Opposite effects of dopamine D2 and D3 receptors on learning and memory in the rat
Introduction
Brain dopamine receptors were originally divided into D1 and D2 subtypes (Spano et al., 1978; Kebabian and Calne, 1979) on the basis of pharmacological and biochemical evidence. For a decade, the dual receptor concept served as the foundation for the study of dopamine receptors. However, following the introduction of gene cloning procedures, three novel dopamine receptor subtypes have been characterized over the past five years and called D3, D4 and D5 (for a review, see Gingrich and Caron, 1993; Sokoloff and Schwartz, 1995). Detailed structural, pharmacological and biochemical studies, however, pointed out that all dopamine receptor subtypes fall into one of the two initially recognized receptor categories. Thus, the dopamine D1-like family includes D1 and D5 receptors, while the dopamine D2-like family includes D2, D3 and D4 receptors. Although the structural and biochemical characteristics and the distribution of the different dopamine receptor subtypes have been largely elucidated, the function of many of these receptors is still completely unknown. In particular, the lack of compounds able to completely discriminate between dopamine D3, D4 and D5 receptors has so far limited understanding of their function. Although all the dopamine D2-like receptors bind the hallmark dopamine D2 receptor ligands with high affinity, some important selectivities have emerged in recent years. The neuroleptic, clozapine, is approximately 10 times more potent at dopamine D4 than at dopamine D2 and D3 receptors (Van Tol et al., 1991), while raclopride and remoxipride exhibit 10–20-times lower affinity at the dopamine D4 than at the dopamine D2 and D3 receptors. Quinpirole and 7-OH-DPAT (7-hydroxy-N,N-di-n-propyl-2-aminotetralin) show 100- and 10-times higher affinity for dopamine D3 than for dopamine D2 receptors, respectively (Sokoloff et al., 1990; Levesque et al., 1992). More recently, antagonists relatively selective for the dopamine D3 receptor have been developed, such as nafadotride (N[n(butyl 2-pyrrolidinyl)methyl] 1-metoxy 4-cyano, naphthalene 2-carboxamide), which is characterized by a 10 times higher affinity for the dopamine D3 receptor than for the dopamine D2 receptor (Griffon et al., 1995). This compound readily crosses the blood–brain barrier and is selective for dopamine D3 receptors in the range of doses from 0.2 to 1 mg/kg. At higher doses (5–10 mg/kg), nafadotride acts on both dopamine D2 and D3 receptors. Mesolimbocortical dopamine plays a role in learning and memory. In the monkey, activation of both dopamine D1 and D2 receptors in the prefrontal cortex has been reported to improve performance in a working memory task (Sawaguchi and Goldman-Rakic, 1991, Sawaguchi and Goldman-Rakic, 1994; Arnsten et al., 1995). In the rat, activation of both dopamine D1 and D2 receptors in the hippocampus facilitates acquisition and retention of different working memory tasks (Packard and White, 1991; White and Viaud, 1991; White et al., 1993; Levin and Rose, 1995). In line with this, it has been reported that dopamine neurons originating from the ventral tegmental area and projecting to the lateral and medial septum (Lindvall and Bjorklund, 1983), exert a facilitatory influence on the activity of the septo-hippocampal cholinergic system (Imperato et al., 1993, Imperato et al., 1994; Hersi et al., 1995) which plays a key role in learning and memory (Grecksch and Matthies, 1981; Brito et al., 1983; Hepler et al., 1985). The specific receptor subtypes mediating these effects of dopamine, however, are still unknown. In addition to the dopamine D2, D3 and D4 receptors are expressed in the hippocampus and dopamine D3 receptors are present in the septal area (Bouthenet et al., 1991), suggesting a possible contribution of these receptor subtypes to the behavioral effects of dopamine D2-like receptor agonists. In the present study, using relatively selective dopaminergic drugs, we investigated the role of dopamine D2 and D3 receptors in learning and memory. The transient amnesia induced by scopolamine in the passive avoidance test was used as behavioral experimental model. Changes noted in the short-term memory of the passive avoidance response have been, in fact, related to hippocampal activity (Schwegler et al., 1981). The results suggest that dopamine D2 and D3 receptors are both involved, with opposite roles, in learning and memory. In particular, while activation of dopamine D2 receptors facilitates the memory process, dopamine D3 receptors play an inhibitory influence on memory consolidation.
