Effects of serotonin 5-HT 2A/2C antagonists on associative learning in the rabbit

Welsh, Sarah E; Romano, Anthony G.; Harvey, J A

doi:10.1007/s002130050605

Cited by 44 publications

(35 citation statements)

References 20 publications

(25 reference statements)

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“…Given the low but still significantly higher level of NMRs to the tone during habituation, it is possible that there may have been a nonassociative effect of copper when added to the drinking water. There is some precedent for other compounds having nonassociative effects on the rabbit NMR including 4-aminopyridine that was found to increase sensitivity to tone and air puff (Wang, Darwish, & Schreurs, 2006) and a serotonin antagonist that was found to reduce sensitivity to air puff (Welsh, Romano, & Harvey, 1998). The only animal model of altered copper levels in the brain is the Long-Evans Cinnamon rat that shares many of the pathological and biological characteristics of Wilson's disease, a genetic disorder of copper metabolism in which copper accumulates in the body.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol enhances classical conditioning of the rabbit heart rate response

Schreurs

Smith-Bell

Darwish

et al. 2007

Behavioural Brain Research

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The cholesterol-fed rabbit is a model of atherosclerosis and has been proposed as an animal model of Alzheimer's disease. Feeding rabbits cholesterol has been shown to increase the number of beta amyloid immunoreactive neurons in the cortex. Addition of copper to the drinking water of cholesterol-fed rabbits can increase this number still further and may lead to plaque-like structures. Classical conditioning of the nictitating membrane response in cholesterol-fed rabbits is retarded in the presence of these plaque-like structures but may be facilitated in their absence. In a factorial design, rabbits fed 2% cholesterol or a normal diet (0% cholesterol) for 8 weeks with or without copper added to the drinking water were given trace classical conditioning using a tone and periorbital electrodermal stimulation to study the effects of cholesterol and copper on classical conditioning of heart rate and the nictitating membrane response. Cholesterol-fed rabbits showed significant facilitation of heart rate conditioning and conditioning-specific modification of heart rate relative to normal diet controls. Consistent with previous research, cholesterol had minimal effects on classical conditioning of the nictitating membrane response when periorbital electrodermal stimulation was used as the unconditioned stimulus. Immunohistochemical analysis showed a significant increase in the number of beta amyloid positive neurons in the cortex, hippocampus and amygdala of the cholesterol-fed rabbits. Supplementation of drinking water with copper increased the number of beta amyloid positive neurons in the cortex of cholesterol-fed rabbits but did not produce plaque-like structures or have a significant effect on heart rate conditioning. The data provide additional support for our finding that, in the absence of plaques, dietary cholesterol may facilitate learning and memory. Cholesterol enhances rabbit heart rate conditioningThe cholesterol-fed rabbit has been used as an animal model of atherosclerosis since 1913 when Anitchkow first demonstrated that a cholesterol diet induced vascular lesions (Bocan, 1998;Fan & Watanabe, 2000;Finking & Hanke, 1997;Moghadasian, 2002). More recently, the cholesterol-fed rabbit has been proposed as an animal model of Alzheimer's disease (Ghribi, Larsen, Schrag, & Herman, 2006;Sjogren, Mielke, Gustafson, Zandi, & Skoog, 2006 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Sparks, 1997;Sparks, Martin, Gross, & Hunsaker III, 2000;Zatta, Zambenedetti, Stella, & Licastro, 2002). Based on the observation that patients with heart disease had beta amyloid st...

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Section: Discussionmentioning

confidence: 99%

Cholesterol enhances classical conditioning of the rabbit heart rate response

Schreurs

Smith-Bell

Darwish

et al. 2007

Behavioural Brain Research

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“…In a separate study, the 5-HT 2A/2C antagonist pizotifen was also found to retard the acquisition of the rabbit's eyeblink response (Table 3; Ginn and Powell 1986). Explicitly unpaired CS-US procedures indicated that the retardation of CR acquisition produced by these drugs was due to a decrease in associative learning (Welsh et al 1998b). In agreement with results in the rabbit, ritanserin also retarded classical aversive conditioning in humans (Table 2; Hensman et al 1991).…”

Section: Effect Of Serotonin 5-ht 2a Antagonists On Associative Learningmentioning

confidence: 91%

“…Drug effects are expressed as the percentage of vehicle controls. Data are taken from Welsh et al (1998b) and Romano et al (2000).…”

Section: Figurementioning

confidence: 99%

Role of the Serotonin 5-HT_2A Receptor in Learning

Harvey¹

2003

Learn. Mem.

