Drug abuse and dependence define behavioral states involving increased allocation of behavior towards drug seeking and taking at the expense of more appropriate behavioral patterns. As such, addiction can be viewed as increased control of behavior by the desired drug (due to its unconditioned, rewarding properties). It is also clear that drug-associated (conditioned) stimuli acquire heightened abilities to control behaviors. These phenomena have been linked with dopamine function within the ventral striatum and amygdala and have been described specifically in terms of motivational and incentive learning processes. New data are emerging that suggest that regions of the frontal cortex involved in inhibitory response control are directly affected by long-term exposure to drugs of abuse. The result of chronic drug use may be frontal cortical cognitive dysfunction, resulting in an inability to inhibit inappropriate unconditioned or conditioned responses elicited by drugs, by related stimuli or by internal drive states. Drug-seeking behavior may thus be due to two related phenomena: (1) augmented incentive motivational qualities of the drug and associated stimuli (due to limbic/amygdalar dysfunction) and (2) impaired inhibitory control (due to frontal cortical dysfunction). In this review, we consider the neuro-anatomical and neurochemical substrates subserving inhibitory control and motivational processes in the rodent and primate brain and their putative impact on drug seeking. The evidence for cognitive impulsivity in drug abuse associated with dysfunction of the frontostriatal system will be discussed, and an integrative hypothesis for compulsive reward-seeking in drug abuse will be presented.

Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli.

Tuberculosis remains the leading cause of death in the world from a single infectious disease, although there is little knowledge of the mechanisms of its pathogenesis and protection from it. After a century of decline in the United States, tuberculosis is increasing, and strains resistant to multiple antibiotics have emerged. This excess of cases is attributable to changes in the social structure in cities, the human immunodeficiency virus epidemic, and a failure in certain major cities to improve public treatment programs. The economic costs of not adequately addressing the problem of tuberculosis in this country are estimated from an epidemiological model.

https://science.sciencemag.org/content/sci/257/5073/1055.full.pdf

Tuberculosis: commentary on a reemergent killer.

The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

https://science.sciencemag.org/content/sci/281/5383/1640.full.pdf

Distinct Mechanism for Antidepressant Activity by Blockade of Central Substance P Receptors

https://www.cell.com/trends/neurosciences/pdf/0166-2236(91)90141-G.pdf

The dopamine hypothesis of the reinforcing properties of cocaine

The reason for the high frequency of depression and anxiety in Parkinson's disease is poorly understood. Degeneration of neurotransmitter systems other than dopamine might play a specific role in the occurrence of these affective disorders. We used [11C]RTI-32 PET, an in vivo marker of both dopamine and noradrenaline transporter binding, to localize differences between depressed and non-depressed patients. We studied eight and 12 Parkinson's disease patients with and without a history of depression matched for age, disease duration and doses of antiparkinsonian medication. The depressed Parkinson's disease cohort had lower [11C]RTI-32 binding than non-depressed Parkinson's disease cases in the locus coeruleus and in several regions of the limbic system including the anterior cingulate cortex, the thalamus, the amygdala and the ventral striatum. Exploratory analyses revealed that the severity of anxiety in the Parkinson's disease patients was inversely correlated with the [11C]RTI-32 binding in most of these regions and apathy was inversely correlated with [11C]RTI-32 binding in the ventral striatum. These results suggest that depression and anxiety in Parkinson's disease might be associated with a specific loss of dopamine and noradrenaline innervation in the limbic system.

/pdf/depression-in-parkinson-s-disease-loss-of-dopamine-and-3r1zfj5rar.pdf

Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system.

