Dysregulated Function of Mesoaccumbal and Nigrostriatal Dopamine Systems in 5HT2CR Mutant Mice

5-HT2CR mRNA is prominently expressed in the striatum (Str) and nucleus accumbens (NAc) (Eberle-Wang et al. 1997), two subcortical regions vital for coordinating many important behaviors such as motor program selection and responses to appetitive stimuli. The Str and NAc also play vital roles in how the phenotypes of Parkinson's disease and substance abuse, two highly morbid and difficult-to-treat clinical conditions, are expressed. Studies of basal ganglia physiology and behavior in 5-HT2CR mutant mouse models have provided important insights into potential strategies to address these devastating problems (Fig. 4.1).

Neither substantia nigra pars compacta (SNc) or ventral tegmental area (VTA) dopaminergic neurons, the projection neurons for the nigrostriatal and mesoaccumbal tracts, respectively, express 5-HT2CRs. However, neurons of the substantia nigra pars reticulata (SNr), a significant source of input to both the SNc and VTA, highly express 5-HT2CRs (Di Giovanni et al. 2001; Invernizzi et al. 2007). There is also an extensive literature suggesting that in both mouse and rat models, pharmacological inhibition of the 5-HT2CR evokes a marked increase in VTA firing rates (Di Giovanni et al. 1999; Di Giovanni et al. 2000), and a smaller, but still significant increase in SNc firing rates (Di Giovanni et al. 1999). Burst firing is also more prominent in VTA and SNc neurons following 5-HT2CR pharmacological blockade (Di Giovanni et al. 1999; Gobert et al. 2000). It was thus interesting to observe that chloral hydrate anesthetized constitutive 5-HT2CR -/Y mice do not show a marked increase in VTA neuronal firing rate or bursting compared with wild-type litter-mates (Abdallah et al. 2009). By contrast, this same study demonstrated significant increases in baseline SNc neuronal firing and number of action potentials in bursts from SNc neurons of constitutive 5-HT2CR /Y mice.

Although constitutive 5-HT2CR /Y mutant mice show only a modest elevation of baseline firing rate in SNc projection neurons, there is a much more pronounced effect appreciated in extracellular dopamine concentrations at these neuron terminal fields. Using no net flux microdialysis, the most sensitive assay for detecting baseline differences in extracellular neurotransmitter concentrations, we noted higher extracellular dopamine concentrations in both Str and NAc of constitutive 5-HT2CR /Y mice (Abdallah et al. 2009).

The above-described differences in ascending dopaminergic system regulation between intact and constitutive 5-HT2CR /Y mice are associated with observable changes in how mice perform a number of important behaviors organized through the Str and NAc. Regarding striatal function, constitutive 5-HT2CR /Y mice are more likely to inappropriately terminate a bout of syntactic grooming compared with

Nucleus Accumbens

Fig. 4.1 Serotonin2C-receptor-mediated actions on ascending dopaminergic function. (a) Under baseline conditions, dopaminergic neurotransmission in the striatum and nucleus accumbens is regulated through activity of the nigrostriatal and mesoaccumbal projections. Important target behaviors, including grooming, exploration of novel environments, and responses to psychstimu-lant drugs demonstrate characteristic normal phenotypes. (b) With constitutive loss of 5-HT2CR function, there is a significant increase in nigrostriatal dopaminergic activity, as measured by both increased neuronal firing rates and increased burst firing of SNc neurons. This change in turn leads to a significant increase in extracellular dopamine concentrations in both the striatum and nucleus accumbens. 5-HT2CR loss in basal ganglia nuclei distal to the striatum in turn contributes to observed dysruption of a number of target behaviors, including aberrant grooming, increased ste-reotypic motor patterns, and markedly enhanced motivation to self-administer psychostimulants

