The Effects of D2 Receptors on the Inverted U-Shape Response Curve to Psychostimulants

Introduction

Behavioral traits such as impulsiveness are highly correlated with the propensity of animals to self-administer drugs. Piazza et al (1989) placed rats in a novel environment, measured their locomotor activity for two hours, and then classified every rat as either a high or low responder to novelty. Upon subsequent exposure to amphetamine, high novelty responding rats showed significantly increased levels of self-injections of low doses of the psychoactive compound. Additionally, rats screened for high impulsivity by preferentially choosing small, immediate food reinforcement over larger, delayed reinforcement self-administer cocaine more quickly and are more vulnerable to reinstating cocaine use following extinction (Perry et al, 2008). The reliable correlation between behavioral phenotype and propensity for rodent models to self-administer psychostimulants indicates that differences on the neural level mediate both traits. Physiologically, differences in the dopamine system are believed to be one of the major factors responsible for the variance of individual responses to psychostimulants, especially in the nucleus accumbens and prefrontal cortex (Dalley et al, 2007). The reinforcing aspects of most drugs of abuse are eliminated by blocking the output of neurons in the nucleus accumbens or their dopamine-based inputs (Wise, 2002). Dopamine subtype D2 receptors appear to play an especially important role in responses to dopamine-dependent drugs, although the specific mechanism of action is not completely clear (Farnsworth et al, 2009).

There is evidence that D1 receptors in the prefrontal cortex operate under an inverted U-shaped dose-dependent response curve, such that stimulation above and below the optimal level will decrease function. Williams and Goldman-Rakic (1995) measured individual neuronal activity in the dorsolateral prefrontal cortex (dlPFC) of two monkeys during an oculomotor task in which they had to remember the spatial position of a stimulus and update that memory on a trial to trial basis. Additionally, they designed carbon-fiber electrodes with three barrels for iontophoresic drug injection during recording. They found that low doses of a selective D1 antagonist accentuated the memory field of individual neurons by reducing background activity, but that high doses of the same antagonist decreased the memory field of individual neurons by inhibiting firing nonspecifically.  This U-shaped response curve is reminiscent of the Yerkses-Dodson law on the behavioral level that performance is highest at medium arousal but lower at both low and high arousal.  Although the researchers found no such dose-dependent effects in neurons after blocking D2 receptors using the antagonist raclopride, it is possible that D2 receptors would show a similar dose-dependent response curve in other brain regions. The concentration of D2 receptors in the prefrontal cortex is only one-tenth as great as that of D1 receptors, indicating that they are much less involved in this memory-dependent task.

Indeed, there is some evidence that D2 receptors in the nucleus accumbens may mediate the overall response curves seen upon stimulation with exogenous chemicals. D2 receptors are at their highest concentrations in the striatum, and their relative concentration as compared to D1 receptors is much higher in the nucleus accumbens than the prefrontal cortex (Worsley et al, 2000). This paper will review the effects of D2 receptors on the observed U-shaped dose dependent response curve of animal’s responses to a variety of psychostimulants, and propose a model to explain these effects across drugs.

Cocaine

Cocaine inhibits the action of neuronal dopamine transporters, which increases the concentration of dopamine in the synapse. Although the specific mechanism is hotly debated, pretreatment with the D2 receptor antagonist eticlopride prevents the decrease in total dopamine transport, suggesting that activation of this receptor is instrumental in mediating the effects of the drug (Farnsworth et al, 2009). Cocaine use not only modulates D2 receptor availability, but D2 receptor availability is a predisposing trait to cocaine use. Nader et al (2006) used PET scans to measure the ratio of the uptake of a D2 radioligand in the cerebellum as well as the basal ganglia of 12 rhesus monkeys, indicative of D2 receptor availability. They found a consistently inverse correlation between rates of cocaine self-administration and pre-tested D2 receptor availability, a statistically significant effect from weeks 4-10 of 10. Their results suggest that monkeys with lower levels of D2 availability may require additional stimulation of D2 receptors in order to achieve the same optimal sensation.

Other researchers have found an association between the level of D2 receptors and cocaine use in rodent models. Dalley et al (2007) measured impulsivity in outbred rats with a visual attention task, and based on these results grouped the rats into either high-responder (HR) or low-responder (LR) phenotypes. Using micro-PET and a D2/D3 antagonist they measured D2/D3 receptor availability in the ventral striatum (which contains the nucleus accumbens) as well as the dorsolateral striatum. Compared to LR rats, HR rats had decreased receptor availability in the ventral striatum (p=0.037), but not the dorsolateral striatum. They also measured overall dopamine release in the nucleus accumbens of both groups but found no difference, suggesting that the key difference between groups is a reduction in the number of D2-like receptors in HR rats. Finally, they measured rates of cocaine self-administration and found that HR rats injected cocaine at a significantly higher rate than their LR counterparts (p<0.001).

