Pro-Dopamine Regulator - (KB220) to Balance Brain Reward Circuitry in Reward Deficiency Syndrome (RDS)

Abstract

We are faced with a worldwide opiate/opioid epidemic that is devastating. According to the Centers for Disease Control and Prevention (CDC), at least 127 people, young and old, are dying every day in America due to narcotic overdose. The Food and Drug Administration (FDA) has approved Medication-Assisted Treatments (MATs) for opiate/opioids as well as alcohol and nicotine. The mechanism of action of most MATS favors either blocking of dopaminergic function or a form of Opiate Substitution Therapy (OST). These treatment options are adequate for short-term treatment of the symptoms of addiction and harm reduction but fail long-term to deal with the cause or lead to recovery. There is a need to continue to seek better treatment options. This mini-review is the history of the development of one such treatment; a glutaminergic-dopaminergic optimization complex called KB220. Growing evidence indicates that brain reward circuitry controls drug addiction, in conjunction with "anti-reward systems" as the "anti-reward systems" can be affected by both glutaminergic and dopaminergic transmission. KB220 may likely alter the function of these regions and provide for the possible eventual balancing the brain reward system and the induction of "dopamine homeostasis." Many of these concepts have been reported elsewhere and have become an integral part of the addiction science literature. However, the concise review may encourage readership to reconsider these facts and stimulate further research focused on the impact that the induction of "dopamine homeostasis" may have on recovery and relapse prevention.

Keywords: Metenkephalin; Neurotransmitter signaling; Opioid epidemic; Reward cascade.

Figure 1

It is an illustration of the Brain Reward Cascade, which involves the release of serotonin at the hypothalamus, where it stimulates enkephalin. The enkephalin then inhibits GABA at the substantia nigra, which, in turn, regulates the amount of dopamine released at the nucleus accumbens (or “reward site”). The dopamine originates in the VTA. Various receptors (including 5HT2a receptors, μ-opiate receptors, GABAA receptors, GABAB receptors, and dopamine receptors) are utilized in the reward cascade. Recent evidence demonstrates the role of the dorsal raphe nuclei in this cascade [85]. It is well known that, under normal conditions, dopamine in the nucleus accumbens through a number of cascading events and neurotransmitter interaction works to maintain a person’s normal drives [86](with permission).

Figure 2

Elimination of amino-acids. The carbon skeletons of amino acids are broken down into metabolites that can either be oxidized into CO₂ and H₂O to generate ATP, or can be used for gluconeogenesis. The catabolism of amino acidsaccounts for 10 to 15% of the human body’s energy production. Each of the 20 amino acids has aseparate catabolic pathway, yet all 20 pathways converge into 5 intermediates, all of which can enter thecitric acid cycle. From the citric acid cycle the carbon skeletons can be completely oxidized into CO₂ or diverted into gluconeogensis or ketogenesis. Glucogenic amino acids are broken down into one of the following metabolites: pyruvate, α-ketoglutarate, succinyl CoA, fumarate or oxaloacetate. Ketogenic amino acids are broken down intoacetoacetate or acetyl-CoA. Larger amino acids, tryptophan, phenylalanine, tyrosine, isoleucine andthreonine are both glucogenic and ketogenic. Only two amino acids are purely ketogenic they are lysine and leucine. If two of the amino acids are purely ketogenic and five amino acids are both ketogenic and glucogenic, than that leaves 13 amino acids that are purely glucogenic: Arginine, Glutamate, Glutamine, Histidine, Proline, Valine, Methionine, Aspartate, Asparagninen, Alaanine, Serine, Cysteine, and Glycine [87].

Figure 3

Isoquinolone salsolinol. Chemical structure of Isoquinolone Salsolinol a consequence of condensation of dopamine and acetaldehyde and an agonist at the opiate receptor a brain mechanism shared by alcohol and opiates (internet image).

Figure 4

Chemical structure of met-enkephalin. It is an image ofthe natural brain opiate peptide – methionine–enkephalin (METENK) (internet image).

Figure 5

Resting-state fMRI one hour after one dose of KB220 variant. Left side placebo (n=5) Right side KB220 variant (n=5) It represents a fMRI cross-over study in five abstinent heroin addicts receiving either placebo or KB220Z (Synaptose) one –hour prior to testing. It is noteworthy, that following oral KB220Z there is BOLD activation in the NAc and a attenuation of high BOLD activation in the putamen. This illustration suggests a balancing of dopamine function in the brain at the reward site [63] (with permission).

Figure 6

Discharge Against Medical Advise (AMA) control vs. KB220 variant. Study 1 (p<0.014) [79] Study 2 (p<0.05) [28]

Figure 7

Relapse control vs. KB220 variant. Study 1 Brown et al. Journal of Psychoactive Drugs 22: 173–187 (1990) after 10 months (p<0.001) [29]. Study 2 Chen et al. Advances in Therapy 24: 402–414 (2007) after 12 months (p<0.001) [59].