A review of central 5-HT receptors and their function

It is evident that in the last decade or so, a vast amount of new information has become available concerning the various 5-HT receptor types and their characteristics. This derives from two main research approaches, operational pharmacology, using selective ligands (both agonists and antagonists), and, more recently, molecular biology. Although the scientific community continues to deliberate about the hierarchy of criteria for neurotransmitter receptor characterisation, there seems good agreement between the two approaches regarding 5-HT receptor classification. In addition, the information regarding transduction mechanisms and second messengers is also entirely consistent. Thus, on the basis of these essential criteria for receptor characterisation and classification, there are at least three main groups or classes of 5-HT receptor: 5-HT1, 5-HT2, and 5-HT3. Each group is not only operationally but also structurally distinct, with each receptor group having its own distinct transducing system. The more recently identified 5-HT4 receptor almost undoubtedly represents a fourth 5-HT receptor class on the basis of operational and transductional data, but this will only be definitively shown when the cDNA for the receptor has been cloned and the amino acid sequence of the protein is known. Although those 5-HT receptors that have been fully characterised and classified to date (and, hence, named with confidence) would seem to mediate the majority of the actions of 5-HT throughout the mammalian body, not all receptors for 5-HT are fully encompassed within our scheme of classification. These apparent anomalies must be recognised and need further study. They may or may not represent new groups of 5-HT receptor or subtypes of already known groups of 5-HT receptor. Even though the cDNAs for the 5-ht1E, 5-ht1F, 5-ht5, 5-ht6, and 5-ht7 receptors have been cloned and their amino acid sequence defined, more data are necessary concerning their operational and transductional characteristics before one can be confident of the suitability of their appellations. Therefore, it is important to rationalise in concert all of the available data from studies involving both operational approaches of the classical pharmacological type and those from molecular and cellular biology.(ABSTRACT TRUNCATED AT 400 WORDS)

International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin).

Here we provide a review of the animal and human literature concerning the role of the amygdala in fear conditioning, considering its potential influence over autonomic and hormonal changes, motor behavior and attentional processes. A stimulus that predicts an aversive outcome will change neural transmission in the amygdala to produce the somatic, autonomic and endocrine signs of fear, as well as increased attention to that stimulus. It is now clear that the amygdala is also involved in learning about positively valenced stimuli as well as spatial and motor learning and this review strives to integrate this additional information. A review of available studies examining the human amygdala covers both lesion and electrical stimulation studies as well as the most recent functional neuroimaging studies. Where appropriate, we attempt to integrate basic information on normal amygdala function with our current understanding of psychiatric disorders, including pathological anxiety.

The amygdala: vigilance and emotion

https://www.utdallas.edu/~tres/plasticity2009/Mogenson.etal.1980.pdf

From motivation to action: functional interface between the limbic system and the motor system

Converging evidence now indicates that the amygdala plays a crucial role in the development and expression of conditioned fear. Conditioned fear is a hypothetical construct used to explain the cluster of behavioral effects produced when an initially neutral stimulus is consistently paired with an aversive stimulus. For example, when a light, which initially has no behavioral effect, is paired with an aversive stimulus such as a footshock, the light alone can elicit a constellation of behaviors that are typically used to define a state of fear in animals. To explain these findings, it is generally assumed (cf. McAllister & McAllister 1971 ) that during light-shock pair­ ings (training session ), the shock elicits a variety of behaviors that can be used to infer a central state of fear (unconditioned responses-Figure 1 ). After pairing , the light can produce the same central fear state and thus the same set of bchaviors formerly produced by thc shock. Moreover, the behavioral effects that are produced in animals by this formerly neutral stimulus (now called a conditioned stimulus-CS ) are similar in many respects to the constellation of behaviors that are used to diagnose gener­ alized anxiety in humans (Table 1 ). This chapter summarizes data sup­ porting the idea that the amygdala, and its many efferent projections, may represent a central fear system involved in both the expression and acquisition of conditioned fear.

