Dose-response characteristics of methylphenidate on locomotor behavior and on sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats

Abstract

BackgroundMethylphenidate (MPD) is a psychostimulant commonly prescribed for attention deficit/hyperactivity disorder. The mode of action of the brain circuitry responsible for initiating the animals' behavior in response to psychostimulants is not well understood. There is some evidence that psychostimulants activate the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC).MethodsThe present study was designed to investigate the acute dose-response of MPD (0.6, 2.5, and 10.0 mg/kg) on locomotor behavior and sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats previously implanted with permanent electrodes. For locomotor behavior, adult male Wistar-Kyoto (WKY; n = 39) rats were given saline on experimental day 1 and either saline or an acute injection of MPD (0.6, 2.5, or 10.0 mg/kg, i.p.) on experimental day 2. Locomotor activity was recorded for 2-h post injection on both days using an automated, computerized activity monitoring system. Electrophysiological recordings were also performed in the adult male WKY rats (n = 10). Five to seven days after the rats had recovered from the implantation of electrodes, each rat was placed in a sound-insulated, electrophysiological test chamber where its sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10.0 mg/kg MPD injection. Time interval between injections was 90 min.ResultsResults showed an increase in locomotion with dose-response characteristics, while a dose-response decrease in amplitude of the components of sensory evoked field responses of the VTA, NAc, and PFC neurons. For example, the P3 component of the sensory evoked field response of the VTA decreased by 19.8% ± 7.4% from baseline after treatment of 0.6 mg/kg MPD, 37.8% ± 5.9% after 2.5 mg/kg MPD, and 56.5% ± 3.9% after 10 mg/kg MPD. Greater attenuation from baseline was observed in the NAc and PFC. Differences in the intensity of MPD-induced attenuation were also found among these brain areas.ConclusionThese results suggest that an acute treatment of MPD produces electrophysiologically detectable alterations at the neuronal level, as well as observable, behavioral responses. The present study is the first to investigate the acute dose-response effects of MPD on behavior in terms of locomotor activity and in the brain involving the sensory inputs of VTA, NAc, and PFC neurons in intact, non-anesthetized, freely behaving rats previously implanted with permanent electrodes.

Methylphenidate modulates the locus ceruleus neuronal activity in freely behaving rat

“…The above reports indicate that LC neurons are electrophysiological quiet during low vigilance states such as sleep or in the lack of sensory input, while during active walking or exposed to a strong stimulus, the LC neurons markedly increase its firing rate. Consistent with the above studies, the present experiment found that after administration of MPD most of LC units significant increase their firing rate, since administration of MPD (2.5mg/kg or above) resulted in an increase in locomotor activity (Askenasy et al, 2007;Gaytan et al, 2000a; 2000b; 2002;Yang et al, 2003a; 2006a; 2006b; 2006c; 2007; 2010). …”

“…Previous dose response experiments using MPD from 0.1 to 40 mg/kg found that 2.5 mg/kg MPD (i.p.) elicited behavioral and neurophysiological sensitization ( Gaytan et al, 1996;Lee et al, 2009; Podet et al, 2010;Yang et al, 2001; 2003b; 2006a; 2006c; 2007; 2010; 2011). Thus, the 2.5 mg/kg MPD dose was used in this experiment.…”

“…Activity after MPD administration on ED10 to activity post MPD on ED1. Statistical significance between the above comparisons were based on the critical ratio test ( $\mathrm{normalC}.\mathrm{normalR}.=false(\mathrm{normalE}-\mathrm{normalC}false)/false(\sqrt{E}+\mathrm{normalC}false)=\pm 1.96=\mathrm{normalP}=0.05$) where C is the control and E is the drug activity (Claussen and Dafny 2012; Dafny 1980;Yang et al, 2006a; 2006b; 2006c). P < 0.05 was considered significant.…”

Ritalin Use Modifies Alcohol Effects in Rats

“…The acute dose response for the 2.5 and 10.0 mg/kg MPD groups (moderate and high MPD doses [8]) shows increases in locomotor activity in comparison to their baseline recordings (Figure 2). This is expected: prior MPD dose response experiments have shown similar results [16]- [21] [25] [37], indicating that chronic MPD administration elicits persistent changes in the CNS [38] [39].…”

“…), are calculated as freebase. Dosages were selected from prior MPD dose response studies [6] [14]- [19] [21]. These studies assessed the dose responses of eight different concentrations of MPD, in which three were selected.…”