

Nicotine-induced decreases in VTA electrical self-stimulation thresholds: blockade by haloperidol and mecamylamine but not scopolamine or ondansetron

Abstract The effects of repeated daily injections of (–)-nicotine (+) hydrogen tartrate (mg kg–1 SC) on electrical self-stimulation of the ventral tegmental area were investigated. Nicotine reduced the frequency required to maintain half-maximal response rates with animals responding in rate-frequency threshold tests. Under these conditions, nicotine induced an increase in the total number of self-stimulation responses per session, but had no statistically significant effects on the maximal response rate. These effects of nicotine were observed by the second day of administration of this drug. Acute injections of the D2-like dopamine receptor antagonist haloperidol (0.03 mg kg–1 SC) and of the nicotinic acetylcholine receptor antagonist mecamylamine (1 mg kg–1 SC) attenuated the effects of nicotine, indicating that the observed effects involve stimulation of D2-like dopamine receptors as a result of nicotinic receptor activation. The muscarinic acetylcholine receptor antagonist scopolamine (3 mg kg–1 SC) and the serotonin 5-HT3 receptor antagonist ondansetron (0.01 and 0.1 mg kg–1 SC) did not alter the effects of nicotine. The results of this study indicate that repeated daily administration of (–)-nicotine increases the rewarding effects of electrical self-stimulation of the ventral tegmental area. These data are consistent with the proposal that repeated daily injections of nicotine positively effect a mesolimbic dopaminergic substrate of reward.

Effects of the antidepressant/antipanic drug phenelzine on GABA concentrations and GABA-transaminase activity in rat brain.

The effects of long-term (28-day) administration of several antidepressant/antipanic drugs [imipramine, desipramine, tranylcypromine and phenelzine (PLZ)] on gamma-aminobutyric acid-tranaminase (GABA-T) activity and GABA levels were investigated in rat frontal cortex. Of the drugs investigated, only PLZ inhibited GABA-T and elevated GABA levels. Additional short-term experiments were conducted with PLZ, and they demonstrated a dose-dependent inhibition of GABA-T in rat whole brain. Time-response studies on inhibition of GABA-T in whole brain demonstrated that at a dose of PLZ of 15 mg/kg i.p. inhibition of GABA-T remained relatively constant from 1 to 8 hr and that the enzyme was still inhibited by 23% at 24 hr after PLZ administration.

Reciprocal changes in striatal dopamine and β-phenylethylamine induced by reserpine in the presence of monoamine oxidase inhibitors

SummaryRecent studies have demonstrated that selective monoamine oxidase inhibition may induce changes in brain β-phenylethylamine availability following lesions. The present study used this approach to re-assess the possible effects of reserpine on striatal concentrations of β-phenylethylamine and of other amines and selected metabolites. Mice were injected with pargyline (2,200 mg kg−1, 4 h), clorgyline (2 mg kg−1, 2 h) or (−)deprenyl (2 mg kg−1, 2 h) alone or in combination with reserpine (1,10 mg kg−1, 2 h). Increases in β-phenylethylamine accumulation were observed in the presence of both (−)deprenyl or pargyline respectively after reserpine except in the case of combined 200 mg kg−1 of pargyline plus 1 mg kg−1 of reserpine. In this condition, a minimal dopamine decrease was observed (to 80% of the concentration of pargyline-treated controls). Increases in β-phenylethylamine concentration were not observed with reserpine alone (1 or 10 mg kg−1). In the latter condition, the concentrations of β-phenylethylamine remained at control values due to the activity of monoamine oxidase B. Changes in p-tyrosine, 5-hydroxytryptamine or tryptophan did not consistently accompany increases in β-phenylethylamine accumulation. Increased β-phenylethylamine accumulation was always accompanied by the decreases in dopamine induced by reserpine in mice with either non-selective (200 mg kkg−1 pargyline) or type B monoamine oxidase inhibition (2 mg kg−1 pargyline or deprenyl). These data suggest that although the changes in β-phenylethylamine accumulation may not be due simply to p-tyrosine availability they are related to dopamine levels in the intact striatum.

