Effect of serotonin depletion on 5-HT2A-mediated learning in the rabbit: evidence for constitutive activity of the 5-HT2A receptor in vivo.
A G Romano, Jennifer L Quinn, R Liu, K D Dave, D Schwab, G Alexander, Vincent J. Aloyo, John A. Harvey
Psychopharmacology January 2006 DOI: 10.1007/s00213-005-0245-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Rats receiving intraventricular 5,7-DHT injections and eyeblink conditioning |
| Interventions | 5 7-dihydroxytryptamine (5 7-DHT) lysergic acid diethylamide (LSD) MDL11 939 |
| Dose | 760 or 1,140 microg/side (1.88 or 2.82 micromol/side) of 5,7-DHT |
| Duration | Eight daily conditioning sessions |
| Topics | Serotonin |
| Key findings | Depleting serotonin by up to 85-90% in cortex and hippocampus did not impair trace eyeblink conditioning or alter LSD's enhancement and MDL11,939's retardation of learning. The authors argue that Pavlovian trace eyeblink conditioning is regulated predominantly by constitutive activity of the 5-HT2A receptor rather than by serotonin release onto the receptor during learning. |
Abstract
Associative learning during Pavlovian eyeblink conditioning has been shown to be regulated by 5-HT2A receptors. The existence of inverse agonists that retard learning through an action at the 5-HT2A receptor suggests the existence of constitutive activity at that receptor and that depletion of serotonin should have minimal effects on learning. We examined whether depletion of serotonin would impair trace eyeblink conditioning or the enhancement of conditioning produced by the agonist lysergic acid diethylamide (LSD) and the retardation of conditioning produced by the inverse agonist MDL11,939. Animals received bilateral intraventricular injections of 5,7-dihydroxytryptamine (5,7-DHT) at doses of 760 or 1,140 microg/side (1.88 or 2.82 micromol/side) and were later exposed to eight daily conditioning sessions. Serotonin depletion produced by the lower dose of 5,7-DHT was 71 and 72% in cortex and hippocampus, respectively, with no change in 5-HT2A receptor density, no effect on learning, and no effect on the ability of LSD to enhance and MDL11,939 to retard learning. The higher dose of 5,7-DHT produced serotonin decreases of 85 and 90% in cortex and hippocampus, respectively, accompanied by a 96% decrease in the density of the serotonin transporter, but no significant effect on learning. Pavlovian trace eyeblink conditioning is regulated predominantly by the constitutive activity of the 5-HT2A receptor rather than by serotonin release onto the receptor during learning. It was suggested that the 5-HT2A receptor regulates learning by modulating the release of dopamine, acetylcholine, and glutamate, transmitters known to affect eyeblink conditioning.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 6
- REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics Pharmacological Reviews June 20, 2019
- Serotonin 2A receptors are a stress response system: implications for post-traumatic stress disorder. Behavioural Pharmacology April 1, 2019
- Intrahippocampal LSD accelerates learning and desensitizes the 5-HT(2A) receptor in the rabbit, Romano et al. Psychopharmacology October 1, 2010
- Learning as the unifying mechanism of psychedelic action Journal of Psychopharmacology December 26, 2025
- Serotonin and brain function: a tale of two receptors. Journal of Psychopharmacology August 31, 2017
and 1 more in the library
Cites 7
- Lysergic acid diethylamide and [−]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex Brain Research August 27, 2004
- Hallucinogens. Pharmacology & Therapeutics February 1, 2004
- Activation of 5-HT2 receptors enhances the release of acetylcholine in the prefrontal cortex and hippocampus of the rat. Synapse September 15, 2004
- Role of the serotonin 5-HT(2A) receptor in learning. Learning & Memory September 1, 2003
- LSD and structural analogs: pharmacological evaluation at D1 dopamine receptors. Psychopharmacology April 1995
and 2 more in the library