Multiple evidence of a segmental defect in the anterior forebrain of an animal model of hyperactivity and attention deficit
Introduction
The frontal and posterior parietal cortices are thought to be the neural sites responsible for attentive processes pertaining to the motivational/emotional and the visuo-spatial domain, respectively [1], [2].
The major pathology of attentive processes is represented by Attention-Deficit Hyperactivity Disorder in children (ADHD; see Ref. [3] for a review). ADHD is a neurodevelopmental disorder characterized by attentional problems, hyperkinesis, restlessness, and disturbances in timing. It affects mostly male children [3] with a high genetic component as demonstrated by family, twin and adoption studies, and the allelic polymorphism of the dopamine (DA) D-4 receptor gene and the DA transporter protein (DAT) [4].
The most widely studied model system for ADHD is represented by the spontaneously hypertensive rat (SHR) [5]. Some of the behavioral problems of ADHD children and SHR have been linked to dysfunction of the mesocorticolimbic DA system that innervates the nucleus accumbens, and the prefrontal cortex (see Ref. [6] for a review) and is a major component of a multiple system involved in attention and reinforcement mechanisms [7], [8]. DA is known to bind to a heterogeneous class of synaptic and extra-synaptic receptors of the D-1 and D-2 subfamilies [9], thus increasing the signal-to-noise ratio [10].
We have focused upon the most anterior portion of the forebrain including structures such as the nucleus accumbens (ACB), that constitutes an anatomical and physiological unit, which has been divided into three subterritories: the “rostral pole”, the “core”, and the “shell” [11]. ACB is the target of a wide glutamate innervation from prefrontal cortex, midline intralaminar thalamic nuclei, hippocampus, basal amygdala nuclei [12], [13], as well as an extensive DA projection from the ventral tegmental area (VTA), serotonin fibers from raphĕ nuclei and histamine fibers from the posterior hypothalamus. In turn, ACB sends efferent to all mesencephalic DA sources [14]. The “core” projects to the prefrontal cortex, while the shell and rostral pole have a wide output to the lateral hypothalamus, basal amygdala and hippocampus [14].
The Ca2+/calmodulin-dependent protein kinase II (CaMKII; see Ref. [15] for a review) is a member of the serine/threonine kinase family that constitutes the main protein of the postsynaptic density, but is present also at the presynaptic terminal [16]. CaMKII is a multifunctional protein that acts as one of the major molecular devices in signal transduction, on which converge several signals derived from the cross-talk between different second messenger systems.
Transcription factors, such as c-FOS and JUN-B, are members of a numerous and heterogeneous gene superfamily, also referred to as immediate early genes (IEG; [17]). They code for proteins, which mediate many of the long-term neuronal responses to trans-synaptic signals [18]. In fact, they dimerize and enter the nucleus where they bind to specific DNA binding sites, such as the AP-1 site [17] for FOS and JUN-B and the SP-1 site for ZIF/268.
Therefore, using the D-1 and D-2 dopamine receptor types, CaMKII, and the transcription factors c-FOS and JUN-B as markers of neuronal activity, the aim of this study was to investigate their spatial distribution in the antero-posterior plane in the juvenile SHR and Wistar-Kyoto Normotensive (WKY) controls.
Section snippets
Animals
Juvenile (4-week-old) male SHRs and WKY controls (Charles-River, Italy) were housed in standard cages during a 2-week period for acclimatization and handling. All other parameters fulfilled the requirements of the “Guide for the Care and Use of Laboratory Animals” by the National Research Council, implemented by EU rules.
Procedures
Rats were either given no injection (basal conditions) or given a daily intraperitoneal injection of vehicle (vehicle control) or methylphenidate-HCl (3 mg/kg) for 14 days. Rats
Dopamine receptor autoradiography
A higher density of DA D-1 binding sites and a lower density of D-3 autoreceptors was demonstrated in the SHR, by saturation analysis (Fig. 1) for the D-1 sites by 3H-SCH23390 and by competition analysis with 3H-raclopride as ligand and 7-OH-DPAT as nonlabeled displacer for the D-3 sites, respectively (see Table 1 for a summary of the results). This was assessed in a pool of sections from anterior but not posterior portions of different forebrain structures. A significantly higher level of D-1
Discussion
The multiple high resolution light microscope imaging probe analysis used in this series of studies revealed the existence of a segmental defect in the anterior forebrain of a genetic model of hyperactivity and attention deficit, i.e. the juvenile prehypertensive SHR rats. This defect comprises the most rostral portion of the dorsal and ventral striatum and the olfactory tubercle.
This has been demonstrated by multiple neuronal markers, namely: (1) an increased density of dopamine D-1 [25] and
Acknowledgements
This project has been supported by EU HCM grant (1994–96) and by Telethon-Italy grant E.513 (1997-98).
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Review of rodent models of attention deficit hyperactivity disorder
2022, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Overall, these studies suggest hypodopaminergic function in the SHR model. While some studies find no differences in DRD1, DRD2, and DRD3 expression (Fuller et al., 1983; Van den Buuse et al., 1992; Linthorst et al., 1993), others show an upregulation of DRD1 and DRD2 expression in nucleus accumbens, striatum, and frontal cortex (Chiu et al., 1982; Le Fur et al., 1983; Chiu et al., 1984; Lim et al., 1989; Sadile, 2000; Papa et al., 2002) but no change in DRD3. Higher DRD1 and DRD2 expression are consistent with decreased dopamine release causing upregulation of receptors.
Performance of spontaneously hypertensive rats in a peak-interval procedure with gaps
2008, Behavioural Brain ResearchInterval bisection in spontaneously hypertensive rats
2007, Behavioural ProcessesNeural systems implicated in delayed and probabilistic reinforcement
2006, Neural NetworksCitation Excerpt :It is innervated by dopamine (DA) neurons that respond to errors in reward prediction in a manner appropriate for a teaching signal (Schultz, 1998; Schultz et al., 1997; Schultz & Dickinson, 2000; Schultz et al., 1998), as discussed above, and interventional studies have shown it to be a key site for the motivational impact of impending rewards (reviewed by Cardinal, Parkinson, Hall, et al. (2002), Everitt et al. (1999), Parkinson, Cardinal, and Everitt (2000), Robbins et al. (2005), Robbins and Everitt (1996), Salamone, Cousins, and Snyder (1997)). Acb abnormalities have also been observed in rat models of ADHD (Carey et al., 1998; de Villiers et al., 1995; Papa et al., 1996, 1998; Russell et al., 1998; Russell, 2000; Sadile, 2000). Causal experimental studies have shown that lesions of the AcbC produce impulsive choice, reducing rats’ preference for large/delayed rewards, compared to small/immediate rewards (Cardinal, Pennicott, Sugathapala, Robbins, & Everitt, 2001; Cardinal, Robbins, et al., 2003; Cardinal, Parkinson, et al., 2003).