The importance of serotonergic mechanisms for the induction of hyperactivity by amphetamine and its antagonism by intra-accumbens (3,4-dihydroxy-phenylamino)-2-imidazoline (DPI)

doi:10.1016/0028-3908(79)90112-6

Neuropharmacology

Volume 18, Issue 7, July 1979, Pages 605-609

https://doi.org/10.1016/0028-3908(79)90112-6 Get rights and content

Abstract

The present studies analyzed the role of serotonergic mechanisms in the action of two agents having purportedly different actions on the dopamine mechanisms of the rat nucleus accumbens. amphetamine and (3,4-dihydroxy-phenylamino)-2-imidazoline (DPI). Amphetamine, given by the intraperitoneal or intra-accumbens route, caused locomotor hyperactivity. This was shown to be specific for dopamine since it was antagonized by the dopamine antagonist, fluphenazine, but not by the α- and β-adrenolytics, piperoxan and propranolol, or the cholinolytic, atropine. Intra-accumbens DPI antagonized the amphetamine hyperactivity and this effect was not mimicked by the α-agonist, clonidine. The importance of serotonin for the actions of both amphetamine and DPI was established. Thus, intra-accumbens serotonin reduced amphetamine hyperactivity whilst lesions of the medial raphé nucleus, which depleted mesolimbic serotonin, enhanced the same response. Further, the inhibitory effects of DPI against amphetamine were antagonized by the serotonergic antagonists, methysergide and cypro-heptadine, but not by piperoxan, propranolol or atropine. Also, lesions of the medial raphé nucleus markedly reduced the inhibitory effect of DPI. Finally, threshold doses of intra-accumbens DPI and serotonin synergized to reduce amphetamine hyperactivity.