Acute fluoxetine treatment potentiates amphetamine hyperactivity and amphetamine-induced nucleus accumbens dopamine release: possible pharmacokinetic interaction

Abstract Amphetamine stimulates locomotor activity, in large part by activating central dopaminergic systems. Serotonin shares on overlapping distribution with dopamine and has been shown to modulate dopaminergic function and dopamine-mediated behaviors. The present study examined whether increasing serotonergic function, via the selective serotonin reuptake inhibitor fluoxetine, would alter the stimulatory effects of amphetamine on locomotor activity and dopamine overflow in the nucleus accumbens. In addition, the present study determined whether fluoxetine treatment would alter the metabolism of amphetamine. Results show that 5.0 mg/kg fluoxetine potentiated the locomotor activity induced by amphetamine (0.5–1.0 mg/ kg), and enhanced the increased dopamine overflow in the nucleus accumbens induced by amphetamine. Fluoxetine treatment also resulted in a higher concentration of amphetamine in the CNS. Together, these findings indicate that acute fluoxetine treatment potentiates the locomotor stimulating and dopamine activating effects of amphetamine. Further, the results indicate that fluoxetine potentiates the effects of amphetamine by decreasing the metabolism of amphetamine, probably through inhibition of cytochrome P450 isozymes.

Differential effects of antidepressants on GABAB and β-adrenergic receptors in rat cerebral cortex

The effects of chronic administration of antidepressant drugs on beta-adrenergic and gamma-amino-butyric acid (GABA)B receptors have been assessed with radioligand binding. Tricyclics [imipramine (IMI), 30 mg/kg/day, and desmethylimipramine (DMI), 10 mg/kg day] or monoamine oxidase inhibitors [(+/-)-tranylcypromine (TCP), 1 mg/kg/day, and phenelzine (PLZ), 10 mg/kg/day] were administered to male Sprague-Dawley rats by constant infusion via Alzet 2ML4 osmotic minipumps for 28 days. Pumps were implanted s.c. in the interscapular region. On day 28 the animals were killed and their brains removed; [3H]GABA binding to GABAB receptors was measured in frontal cortex and the remaining cortical tissue was used to measure [3H]dihydroalprenolol ([3H]DHA) binding to beta-adrenoceptors. All drugs tested induced a significant decrease in density (Bmax) of [3H]DHA binding, although no significant changes in affinity (Kd) were observed. [3H]GABA binding was not altered significantly by chronic antidepressant treatment. TCP-treated animals showed a tendency towards increased [3H]-GABA binding, but the differences did not reach statistical significance. No effects on Kd were observed. These data do not support the proposal that an increase in the total population of cortical GABAB receptors is a common effect of chronic antidepressant treatment.

Effects of emotional context on impulse control.

High risk behaviors such as narcotic use or physical fighting can be caused by impulsive decision making in emotionally-charged situations. Improved neuroscientific understanding of how emotional context interacts with the control of impulsive behaviors may lead to advances in public policy and/or treatment approaches for high risk groups, including some high-risk adolescents or adults with poor impulse control. Inferior frontal gyrus (IFG) is an important contributor to response inhibition (behavioral impulse control). IFG also has a role in processing emotional stimuli and regulating emotional responses. The mechanism(s) whereby response inhibition processes interact with emotion processing in IFG are poorly understood. We used 4.7 T fMRI in 20 healthy young adults performing a rapid event-related emotional Go/NoGo task. This task combined the Go/NoGo task, which is a classic means of recruiting response inhibition processes, with emotionally neutral and aversive distractor images. In IFG, both response inhibition in an emotionally neutral context (neutral NoGo trials) and aversive emotional picture processing (aversive Go trials) evoked activation greater than the simple response baseline (neutral Go trials). These results are consistent with the literature. Activation for response inhibition in aversive contexts (aversive NoGo-neutral Go trials) was approximately the sum of response inhibition activation (neutral NoGo-neutral Go) and aversive emotional distractor activation (aversive Go-neutral Go). We conclude that response inhibition and aversive emotional stimulus processing activities combine additively (linearly) in IFG, rather than interfering with each other (sub-linearly) or mutually-enhancing each other (super-linearly). We also found previously undocumented interaction effects between response inhibition (NoGo vs. Go) and emotional context (aversive vs. neutral distractor pictures) in bilateral posterior middle temporal gyrus and angular gyrus, right frontal eye field, and other brain regions. These results may reflect the interaction of attention processes driven by emotional stimuli with conflict resolution processes related to Go/NoGo performance.