Caine et al (2002) evaluated the cocaine dose-response curve in mutant D2 receptor-lacking mice. The typical dose-dependent response curve of mice to various doses of cocaine is an inverted U-shape. The mutant mice did not deviate significantly from the wildtype’s inverted U-shape response low doses, but at the two highest doses had significantly more self-injections per hour of cocaine (p<0.01 for each). The fact that D2 receptor lacking mice were reinforced by cocaine at all suggests that the D2 receptor is not the only pathway for the rewarding effects of cocaine, although it is possible that the mutant mice may have compensatory changes in other receptors and systems not found in normal mice (Thanos et al, 2008). The researchers also injected normal mice with a D2 antagonist which resulted in an overall rightward shift of the inverted U-shape curve. Such a rightward shift of the dose-dependent response curve of cocaine self-administration following D2 antagonist injection in the CNS is a consistent finding. For example, Negus et al (1996) found a rightward shift in the dose-response curve of monkeys responding to cocaine when treated with the D1 and D2 receptor antagonist flupenthixol.

Finally, in a clinical proof of principle, Thanos et al (2008) infused an adenovirus with the D2 receptor gene into the nucleus accumbens, in an attempt to upregulate its expression. Following this upregulation, the average number of cocaine-seeking self-administered lever presses was significantly lower as compared to baseline for six days. Overall, the effects of D2 receptor availability in rhesus monkeys, normal mice subjected to D2 antagonist, and D2 receptor “knock-out” mice on cocaine self-administration all point to a clear trend. A lack of D2 receptors increases the levels of responding towards cocaine, especially in later weeks and at higher doses. This suggests that dopamine D2 receptors in the nucleus accumbens are responsible in part for the reinforcing effects of cocaine, such that a lack of D2 receptor availability causes a rightward shift in self-adminitration patterns.

Nicotine

Nicotine is another psychostimulant that acts in part on D2 receptors in the nucleus accumbens. Fehr et al (2008) identified smoking and non-smoking human subjects and determined levels of D2 receptor availability in each using PET scanning in combination with the receptor ligand fallypride. They found lower levels of D2/D3 receptor availability in the striatum among smokers than non-smokers. A genetic component also suggests indirect evidence that nicotine use is predicted by lower levels of D2 receptors. The dopamine receptor D2 (DRD2) A1 allele has been shown to account for 12% of the variance in D2 receptor availability in a representative Finnish sample, such that individuals with one A1 allele have a significant reduction in D2 receptor availability as compared to those homozygous for the A2 allele (Pohjalainen et al, 1998). This genotype difference has been found to be able to predict the efficacy of attempts to quit smoking, as A1 individuals are significantly more likely to be current rather than former smokers (Morton et al, 2006). Moreover, there is behavioral evidence that smokers with at least one DRD2 A1 allele tend to have enhanced performance in rapid visual information processing tasks as compared to homozygous A2 individuals (Gilbert et al, 2005).

The trends in the physiological data indicate that lower levels of D2 receptors are correlated with an increased likelihood to be a smoker, and the trends in the genetic data rule out the objection that these differences are solely because of nicotine use but not indicative of an increased propensity to use nicotine. The behavioral results are particularly intriguing, because they suggest that subjects with lower levels of D2 receptors may be more stimulated by the same dose of nicotine, indicative of a possible rightward shift of the dose-response curve.

Ritalin

Like cocaine, methylphenidate (Ritalin) is a psychostimulant that binds to dopamine transporters and increases extracellular levels, although the impact of the two drugs are strikingly different, which may be due to their differential effect on muscanaric receptors (Farnsworth et al, 2009). Botly et al (2008) developed a rat model of Ritalin abuse. They found that drug naïve animals learn to self-administer the drug quickly, with similar dose infusions as seen in amphetamine or cocaine models. Injection of the D2 receptor antagonist eticlopride at a high dose significantly increased the number of self-infusions. This finding led the authors to speculate that, as in cocaine use, D2 receptor antagonists block the reinforcing effects of methylphenidate.

Volkow et al (1999) examined the behavioral effects of the drug on 23 males with self-reporting scales, as well as measuring their D2 receptor levels with PET scanning following injection of the D2 antagonist raclopride. Subjects who found the effects of Ritalin as positive (n=12) had significantly lower levels of D2 receptors than those who described the effects as negative (n=9). This is additional evidence for a correlation between D2 receptor levels and the reinforcing effects of the drug.