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The response of mice to an acute administration of methamphetamine was evaluated to further examine potential alterations in dopamine-dependent motor behaviors. Methamphetamine can act as a nicotinic receptor agonist (Liu et al., 2003) but also exerts effects on activity through a dopaminergic mechanism (Thornburg and Moore, 1973) that can be modulated by serotonin (Costall et al., 1979). Methamphetamine stimulates dopamine elevations within striatal pathways to increase activity (Fornai et al., 2009; Zombeck et al., 2009).
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Individual differences in amphetamine sensitization, behavior and central monoamines
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Non-sensitized rats had decreased serotonin concentrations in the shell of the nucleus accumbens when compared to saline-treated and sensitized rats. Direct administration of serotonin to the nucleus accumbens inhibits acute amphetamine-induced locomotion [61,62] via complex interactions with a number of serotonin receptor subtypes [63]. However, it is not known how serotonin function in the nucleus accumbens relates to chronic amphetamine treatment and withdrawal.
Repeated amphetamine treatment results in behavioral sensitization in a high percentage of rats. Alterations to plasma corticosterone, neural monoamines and stress behavior can accompany amphetamine sensitization. Whether these changes occur following repeated amphetamine treatment in the absence of behavioral sensitization is not known. Male Sprague–Dawley rats were treated with amphetamine (2.5 mg/kg, i.p.) or saline once daily for 6 days. Amphetamine-induced locomotion and stereotypy, open-field anxiety behavior, plasma corticosterone and limbic monoamines were measured during withdrawal. Sixty-two percent of amphetamine-treated rats showed behavioral sensitization over the test periods. Only amphetamine-sensitized rats showed increased latency to enter the center of the open-field, as well as increased plasma corticosterone when compared to saline-treated controls. Amphetamine-sensitized rats showed increased dopamine concentrations in the shell of the nucleus accumbens and increased serotonin concentrations in the dorsal hippocampus, which were not observed in amphetamine-treated non-sensitized rats. These findings suggest that anxiety behavior, plasma corticosterone and limbic monoamines concentrations are altered by repeated amphetamine (2.5 mg/kg) treatment, and that these neuroendocrine and behavioral changes are often associated with sensitization to the psychostimulant effects of amphetamine.
Activation of 5-HT<inf>1B</inf> receptors in the nucleus accumbens reduces self-administration of amphetamine on a progressive ratio schedule
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With regard to the issue of where in the brain 5-HT may modulate the effects of psychomotor stimulants evidence suggests that the nucleus accumbens may be one important site. Several studies have shown that infusion of 5-HT into this site inhibits the locomotor stimulant effect of amphetamine (Carter and Pycock, 1978; Costall et al., 1979), or of dopamine itself (Jones et al., 1981). The ability of amphetamine to potentiate responding for Conditioned reinforcement is also attenuated by 5-HT infusions into the nucleus accumbens (Fletcher, 1996).
Brain serotonin interacts with dopamine function in a complex fashion. Previous work from our laboratory showed that activation of 5-HT_1B receptors within the nucleus accumbens attenuates the ability of amphetamine to increase responding for conditioned reinforcement. The primary purpose of these experiments was to determine the impact of 5-HT receptor stimulation, with particular focus on 5-HT_1B receptors in the nucleus accumbens on the reinforcing effect of amphetamine. To this end several experiments determined the effects of injecting 5-HT, and various 5-HT agonists, into the nucleus accumbens on responding for intravenous infusions of amphetamine (60 μg/kg) delivered according to a progressive ratio schedule of reinforcement. Both 5-HT (2.5, 5 and 10 μg) and the selective 5-HT_1B receptor agonist CP93,129 (0.625, 1.25 and 2.5 μg) dose-dependently reduced responding for amphetamine. Injections of 5-HT but not CP93,129 also reduced responding for food under a similar PR schedule. The 5-HT_1A agonist 8-OH-DPAT (5 μg) and the nonselective 5-HT₂ agonist DOI (10 μg) failed to alter amphetamine self-administration. Pretreatment with the selective 5-HT_1B/1D receptor antagonist GR127935 (3 mg/kg) attenuated the ability of 5-HT and CP93,129 to reduce amphetamine self-administration following their injection into the nucleus accumbens. These results extend our previous findings that increasing 5-HT activity in the nucleus accumbens inhibits dopamine-dependent behaviour, and further indicate that activation of 5-HT_1B receptors is particularly important in this regard.
Modulatory effect of p-chlorophenylalanine microinjected into the dorsal and median raphe nuclei on cocaine-induced behaviour in the rat
1999, European Journal of Pharmacology
The present study examined whether a potentiation of cocaine-induced behaviour in rats following peripheral pretreatment with the 5-hydroxytryptamine (5-HT) biosynthesis inhibitor p-chlorophenylalanine may be due to depletion of 5-HT in the dorsal raphe nucleus and/or median raphe nucleus. Following peripheral pretreatment with p-chlorophenylalanine (100 mg/kg, i.p.) for 3 consecutive days, a potentiation of cocaine-induced locomotor activity and rears was observed. To investigate a possible involvement of serotonergic neurones arising in the midbrain raphe nuclei in the observed potentiation, p-chlorophenylalanine (0.5 μg) was microinjected in either the dorsal raphe nucleus or median raphe nucleus followed by behavioural testing 48 h later. Application of p-chlorophenylalanine in the dorsal raphe nucleus resulted in an enhancement of cocaine-induced locomotor activity and head bobs. In contrast, the stimulant effect of cocaine on behaviour was not altered by microinjection of p-chlorophenylalanine in the median raphe nucleus. Peripheral and central administration of p-chlorophenylalanine did not consistently alter the baseline behaviour of saline-treated animals. Biochemical results indicated only a moderate depletion of 5-HT in the midbrain raphe nuclei following peripheral p-chlorophenylalanine administration. Surprisingly, the central application of p-chlorophenylalanine in the dorsal raphe nucleus and median raphe nucleus did not alter the 5-HT levels in the midbrain raphe nucleus investigated. In addition, peripheral and central administration of p-chlorophenylalanine did not alter the 5-HT levels in the nucleus accumbens. In conclusion, the behavioural results suggest that the potentiation of cocaine-induced behaviour following peripheral p-chlorophenylalanine administration may be attributed to the dorsal raphe nucleus but not the median raphe nucleus suggesting that, serotonergic dorsal raphe nucleus neurones may normally mediate a tonic inhibitory effect on cocaine-induced behaviour. Furthermore, the biochemical data may indicate the existence of neurochemical resistance of the midbrain raphe nuclei to the 5-HT depleting effects of p-chlorophenylalanine.
