PubMed · 3766360
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H I Silverman, L Shargel. 1986. Phenylpropanolamine.. https://pubmed.ncbi.nlm.nih.gov/3766360/
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RATIONALE: Motor movements (head bobs) in the rabbit have been shown to be elicited by LSD-like hallucinogenic drugs through actions at central serotonin 5-HT(2A) receptors, though their central locus remains unknown. Serotonergic innervation of the hippocampus has been suggested to play an important role in motor programming including movements of the head. OBJECTIVES: We examined whether intrahippocampal injections of a 5-HT(2A) receptor agonist would elicit head bobs and whether elicitation of head bobs would be modified by increases in hippocampal 5-HT(2A) receptor density. METHODS: Animals received bilateral injections of DOI or its vehicle into the dorsal hippocampus either before or after chronic administration of MDL 11,939 or its vehicle. The number of head bobs was counted continuously for 60 min and reported in blocks of 10 min and this was compared with the density of 5-HT(2A) receptors in dorsal hippocampus. RESULTS: Infusion of DOI into the CA1 region of the dorsal hippocampus elicited head bobs that were blocked by prior intrahippocampal injection of the 5-HT(2A) receptor antagonist ketanserin. Receptor autoradiography revealed that chronic administration of MDL 11,939 produced a 2.5-fold up-regulation of 5-HT(2A) receptors in the CA1 field and dentate gyrus of the hippocampus. This 5-HT(2A) receptor up-regulation was associated with a nearly 2-fold increase in head bobs elicited by infusion of DOI into the CA1 field. CONCLUSIONS: These results indicate that 5-HT(2A) receptors located in the CA1 field of the hippocampus mediate a motor movement, head bobs, and that this mediation is functionally related to receptor density.
Gene expression studies have suggested that dopamine (DA) depletion increases the sensitivity of striatal direct pathway neurons to the effects of serotonin (5-HT) via the 5-HT(2) receptor. The present study examined the possible influence(s) of 5-HT(2A) or 5-HT(2C) receptor-mediated signaling locally within the striatum on motor behavior triggered by 5-HT(2) receptor agonism in the neonatal DA-depleted rat. Male Sprague-Dawley rats were treated with 6-hydroxydopamine (6-OHDA; 60 microg in 5 microl per lateral ventricle) on postnatal day 3 to achieve near-total DA depletion bilaterally. Sixty days later, sham-operated (saline-injected) or 6-OHDA-treated rats were challenged with the 5-HT(2A/2C) agonist DOI [(+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane] or saline either by systemic treatment or bilateral intrastriatal infusion. Motor behavior was quantified for 60 min after agonist injection using computerized activity monitors. Systemic DOI treatment (0.2 or 2.0 mg/kg i.p.) was more effective in inducing motor activity in the DA-depleted group compared with intact controls. Intrastriatal DOI infusion (1.0 or 10.0 microg/side) also produced a significant rise in motor activity in the DA-depleted group during the 30- to 60-min period of behavioral analysis but did not influence behavior in intact animals. The effects of intrastriatal DOI infusion were blocked by intrastriatal coinfusion of the 5-HT(2) antagonist ketanserin (1.0 microg) and the 5-HT(2A)-preferring antagonist M100907 [(R)(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol; 1.0 microg] but not the 5-HT(2C)-preferring antagonist RS102221 [8-[5-(2,4-dimethoxy-5-(4-trifluoromethylsulfo-amido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione; 1.0 microg]. Such results support the hypothesis that 5-HT(2A) receptor-mediated signaling events are strengthened within the striatum under conditions of DA depletion to provide a more potent regulation of motor activity.
Dopamine (DA) is a neurotransmitter involved in the control of locomotion, emotion, cognition, and reward. Administration of lithium salts is known to inhibit DA-associated behaviors in experimental animal models through unknown mechanisms. Here, we used a pharmacogenetic approach to show that DA can exert its behavioral effects by acting on a lithium-sensitive signaling cascade involving Akt/PKB and glycogen synthase kinase 3 (GSK-3). In the mouse striatum, increased DA neurotransmission arising either from administration of amphetamine or from the lack of the DA transporter results in inactivation of Akt and concomitant activation of GSK-3alpha and GSK-3beta. These biochemical changes are not affected by activation of the cAMP pathway but are effectively reversed either by inhibition of DA synthesis, D2 receptor blockade, or administration of lithium salts. Furthermore, pharmacological or genetic inhibition of GSK-3 significantly reduces DA-dependent locomotor behaviors. These data support the involvement of GSK-3 as an important mediator of DA and lithium action in vivo and suggest that modulation of the Akt/GSK-3 pathway might be relevant to DA-related disorders, such as attention deficit hyperactivity disorder and schizophrenia.