Novel Targets for Medication Development

Partial Receptor Agonists – Dopamine Partial Agonists

The mesocorticolimbic dopamine system projects from the ventral tegmental area to basal forebrain sites, the nucleus accumbens, and the central nucleus of the amygdala and plays a key role in motivation in general. Activation of the mesocorticolimbic dopamine system is important for directing behavior toward salient rewarding stimuli. Mesocorticolimbic dopamine activity appears to be critical for the reinforcing actions of indirect sympathomimetics, such as cocaine and amphetamines, and is involved in the incentive salience actions of other drugs of abuse, such as opioids and alcohol.

Based on the allostatic view of addiction, dopaminergic function is compromised during acute withdrawal from all major drugs of abuse. Withdrawal from most major drugs of abuse is also associated with decreases in the firing of dopaminergic neurons in the ventral tegmental area, resulting in blunted dopaminergic responses in human imaging studies during abstinence.

Given the role of dopamine in the acute reinforcing effects of drugs and dysregulated dopamine function during withdrawal, a reasonable hypothesis is that a dopamine partial agonist or functional partial agonist may have efficacy in different components of the addiction cycle. A dopamine partial agonist is a drug that binds to a receptor with high affinity but low efficacy. It also has antagonist properties in situations of high intrinsic activity (when dopamine is flooding the synapse) and agonist properties in situations of low intrinsic activity (when there is a low level of dopamine in the synapse). Hypothetically, it also has fewer side effects than full agonists or full antagonists. Because of its intermediate efficacy, a dopamine partial agonist acts as an agonist in the absence of dopamine and acts as an antagonist in the presence of dopamine. Although this approach is theoretically possible, no dopamine receptor partial agonist has progressed past animal studies to date for the treatment of addiction, but see below for a compound that is being tested in human laboratory trials.

D1 receptor antagonists competitively block cocaine self-administration in rats. To date, however, little work has been done with D1 partial agonists. D2 partial agonists have been shown to reverse psychostimulant withdrawal and block the increase in psychostimulant self-administration associated with extended access. However, for psychostimulant addiction, the effects of D2 partial agonists have not been sufficiently robust to merit clinical trials because of side effects and a lack of specificity for compulsive use. Dopamine D2 partial agonists dose-dependently decrease the reinforcing effects of intravenous cocaine and amphetamine self-administration and oral alcohol self-administration in nondependent rats, suggesting a nonspecific reward-reducing action. For alcoholism, OSU-6162 (PNU-96391) is a compound that acts like a partial agonist at both dopamine D2 receptors and serotonin 5-HT2A receptors. It has been termed a “dopamine stabilizer” and has shown antipsychotic and anti-Parkinsonian effects in animal studies. OSU-6162 decreases voluntary alcohol consumption, compulsive-like alcohol seeking, and withdrawal- and cue-induced alcohol seeking. D3 antagonists do not block baseline cocaine self-administration, but they do block progressive-ratio responding, a measure that reflects the compulsivity component of cocaine seeking. Additionally, D3 antagonists block cocaine and alcohol cue-induced reinstatement and have been under consideration for medications for psychostimulant addiction. The hypothesis that dysregulated dopamine tone contributes to the motivational effects of drug withdrawal and reinstatement remains viable, and dopamine modulators with appropriate neuropharmacological and pharmacokinetic profiles may be effective in treating certain aspects of addiction (for further reading, see Steensland et al., 2012).

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