Effects of 5-HT<inf>3</inf> receptor-selective agents on locomotor activity in rats following injection into the nucleus accumbens and the ventral tegmental area
1996, European Journal of Pharmacology
5-Hydroxytryptamine (5-HT) is involved in the modulation of dopaminergic activity in the mesolimbic system, but its sites of action and the receptors involved are not well understood. Locomotor activity responses in rats were monitored in Animex automated activity boxes following injection of 5-HT₃ receptor-selective agents directly into two mesolimbic nuclei, the nucleus accumbens and the ventral tegmental area, via stereotactically implanted injection guide cannulae. Neither spontaneous nor dexamphetamine-stimulated locomotor activity was changed by bilateral intra-nucleus accumbens injection of the selective agonist 2-methyl-5-HT or the selective antagonists ondansetron or granisetron. In contrast, intra-ventral tegmental area injection of 2-methyl-5-HT produced significant long-lasting (approximately 240 min) increases in locomotor activity; intra-ventral tegmental area injection of ondansetron elicited an initial inhibition of spontaneous and dexamphetamine-stimulated locomotor activity (for the 0–30 min period), but granisetron had no effect. The hyperlocomotor response to intra-ventral tegmental area 2-methyl-5-HT was abolished by pretreatment with the catecholamine synthesis inhibitor α-methyl-p-tyrosine, or by pretreatment with ondansetron. Methiothepin pretreatment had no effect on the hyperlocomotor response to 2-methyl-5-HT, although methiothepin itself produced an initial increase in spontaneous locomotor activity (for the 60–120 min period). Intra-ventral tegmental area injection of 5-carboxamidotryptamine, α-methyl-5-HT or renzapride produced no changes in spontaneous locomotor activity. In some of the ventral tegmental area experiments, other behaviours were also monitored. 2-Methyl-5-HT produced forward locomotion, rearing, and increased wakefulness, but did not appreciably alter circling, grooming or sniffing. Ondansetron alone had no effect on any of these behaviours, but it opposed the 2-methyl-5-HT-induced changes. Methiothepin alone increased forward locomotion and wakefulness but did not alter the other behaviours; it had no effect on the responses to 2-methyl-5-HT. These observations show that 5-HT₃ receptors may mediate increased locomotor activity by modulating firing of mesolimbic dopaminergic cell bodies in the ventral tegmental area rather than terminals in the nucleus accumbens.
The role of 5-HT<inf>3</inf> receptors in drug dependence
1995, Drug and Alcohol Dependence
Since the discovery of serotonin receptor subtypes in 1957, the classification of serotonin receptors now includes 5-HT₁ through 5-HT₇ receptors, with further subtypes of receptors in each family. Unique among this expanding group of 5-HT₁ receptor subtypes is the 5-HT₃ receptor, which is the only known 5-HT receptor that directly gates an ion channel. The channel conducts primarily Na⁺ and K⁺, resulting in rapid depolarization followed by a rapid desensitization. The immediate consequence of neuronal depolarization resulting from 5-HT₃ receptor activation is the release of stored neurotransmitter. The subsequent release of stored neurotransmitter, particularly dopamine in the mesolimbic pathways, suggest a potentially important role for this receptor system in neuronal circuitry involved in drug abuse. The following review broadly covers the structure, function and distribution of the 5-HT₃ receptor system in the CNS and data addressing the potential role of this receptor system in modulating the effects of a wide variety of abused drugs. Most of the evidence indicates an association between the ability of 5-HT₃ antagonists to decrease mesolimbic dopamine levels and to attenuate the psychomotor stimulant effects of drugs. However 5-HT₃ receptor antagonists are less robust at attenuating other drug effects that are believed to be related to their abuse liability, such as discriminative stimulus and reinforcing effects. The one exception may be ethanol, which directly potentiates the effects of 5-HT at the 5-HT₃ receptor channel complex. In addition to the implications of an interaction with the mesolimbic dopaminergic system, the ability of 5-HT₃ receptor antagonists to function as anxiolytics suggest they could be useful pharmacotherapies during drug withdrawal. However, further studies are needed since currently available 5-HT₃ receptor antagonists do not have uniform behavioral effects, may interact with other receptor systems, and have atypical dose-response effects.

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The importance of serotonergic mechanisms for the induction of hyperactivity by amphetamine and its antagonism by intra-accumbens (3,4-dihydroxy-phenylamino)-2-imidazoline (DPI)

Abstract

Eur. J. Pharmac.

Neuropharmacology

A sensitive method for spectrophoto-fluorometric assay of catecholamines

Int. J. Neuropharmac.

Basic considerations on the role of concertedly working dopaminergic, GABA-ergic, cholinergic and serotonergic mechanisms within the neostriatum and nucleus accumbens in locomotor activity, stereotyped gnawing, turning and dyskinetic activities

Excitationmediating and inhibition-mediating dopamine receptors: A new concept towards a better understanding of electrophysiological, biochemical, pharmacological, functional and clinical data

Psychopharmacologia