Section snippets
Materials and methods
Male Sprague–Dawley rats (Charles River, Calco, Milan, Italy) weighing 200–250 g were used. The animals (4 rats in each cage) were housed at constant temperature (20°C) and humidity (60%), exposed to light for 12 h daily, from 6.00 a.m. to 6.00. p.m., and given food and water at libitum.
Results
The effects of different doses of the non-selective dopamine receptor agonist, apomorphine, on scopolamine-induced disruption of consolidation of a previously acquired passive avoidance response in the rat are shown in Fig. 1. Administration of scopolamine immediately after acquisition strongly impaired consolidation of the behavioral response, resulting in amnesia in the retention tests performed 2 and 24 h later. Only 15 to 20% of the trained rats retained the passive avoidance response under
Discussion
Mesolimbocortical dopamine plays a role in learning and memory. Activation of both dopamine D1 and D2 receptors in the hippocampus improves acquisition and retention of different working memory tasks in the rat (Packard and White, 1991; White and Viaud, 1991; Levin and Rose, 1995; White et al., 1993). Similarly, in the monkey, stimulation of dopamine D1 and D2 receptors in the prefrontal cortex improves performance in a model of working memory (Sawaguchi and Goldman-Rakic, 1991; Sawaguchi and
Acknowledgements
This work was upported by BIOMED-I BMH1-CT92-1086.
References (35)
- et al.
Localization of dopamine D3 receptor mRNA in the rat using in situ hybridization histochemistry: Comparison with dopamine D2 receptor mRNA
Brain Res.
(1991) - et al.
Dopamine D1 receptor ligands modulate cognitive performance and hippocampal acetylcholine release in memory-impaired aged rats
Neuroscience
(1995) SCH 23390. The first selective D1 dopamine antagonist
Eur. J. Pharmacol.
(1983)- et al.
Effects of haloperidol, sulpiride and SCH 23390 on passive avoidance learning in mice
Eur. J. Pharmacol.
(1988) - et al.
Effects of dopamine receptor agonists on passive avoidance learning in mice: Interaction of dopamine D1 and D2 receptors
Eur. J. Pharmacol.
(1992) - et al.
Stimulation of both D1 and D2 receptors facilitates in vivo acetylcholine release in the hippocampus
Brain Res.
(1993) Mesencephalic dopaminergic afferents to the lateral septal nucleus of the rat
Brain Res.
(1975)- et al.
Acetylcholine release in the hippocampus: Regulation by monoaminergic afferents as measured by in vivo microdialysis
Brain Res.
(1992) - et al.
The central effects of a novel dopamine agonist
Eur. J. Pharmacol.
(1978) - et al.
Novel dopamine receptors half a decade later
Trends Pharmacol. Sci.
(1995)
Localized intracaudate dopamine D2 receptor activation during the post-training period improves memory for visual or olfactory conditioned emotional responses in rats
Behav. Neural Biol.
Memory enhancement by post-training peripheral administration of low doses of dopamine agonists: Possible autoreceptor effect
Behav. Neural Biol.
Dopamine D2 receptor mechanisms contribute to age-related cognitive decline; The effects of quinpirole on memory and motor performance in monkeys
J. Neurosci.
Memory and septo-hippocampal cholinergic system in the rat
Psychopharmacology
Modulation of cocaine self-administration in the rat through D3 dopamine receptors
Science
Effects of the novel compound aniracetam (Ro 13-5057) upon impaired learning and memory in rodents
Psychopharmacology
Opposing roles for dopamine D2 and D3 receptors on neurotensin mRNA expression in nucleus accumbens
Eur. J. Neurosci.
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2015, Neurobiology of Learning and MemoryCitation Excerpt :The scopolamine effect on memory consolidation of the step-down and step-through passive avoidance task performed under low-moderate shock intensities (range 0.3–0.8 mA) has been extensively studied in rats. In the step-down passive avoidance task, independently of the scopolamine dose (0.15 or 1 mg/kg i.p.) and the delay of its administration after the acquisition (immediately, 30 min or 6 h), impaired memory consolidation was found on the 24 h retention trial, in both, single (Gutierres et al., 2012) and well trained rats (Doyle, Regan, & Shiotani, 1993; Sigala et al., 1997). Moreover, the amnesic effect obtained at the 24 h retention trial, persisted on the 48 h retention trial too (Doyle et al., 1993).