Comparable changes in synaptic dopamine induced by methylphenidate and by cocaine in the baboon brain

Abstract

Though the blockade of dopamine transporters (DAT) is associated with cocaine's and methylphenidate's reinforcing effects, it is the stimulation of dopamine (DA) receptors, achieved by increases in synaptic DA, that enables these effects to occur. Positron emission tomography (PET) and [11C]raclopride were used to assess the levels of occupancy of DA D2 receptors by dopamine achieved by doses of cocaine or methylphenidate previously documented to block over 70% of DAT. Studies were performed in five baboons using a paired scan protocol designed to measure DA D2 receptor availability (Bmax/Kd) at baseline conditions and after intravenous administration of either cocaine or methylphenidate. Cocaine (1-2 mg/kg) or methylphenidate (0.5 mg/kg) administered 5 min prior to [11C]raclopride decreased Bmax/Kd by 29+/-3% and 32 + 4%, respectively. Smaller reductions in Bmax/Kd (13% for cocaine given 30 min before [11C]raclopride and 25+/-10% for methylphenidate given 40 min before [11C]raclopride) were seen with longer periods between drug and radioligand. These observations are consistent with the slower striatal clearance kinetics of [11C]methylphenidate than [1C]cocaine observed in previous PET experiments and with the approximately twofold higher potency of methylphenidate than cocaine in in vitro experiments. Though the elevation of synaptic DA induced by >70% occupancy of DAT by these drugs lead to a modest increase in occupancy of D2 receptors (25-30%), further studies are required to assess if this is an underestimation because of differences in D2 receptor binding kinetics between raclopride and DA.

Estimating neurotransmitter kinetics with ntPET: A simulation study of temporal precision and effects of biased data

“…The temporal resolution that we report here may be sufficient to provide answers that have previously eluded researchers. For instance, PET investigators have compared the kinetics of cocaine and methylphenidate (Volkow et al, 1995;Volkow et al, 1999) and the effects of long-and short-acting methylphenidate (Spencer et al, 2006), and surmised that the speed of their respective dopamine responses may predict their addictive liabilities. However, it would be impossible to test this hypothesis with PET by measuring change in binding potential.…”

“…NT parameters (Eq. 6) were selected such that the shape of F NT (t) resembled the release of dopamine (DA) in response to cocaine (based on (Volkow et al, 1999); see development in (Yoder et al, 2004)), a drug known to cause acute elevation of synaptic DA concentration. The magnitude of F NT (t) (peak value at 200% of baseline) was chosen to yield a change in BP (see below) less than 0.2, indicative of a modest effect on tracer binding.…”

“…PET and SPECT studies have detected NT release in response to pharmacological challenges, including amphetamine (e.g., Dewey et al, 1993;Innis et al, 1992;Laruelle et al, 1995;Mach et al, 1997), cocaine (Mach et al, 1997;Volkow et al, 1999), methylphenidate (Mach et al, 1997;Spencer et al, 2006;Volkow et al, 1999;Volkow et al, 1994) and other drugs, as well as behavioral challenges such as videogaming (Koepp et al, 1998), gambling and monetary reward (Pappata et al, 2002;Zald et al, 2004), and other tasks. In conventional PET analyses, NT release is detected by change in binding potential (BP: e.g., Logan et al, 1996;Logan et al, 1990), an index of the time-averaged decrease in receptor availability from baseline to activation condition.…”

“…However, the time course of neurotransmitter release in response to specific stimuli has not been measured in humans and may encode pertinent information about brain function. It has been hypothesized that the speed of dopamine release elicited by a drug may be a strong indicator of the drug's addictive liability and potential for abuse (Spencer et al, 2006;Volkow et al, 1995;Volkow et al, 1999;Volkow and Swanson, 2003). Boileau et al (2007) speculated that amphetamine-and placebo-induced dopamine responses may follow distinct time courses, but noted that PET was not capable of distinguishing such differences.…”

Dopamine increases in striatum do not elicit craving in cocaine abusers unless they are coupled with cocaine cues

“…Indeed, intravenous MP, which induces fast DA increases (Volkow and Swanson, 2003), significantly increases cocaine craving in cocaine abusers even when administered in a laboratory setting devoid of cocaine cues (Volkow et al, 1997). The craving in this case may occur because the fast and large DA increases induced by intravenous MP are equivalent to the DA increases induced by intravenous cocaine (Volkow et al, 1999b), producing an internal state that is a powerful and recognizable cocaine-related cue.The dynamic characteristics of the DA increases are known to modulate the reinforcing effects of stimulant drugs, fast DA increases are associated with reward whereas slow increases are not (Volkow and Swanson, 2003). This is consistent with the involvement of "phasic" DA cell firing (induces a large transient DA increase), rather than "tonic" DA cell firing (induces stable DA levels), in encoding for reward and reward prediction (Grace et al, 2007).…”