188

148

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This study reviews the role of the serotonin 5-HT 2A receptor in learning as measured by the acquisition of the rabbit's classically conditioning nictitating membrane response, a component of the eyeblink response. Agonists at the 5-HT 2A receptor including LSD (d-lysergic acid diethylamide) enhanced associative learning at doses that produce cognitive effects in humans. Some antagonists such as BOL (d-bromolysergic acid diethylamide), LY53,857, and ketanserin acted as neutral antagonists in that they had no effect on learning, whereas others (MDL11,939, ritanserin, and mianserin) acted as inverse agonists in that they retarded learning through an action at the 5-HT 2A receptor. These results were placed in the context of what is known concerning the anatomical distribution and electrophysiological effects of 5-HT 2A receptor activation in frontal cortex and hippocampus, as well as the role of cortical 5-HT 2A receptors in schizophrenia. It was concluded that the 5-HT 2A receptor demonstrates constitutive activity, and that variations in this activity can produce profound alterations in cognitive states.The past few decades have brought an increasing awareness of serotonin's role in behavior. The development of drugs acting on the serotonergic system of brain that allow for the treatment of depression, anxiety, appetite regulation, and post-traumatic stress disorders has focused a great deal of attention on the role of serotonin in processes involving emotional states. Commensurate with our increasing understanding of the role of serotonin in behavioral processes has been the identification of at least seven serotonin (5-hydroxytryptamine; 5-HT) receptor sub-types. More recently, investigators have focused on the role of serotonin in cognitive functions, including learning and memory (Harvey 1996;Barnes and Sharp 1999;Meneses 1999Meneses , 2002Williams et al. 2002) and in the deficits in attention and associative processes seen in schizophrenia (Meltzer 1999). Serotonin receptor subtypes that have been demonstrated to occur in brain regions capable of playing a role in learning and memory include the 5-HT 1 , 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 6 , and 5-HT 7 class of receptors (Barnes and Sharp 1999;Meneses 2002). Table 1 summarizes studies that have examined the effects of serotonin agonists on learning. It can be seen that agonists at the 5-HT 1A receptor subtype had either no effect (n = 2) or impaired learning (n = 3), whereas both 5-HT 2A/2C and 5-HT 4 receptor agonists primarily improved learning. The majority of serotonin antagonists are reported to have no effect on learning (Table 2). Thus, all of the 5-HT 1A (n = 4) and 5-HT 3 (n = 4) antagonists that have been examined were found to have no effect on learning. However, two of the six 5-HT 2A/2C antagonists impaired learning, as did one of the two 5-HT 4 antagonists.Although the data cited above indicate that activation of serotonin receptors or their blockade can produce alterations in learning, these data do not provide the consistent outcomes that woul...

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“…The presence of 5HT 2A R and the known serotonergic innervation of the NAc shell and CPN (Soghomonian et al, 1987(Soghomonian et al, , 1989Van Bockstaele and Pickel, 1993;Van Bockstaele et al, 1996) suggest involvement in limbic and motor functions, respectively, that are ascribed to these regions (Welsh et al, 1998). As the target for converging excitatory afferents from the prefrontal cortex, hippocampus, and amygdala (Lopes da Silva et al, 1984;Mogenson and Nielsen, 1984;Yang and Mogenson, 1984;Christie et al, 1987;Groenewegen et al, 1987;McGeorge and Faull, 1989;Mulder et al, 1998), the NAc shell region is ideally suited for integration of locomotor activity with cognitive memory functions and associative learning (Welsh et al, 1998).…”

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confidence: 97%