RTI-55 (3 beta-(4-iodophenyl)tropan-2 beta-carboxylic acid methyl ester), one of the most potent inhibitors of dopamine uptake reported to date, was radioiodinated and tested as a probe for the cocaine receptor in Sprague-Dawley rat brain. Saturation and kinetic studies in the striatum revealed that [125I]RTI-55 bound to both a high- and low-affinity site. The Kd for the high-affinity site was 0.2 nM, while the Kd for the low-affinity site was 5.8 nM. The corresponding number of binding sites in the striatum was 37 and 415 pmol/g protein. The pharmacological profile of specific [125I]RTI-55 binding in the striatum was consistent with that of the dopamine transporter. Additionally, [125I]RTI-55 was found to bind with high affinity to the cerebral cortex. Scatchard analysis revealed a single high-affinity component of 0.2 nM with a density of 2.5 pmol/g protein. The pharmacological profile demonstrated by [125I]RTI-55 in the cerebral cortex matched that of the serotonin transporter. Autoradiographic analysis of sagittal brain sections with [125I]RTI-55 binding was consistent with these findings. Specific binding of [125I]RTI-55 was blocked by dopamine uptake inhibitors in areas rich in dopaminergic nerve terminals. Conversely, serotonin uptake inhibitors blocked the binding of [125I]RTI-55 in brain areas rich in serotonergic neurons. These results demonstrate that [125I]RTI-55 may be a very useful ligand for the dopamine and serotonin transporters.

High-affinity binding of [125I]RTI-55 to dopamine and serotonin transporters in rat brain

A series of 3 beta-(p-substituted phenyl)tropane-2 beta-carboxylic acid methyl esters (2) were synthesized and found to possess high affinity for the cocaine binding site in rat striatum. The p-chloro (2c) and p-iodo (2n) compounds, which were the most potent analogues prepared, were found to be 85 and 78 times more potent than (-)-cocaine. The p-bromo (2m) and p-methyl (2d) were also 56 and 60 times more potent than cocaine. QSAR and CoMFA studies were conducted to correlate binding affinity of the cocaine analogues with their structural features. Whereas the QSAR study gave relatively low correlations, the CoMFA study gave a correlation with high predictive value.

Synthesis, ligand binding, QSAR, and CoMFA study of 3 beta-(p-substituted phenyl)tropane-2 beta-carboxylic acid methyl esters.

[125I]RTI-55: a potent ligand for dopamine transporters.

The rate of entry of drugs into brain is thought to be a factor in their abuse liability. In this investigation, we have examined the rate of entry and binding at dopamine transporters in mouse striatum for a variety of dopamine transporter inhibitors. The method utilized was based on measuring the displacement of3H-WIN 35,428 from striatal dopamine transporter sites in vivo at different times. Eleven cocaine analogs (RTI-31, RTI-32, RTI-51, RTI-55, RTI-113, RTI-114, RTI-117, RTI-120, RTI-121, WIN 35,065-2, and WIN 35,428) as well as other dopamine uptake site blockers (bupropion, nomifensine, and methylphenidate) were compared with (−) cocaine for their rates of displacement of3H-WIN 35,428 binding in vivo. The drugs that displayed the fastest occupancy rates were bupropion, (−) cocaine, nomifensine, and methylphenidate. RTI-51, RTI-121, RTI-114, RTI-117, RTI-120, RTI-32, RTI-55, and RTI-113, showed intermediate rates, whereas RTI-31, WIN 35,065-2, and WIN 35,428 exhibited the slowest rates of displacement. While many of the cocaine analogs have proven to be behaviorally and pharmacologically more potent than (−) cocaine, their rates of entry and binding site occupancy were slower than that for (−) cocaine. Earliest times of transporter occupancy by the different drugs were correlated (although weakly) with their degree of lipophilicity (r=0.59;P<0.02). Kinetic effects and metabolism of the compounds could complicate the interpretations of these data. There was no obvious correlation between rate of occupancy in this animal model and abuse liability in humans, which is consistent with the notion that other factors are critical as well.

John W. Boja

Papers

The dopamine hypothesis of the reinforcing properties of cocaine

High-affinity binding of [125I]RTI-55 to dopamine and serotonin transporters in rat brain

Synthesis, ligand binding, QSAR, and CoMFA study of 3 beta-(p-substituted phenyl)tropane-2 beta-carboxylic acid methyl esters.

[125I]RTI-55: a potent ligand for dopamine transporters.

Rate of binding of various inhibitors at the dopamine transporter in vivo.