Fig. 4.1 Serotonin2C-receptor-mediated actions on ascending dopaminergic function. (a) Under baseline conditions, dopaminergic neurotransmission in the striatum and nucleus accumbens is regulated through activity of the nigrostriatal and mesoaccumbal projections. Important target behaviors, including grooming, exploration of novel environments, and responses to psychstimu-lant drugs demonstrate characteristic normal phenotypes. (b) With constitutive loss of 5-HT2CR function, there is a significant increase in nigrostriatal dopaminergic activity, as measured by both increased neuronal firing rates and increased burst firing of SNc neurons. This change in turn leads to a significant increase in extracellular dopamine concentrations in both the striatum and nucleus accumbens. 5-HT2CR loss in basal ganglia nuclei distal to the striatum in turn contributes to observed dysruption of a number of target behaviors, including aberrant grooming, increased ste-reotypic motor patterns, and markedly enhanced motivation to self-administer psychostimulants wild-type mice (Abdallah et al. 2009). Further, constitutive loss of 5-HT2CR function effects syntactic grooming in a manner similar to drugs that increase dopaminergic tone. Constitutive 5-HT2CR -/Y mice also display compulsive behaviors. For example, mutant mice will chew more nonnutritive clay, neatly trim plastic circular mesh, and engage in frequent head-dipping behaviors compared with wild-type mice (Chou-Green et al. 2003b). Correlates of increased dopaminergic tone in the NAc include delayed habituation to a novel environment (Rocha et al. 2002) and increased interactions with a novel object placed in the home cage (Heisler et al. 2007a).

Constitutive 5-HT2CR /Y mice also clearly demonstrate that serotonergic neurotransmission is an important regulator of overall mouse locomotor responses. For example, rodents receiving mCPP demonstrate a modest dose-dependent suppression of locomotion in a home cage or arena environment (Kennett and Curzon 1988; Lucki et al. 1989). However, administration of mCPP to 5-HT2CR mutant mice evokes a dramatic hyperlocomotor response that can be blocked using antagonists of 5-HT1B (Heisler and Tecott 2000) (see also Dalton et al. 2004; Schlussman et al. 1998), 5-HT2A, and 5-HT2B receptors (Dalton et al. 2004). Thus, serotonergic stimulation of global basal ganglia circuits produces both stimulatory and inhibitory locomotor responses, with responses transduced through 5-HT2A, 5-HT2B, and 5-HT2C receptors (which are dominant) causing decreased activity while responses transduced through 5-HT1A and 5-HT1B receptors cause increased locomotor activity (Dalton et al. 2004).

Constitutive 5-HT2CR /Y mice also demonstrate altered responses to drugs of abuse. In wild-type mice, administration of either cocaine (a promiscuous inhibitor of serotonin, dopamine, and norepinephrine reuptake) or d-amphetamine (an inverse agonist of these catecholaminergic reuptake systems) leads to a behavioral response characterized by increased locomotion, locomotor route tracing, and at higher doses, long periods of behavioral stereotypies (Schlussman et al. 1998; Simpson and Iversen 1971). Psychostimulant-evoked locomotion is thought to reflect increasing NAc activation (Gold et al. 1988), while psychostimulant-evoked stereotypies are associated with increasing imbalance in ratio of striasomal to matrix striatal activation (Canales and Graybiel 2000). Constitutive 5-HT2CR /Y mice receiving cocaine demonstrate more locomotor activity at similar doses and time points compared with wild types (Rocha et al. 2002). Concordantly, cocaine-evoked efflux of dopamine into the NAc is much exaggerated in constitutive 5-HT2CR /Y mice compared with wild types. Furthermore, mutant mice receiving d-amphetamine, the selective dopamine reuptake inhibitor GBR 12909 (vanox-erine), and the dopamine D1 receptor agonist SKF-81297 are more sensitive to both the locomotor-activating and stereotypy-development effects of drug treatment (Abdallah et al. 2009). Interestingly, complete loss of 5-HT2CR function did not lead to phenotypic changes in Str extracellular dopamine concentrations following treatment with either cocaine, d-amphetamine, or vanoxerine. Since constitutive 5-HT2CR /Y mice do not display any significant changes in Str or NAc expression of D1 and/or D2 receptors, nor any phenotypic changes in Str medium spiny neurons, it is likely that basal ganglia systems downstream of the Str and NAc are functionally effected by alterations in 5-HT2CR activity.

Finally, constitutive 5-HT2CR /Y mice demonstrate an altered drive to ingest cocaine. While both wild-type and mutant mice learn lever pressing to acquire a cocaine reward at a 1:1 reinforcement, constitutive 5-HT2CR /Y mice will work harder for the same dose of cocaine (as measured by their performance in a progressive ratio reward situation; see Rocha et al. 2002). In fact, constitutive 5-HT2CR /Y mice will make 25% more lever presses for cocaine (over multiple trial sessions) compared with wild types. No phenotypic differences were noted in extinction of operant responses to cocaine, or in reinstatement of lever pressing responses for a nondrug reward.

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