Article Published in Sacramento Medicine, January 1995

This book is more accurately a text in neurochemistry documenting the latest information on neuro-transmitters, hormones, and receptor systems. The editors have organized a series of papers on molecular, cellular, pharmacologic, neural systems, and behavioral effects of various drugs of abuse. It spans topics from the effects of stimulants and opiates on neurotransmitters to the esoteric COUP-TE.

All major drugs of abuse, except alcohol, exert their effects through receptor activation and potentiation or inhibition of specific neurotransmitter activity. However, the complexity of neurotransmitter function makes it difficult to assign them, or the drugs that effect them, a strict "behavioral function." Transmitters communicate information, and the same transmitter can have opposing things to communicate in different areas of the brain, e.g., opiates can stimulate and they can sedate. Both effects occur, although one may predominate clinically.

The common association of opiates to pain and abuse potential has led to a poor understanding and oversimplification of the multifunctional endogenous opiate system. This system is reflective of the general diversity of neurotransmitter systems. To date, 18 opioid peptides have been identified (endorphins, enkephalins, and dynorphins) which interact with 3 different receptors (mu, delta, and kappa) to activate a complex sequence of intracellular events.

Why has the evolutionary process created such diversity? Target cells for hormones and neurotransmitters need to discriminate multiple inputs. Rather than being limited to responding to one neurotransmitter, target cells react to a pattern of receptors activated, i.e., the ratio of delta to mu or muscarinic to kappa, etc. Multiple receptors reacting differentially to various neurotransmitters creates a "neurotransmitter mosaic" with enhanced discrimination capacity.

The most recent focus of brain research in substance abuse is on the intracellular events following receptor activation. Cell surface receptors have been classified into 2 superfamilies: (1) inotropic receptors, which regulate the flow of charged particles through channels called ionophores, causing rapid changes in neuronal excitability and acute drug effects, and (2) G-protein receptors in which guanosine triphosphate-binding proteins act as an intermediate link in signal transduction, producing long-lasting tonic changes mediated through a cascade of intracellular proteins and second messenger systems. Gene expression is mediated by G-protein activation through a "second messenger" phosphoprotein, called Fos, and through induction of a class of proteins called transcription factors which bind to specific DNA sequences in the promoter region of genes to increase the rate at which these genes are transcribed. Since transcription factors (called proto-oncogenes) occupy a third place in the biochemical cascade of cellular events, after receptor and G-protein activation, they are also called third messengers.

Not all receptors are on the cell surface. Steroid receptors occur at the level of nuclear DNA. Steroids enter cells by passive diffusion and activate "steroid response elements" in either the cytoplasm or the nucleus. The activated receptors bind to target genes to stimulate transcription and protein synthesis. The steroid receptor superfamily includes receptors for glucocorticoids, sex steroids, thyroid hormone, and vitamin D3. Mutations in human steroid receptors have been proven to cause genetic diseases of hormone resistance. Testicular feminization (androgen insensitivity syndrome) is due to a mutation of the gene responsible for the androgen receptor. Vitamin D resistant rickets and hyper-cortisolism without Cushing’s syndrome are other diseases of gene-receptor transcription.

What does all this have to do with substance abuse? Myriad changes in cell function have been documented to occur following acute or chronic exposure to "abusable drugs." Some cellular adaptations to the chronic presence of drugs of abuse underlie the phenomenon of tolerance and dependence. Possible mechanisms include uncoupling of receptors from G-proteins, loss of receptor sites (so-called down-regulation), compensatory alterations in other "downstream" neurotransmitters systems, and changes in the expression of genes which control neurotransmitter or receptor synthesis. Conversely, other cellular adaptations may sensitize the cell and create a hyperresponsive reaction (the opposite of tolerance), an effect called kindling. Cocaine and amphetamines seem to be especially associated with this type of cellular supersensitivity. The cellular mechanisms underlying drug craving may reflect sensitization, since exposure to small amounts of drug often results in intense drug cravings.

The discovery of diseases of steroid receptor function suggests that future research will document genetic defects in other receptor systems that might underlie vulnerability to drug use. For example, a subset of opiate addict’s report that their first exposure to opiates made them feel normal and allowed them to function better. Are these patients suffering from a primary endorphin receptor deficit? This might explain some of the dramatic responses to methadone maintenance therapy. Do some addicts, through years of abuse, induce long-lasting or irreversible changes in endorphin gene expression that dictate a need for "endorphin replacement therapy" with methadone or other endorphin analogues? Do chronic pain patients suffer from undiagnosed deficits in the endogenous opiate system? It seems highly likely such diseases will be found, analogous to primary defects in endogenous catecholamine function in primary depression.

However, in spite of a welter of data on effects of drugs on neurotransmitters, receptors, and intracellular mechanisms, the goal of the title, to elucidate the biological basis of substance abuse, remains elusive. There is no mention of the fact that all the main so-called drugs of abuse, except nicotine, are also medicines. How is it, given all the changes in cellular activity produced by opiates, that they can still be used safely in high doses for long periods in the management of chronic pain, without leading to abuse? How can methadone be used for years in heroin addicts and lead to an improvement in neuroendocrine function? How is it that stimulants can be used safely for years for attention deficit disorder and narcolepsy? Further more, we use myriad other psycho-tropics, anti-depressants, and antihypertensives that effect receptor neurotransmitter activity in ways similar to "drugs of abuse." There is no a priori reason to think that long-term effects of this kind of hormone/receptor manipulation are any different from so-called drugs of abuse, although short-term effects may be different.

The important unanswered question, that is not answered by focus on "drugs" as the primary culprit in addiction, concerns the individual differences in response to these various drugs. Some individuals, and animals, are more inclined to compulsively self-administer drugs than others. And a serious problem with the purported addictiveness of certain drugs is that the vast majority of those exposed to opiates, alcohol, cocaine, or marijuana never develop any addiction. With the possible exception of nicotine, addiction is an atypical response to drugs. So, we must focus on the individual response in our efforts to understand addiction. Rather than blindly demonizing drugs, like opiates, which happen to be important medicines, we must try to understand the basis for the atypical responsiveness. The addiction potential of drugs is a relative issue, relative to an individual’s genetics, health, life experiences, and psychological make-up.

Oh, COUP-TF, of course, is chicken upstream promoter-transcription factor, which interacts with the distal promoter sequence of the ovalbumin gene and for more information than this you will have to read the book.