Amphetamines

Methamphetamine (MA) stimulates monoamine release, disrupting the pH gradient of vesicles. This decreases the cell’s ability to sequester dopamine, which causes dopamine to leak into the synaptic cleft, where it forms dopamine associated reactive species (Brown et al, 2000). As in nicotine addiction, patients with methamphetamine dependence were more likely to have one least one A1 allele for the DRD2 gene as compared to healthy subjects, suggesting that lower levels of D2 expression predicts methamphetamine addiction (Han et al, 2008). Thus, responses to amphetamines are also affected by levels of D2 receptors. Additionally, Volkow et al (2001) measured D2 receptor levels in the orbitofrontal cortex (which receives major projections from the nucleus accumbens) of both MA abusers and healthy subjects using PET scanning following raclopride injection. They found that lower levels of D2 receptors were correlated with MA abuse, consistent with data from the other psychostimulating drugs examined.

Synthesis

The behavioral and pharmacological effects of each of these drugs vary widely. But they all share a common feature in that they all stimulate, through some pathway, an increased synaptic concentration of the neurotransmitter dopamine. This consistent with the finding that lower levels of D2 receptor availability in the substantia nigra in humans are correlated with increased novelty-seeking, which is known to be associated with an increased risk of drug abuse (Zald et al, 2008). Grace (2000) proposes a tonic/phasic model of dopamine regulation to understand its relevance to drug action. In his model, phasic dopamine release is the spike-dependent release into the synaptic cleft, and tonic dopamine regulation is mediated by the rapid reuptake of dopamine in the neuron terminal before it can diffuse into the synapse. It has been speculated that D2 receptors are activated when extracellular dopamine concentration increases, and that the receptor decreases exocytotic dopamine release (Farnsworth et al, 2009). Therefore, psychostimulants acting on this system could shift the equilibrium towards an increase in extracellular dopamine rapidly by somehow inhibiting D2 receptors.

Although U-shaped response curves are common in the human body’s responses to exogenous toxins (Calabrese and Baldwin, 2003), they are not required. Nevertheless, within the context of reward activation in the nucleus accumbens, there are reasons that such a dose-dependent response might be adaptive. It would encourage animals to seek more rewards for behaviors that they find stimulating but not so much as to prefer any particular behavior to the exclusion of all others. At the physiological level, D2 receptors could mediate the downward sloping region of the U-shaped response curve through feedback mechanisms designed to keep the synaptic dopamine concentration at equilibrium. If we make the simplifying assumptions that 1) Individual D2 receptors wait until synaptic dopamine levels reach a variable threshold level that is determined independently of the overall amount of D2 receptors before performing negative feedback regulation, 2) Individuals with lower levels of D2 receptors will have a lower steady state of synaptic dopamine concentration, 3) Larger and longer lasting perturbations from baseline levels of synaptic dopamine are perceived by animals as more pleasurable, and 4) Natural selection has designed animals not to consider the value of their actions but simply to maximize their pleasure, then a number of predictions follow.

First, we should expect that animals with lower levels of D2 receptors will find higher drug doses to be more pleasurable than those with higher levels of D2 receptors, because they will experience an enhanced perturbation from baseline and will require more synaptic dopamine before enough D2 receptors begin to perform feedback regulation. This is supported by the finding that a D2 antagonist injection in rodents leads to a rightward shift of the dose-dependent response curve of cocaine self-administration, as well as by the finding that naïve human subjects exposed to Ritalin experience differential affective effects based on D2 receptor levels. Following from that expectation, we should also expect that animals with lower levels of D2 receptors will be more likely to start using psychostimulants, and less likely to stop using them once they have started. This expectation is backed up empirically by the findings that D2 receptor availability is a predisposing trait to cocaine use in rhesus monkeys and that individuals with lower levels of D2 receptors as determined by polymorphisms in the A1 allele of the DRD2 gene are less likely to quit smoking.

This model is clearly imperfect. Thanos et al’s finding that the effects of D2R upregulation disappeared after 6 days instead of 8 days, Nader et al’s finding that levels of D2 receptors did not significantly correlate with cocaine self-administration for the first 3 weeks, and other temporal factors have yet to be integrated. Additionally, some of the parameters are possibly oversimplifying, and assumption number two in some senses merely begs the question. Regardless, it may represent a useful paradigm for further clinical research, and thus deserves consideration as such.

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