Effects of 5-HT_1A Receptor Stimulation on D1 Receptor Agonist-Induced Striatonigral Activity and Dyskinesia in Hemiparkinsonian Rats

Abstract

Accumulating evidence supports the value of 5-HT 1A receptor (5-HT 1A R) agonists for dyskinesias that arise with long-term L-DOPA therapy in Parkinson's disease (PD). Yet, how 5-HT 1A R stimulation directly influences the dyskinetogenic D1 receptor (D1R)-expressing striatonigral pathway remains largely unknown. To directly examine this, one cohort of hemiparkinsonian rats received systemic injections of Vehicle + Vehicle, Vehicle + the D1R agonist SKF81297 (0.8 mg/kg), or the 5-HT 1A R agonist ±8-OH-DPAT (1.0 mg/kg) + SKF81297. Rats were examined for changes in abnormal involuntary movements (AIMs), rotations, striatal preprodynorphin (PPD), and glutamic acid decarboxylase (GAD; 65 and 67) mRNA via RT-PCR. In the second experiment, hemiparkinsonian rats received intrastriatal pretreatments of Vehicle (aCSF), ±8-OH-DPAT (7.5 mM), or ±8-OH-DPAT + the 5-HT 1A R antagonist WAY100635 (4.6 mM), followed by systemic Vehicle or SKF81297 after which AIMs, rotations, and extracellular striatal glutamate and nigral GABA efflux were measured by in vivo microdialysis. Results revealed D1R agonist-induced AIMs were reduced by systemic and intrastriatal 5-HT 1A R stimulation while rotations were enhanced. Although ±8-OH-DPAT did not modify D1R agonist-induced increases in striatal PPD mRNA, the D1R/5-HT 1A R agonist combination enhanced GAD65 and GAD67 mRNA. When applied locally, ±8-OH-DPAT alone diminished striatal glutamate levels while the agonist combination increased nigral GABA efflux. Thus, presynaptic 5-HT 1A R stimulation may attenuate striatal glutamate levels, resulting in diminished D1R-mediated dyskinetic behaviors, but maintain or enhance striatal postsynaptic factors ultimately increasing nigral GABA levels and rotational activity. The current findings offer a novel mechanistic explanation for previous results concerning 5-HT 1A R agonists for the treatment of dyskinesia.

Effects of L-dopa priming on cortical high beta and high gamma oscillatory activity in a rodent model of Parkinson's disease

“…Furthermore, 8-OH-DPAT did not reverse SKF81297-induced decreases in high beta power in contrast to its effects when administered after L-dopa. Moreover, in contrast to its moderate reduction of high gamma power, and in agreement with previous reports (Dupre et al, 2007, 2013), 8-OH-DPAT dramatically reduced SKF81297-induced ALO AIMs (Fig. 5D).…”

“…5H). This effect was associated with increased rotational activity that is distinct from ALO AIMs (Breger et al, 2013) and often observed with this treatment combination (Dupre et al, 2007, 2013). Furthermore, 8-OH-DPAT did not reverse SKF81297-induced decreases in high beta power in contrast to its effects when administered after L-dopa.…”

Effects of noradrenergic denervation by anti-DBH-saporin on behavioral responsivity to l-DOPA in the hemi-parkinsonian rat

“…In support, compounds that reversed parkinsonian motor deficits frequently induced contralateral rotations [34, 35]. Additionally, compounds with low dyskinesia liability, such as bromocriptine, induced strong contralateral circling behavior [36, 37] and many compounds that effectively reduce dyskinesia often do not alter L-DOPA- or DA agonist- induced rotations [38, 39]. In fact, some antidyskinetic compounds actually enhance or extend rotational behaviors in the 6-OHDA lesioned rat model of PD when given in conjunction with L-DOPA or DA agonists [40–42].…”

Effects of 5-HT1A receptor stimulation on striatal and cortical M1 pERK induction by l-DOPA and a D1 receptor agonist in a rat model of Parkinson's disease

“…Striatal D 1 R stimulation can activate pERK and promote dyskinesia (Feyder et al, 2011; Gerfen et al, 2002; Santini et al, 2010; Papadeas et al, 2004) while 5-HT 1A Rs reduce D 1 R-mediated dyskinesia (Dupre et al, 2011, 2013), suggesting that striatal 5-HT 1A Rs may alter dyskinesia by reducing D 1 R supersensitivity. By contrast, some 5-HT 1A Rs increase pERK by activating the Ras pathway (Raymond et al, 1999) and overactivity of the Ras pathway promotes dyskinesia (Fasano et al, 2010).…”

“…In animal models, serotonin 1A receptor (5-HT 1A R) agonists reduce both LID and D 1 R-mediated dyskinesia (Bibbiani et al, 2001; Dupre et al, 2008, 2011, 2013). Following DA-depletion, the expression of 5-HT 1A Rs within the striatum and primary motor cortex (M1) increases, an effect further potentiated by L-DOPA treatment (Frechilla et al, 2001; Huot et al, 2012).…”