The role of the amygdala in fear and anxiety

1 The ability of the selective 5-HT3 receptor antagonist GR38032F to reduce raised mesolimbic dopaminergic activity was studied in behavioural experiments in the rat and marmoset. 2 GR38032F injected into the nucleus accumbens (0.01-1 ng) or peripherally (0.01-1 mg kg-1 i.p.) inhibited the locomotor hyperactivity caused by the acute intra-accumbens injection of amphetamine (10 micrograms) in the rat. Similar treatments with sulpiride and fluphenazine also inhibited the amphetamine-induced hyperactivity. 3 The peripheral administration of GR38032F (0.001-0.1 mg kg-1 i.p., b.d.) during a 13 day period of dopamine infusion (25 micrograms 24 h-1) into the nucleus accumbens of the rat reduced the dopamine-induced hyperactivity response to control (vehicle infused) levels. Locomotor activity remained at control levels after discontinuing the dopamine/GR38032F treatment regimen. 4 The hyperactivity caused by the infusion of dopamine into the rat nucleus accumbens was also inhibited by fluphenazine (0.01-0.05 mg kg-1 i.p., b.d.), but locomotor activity was suppressed to levels below control values and a rebound hyperactivity occurred after discontinuation of the dopamine/fluphenazine treatment regimen. 5 The discontinuation of a concomitant 13 day intra-accumbens infusion of dopamine with haloperidol, 0.01 mg kg-1 i.p.t.d.s., caused a rebound hyperactivity. This hyperactivity was suppressed by GR38032F (0.001-0.1 mg kg-1 i.p.). 6 The unilateral infusion of dopamine (25 micrograms 24 h-1, 13 days) into the left amygdala of rats having right hemispheric dominance (as measured in a turn preference test) caused locomotor hyperactivity. Intraperitoneal administration of GR38032F (0.1-100 micrograms kg-1) or fluphenazine (0.025-0.1 mg kg-1), and the intra-amygdaloid injection of GR38032F (0.1-100 ng) or fluphenazine (25-500 pg), either into the infused or non-infused side, inhibited the dopamine-induced locomotor hyperactivity. 7 Marmosets receiving bilaterial infusions of dopamine (25 micrograms 24 h-1 for 13 days) into the nucleus accumbens also exhibited increased locomotor activity, GR38032F (0.1-1.0 micrograms kg-1 t.d.s.), reduced the hyperactivity to control levels with no rebound hyperactivity following the discontinuation of the dopamine/GR38032F treatment regimen. Fluphenazine (0.01-2.5 mg kg-1 i.p., t.d.s.) also inhibited the hyperactivity, but locomotor activity was reduced to values below control levels and a rebound hyperactivity followed the discontinuation of the dopamine/fluphenazine treatment. 8. It is concluded that the 5-HT3 receptor antagonist GR38032F, and the neuroleptic agents fluphenazine, sulpiride and haloperidol, can reduce raised mesolimbic dopaminergic activity in the rat and marmoset. GR38032F is distinguished from the dopamine receptor antagonists by, firstly, its ability to return the hyperactivity response to control values, without excessive suppression of locomotion even on enhanced dosage regimes and, secondly, by the lack of rebound hyperactivity following abrupt discontinuation of its treatment.

Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain.

1. The highly selective 5-HT3-receptor antagonist, GR38032F, has been tested in five animal models predictive for anxiolytic activity. 2. In the social interaction test in the rat and in a light/dark exploration test in the mouse, GR38032F dose-dependently released suppressed behaviour without modifying locomotor activity. 3. In the cynomolgus monkey and the marmoset, GR38032F reduced anxiety-related symptoms without causing sedation. In the marmoset, the effects were clearly dose-related. 4. GR38032F did not have any detectable activity in the water-lick conflict test in the rat. 5. We conclude that GR38032F is potentially a very potent anxiolytic agent without sedative, anticonvulsant or hypnotic activity.

/pdf/the-potential-anxiolytic-activity-of-gr38032f-a-5-ht3-2yhwknttbw.pdf

The potential anxiolytic activity of GR38032F, a 5-HT3-receptor antagonist.

THE release of cerebral acetylcholine from terminals in the cerebral cortex has been shown to be regulated by 5-hydroxytryptamine (5-HT)1–6 but it is not known which subtype of the 5-HT receptor is involved. 5-HT receptor agonists increase acetylcholine levels in vivol, 2 indicating a reduced turnover, and reduce release of acetylcholine from striatal slices in vitro3–5. Depleting 5-HT by inhibiting synthesis or by destroying the neurons containing 5-HT potentiates acetylcholine release5, and increases acetylcholine turnover in the cerebral cortex and hippocampus6. Selective antagonists for the 5-HT3 receptor subtypes which seem to have effects on mood and activity7–10 may exert their effect through the regulation of acetylcholine release in the cortex and limbic system. Radioligand binding studies show a high density of 5-HT3 receptors in the cholinergic-rich entorhinal cortex11, 12 and we provide evidence that a reduction in cortical cholinergic function can be effected in vitro by 5-HT3 receptors.

5-HT3 receptors mediate inhibition of acetylcholine release in cortical tissue.

The psychopharmacology of 5-HT3 receptors.

Stereotyped behaviour patterns and hyperactivity induced by amphetamine and apomorphine after discrete 6-hydroxydopamine lesions of extrapyramidal and mesolimbic nuclei

Robert J. Naylor

Papers

Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain.

The potential anxiolytic activity of GR38032F, a 5-HT3-receptor antagonist.

5-HT3 receptors mediate inhibition of acetylcholine release in cortical tissue.

The psychopharmacology of 5-HT3 receptors.

Stereotyped behaviour patterns and hyperactivity induced by amphetamine and apomorphine after discrete 6-hydroxydopamine lesions of extrapyramidal and mesolimbic nuclei