Research publications - Association for Research in Nervous and Mental Disease最新文献

The results of the experiments described above suggest that although the abused psychomotor stimulants and opioids have independent actions that contribute to their reinforcing effects, there are common neuronal substrates for some of their rewarding effects. Additionally there is considerable evidence implicating dopamine systems in these rewarding effects. The neuronal systems involved in these pharmacological actions may be similar to those involved in the rewarding effects of electrical stimulation to the brain. Although both classes of compounds cause euphoria in humans and are reinforcing in animals, the opioids are also central nervous system depressant drugs. These depressant properties influence the subjective effects in humans and possibly the nature of the rewarding effect in animals. Experiments using the 2-deoxyglucose procedure indicate that BSR to either the ventral tegmental area or the medial forebrain bundle results in functional activation throughout the mesocorticolimbic system. The major effects are found in the nucleus accumbens, olfactory tubercle, and the medial prefrontal cortex. Cocaine produces increases in metabolic rates similar in distribution to BSR. Morphine, however, only causes significant increases in functional activity in the olfactory tubercle. Further, only in this brain site did the combination of BSR plus morphine or cocaine cause increases in functional activity over that of stimulation alone. These findings suggest that the olfactory tubercle plays a major role in the pharmacological actions of both the psychomotor stimulants and the opioids as well the rewarding effects of electrical stimulation of the brain.

Repetitive use of psychoactive drugs produces a variety of learned behaviors. These can be classified in the laboratory according to an operant/classical paradigm, but in vivo the two types of learning overlap. The classically conditioned responses produced by drugs are complex and bi-directional. There has been progress in classifying and predicting the types of conditioned responses, but little is known of mechanisms. New techniques for understanding brain function such as micro-dialysis probes in animals and advanced imaging techniques (PET and SPECT) in human subjects may be utilized in conditioning paradigms to "open the black box." Because the existence of conditioned responses in drug users is now well-established, clinical studies have been instituted to determine whether modification of conditioned responses can influence clinical outcome. A recently completed study in cocaine addicts has produced evidence that outcome can be improved by a passive extinction technique over an 8 week outpatient treatment program.

At this time, 27 years after the initial studies on development of methadone for the maintenance treatment of opiate addiction were begun, it has been shown that [table; see text] methadone meets most criteria for a pharmacologic agent for chronic treatment of an addiction. It is effective after oral dosing: it has a long biological half-life in humans, it causes minimal side effects when used in chronic treatment, and it has no true toxic effects or serious side effects. Also methadone has been shown to be very effective when appropriately used in programs which combine pharmacotherapy with the best elements of "drug free" treatment, that is, counseling and psychological support. In addition to pharmacological treatment, there should be access to, if not on-site, medical and behavioral care as needed, as well as linkage to resources for various aspects of rehabilitation. At this time many of the actions, as well as the specific sites of action, and mechanisms of actions of methadone as used in chronic treatment of opiate addiction have been defined by scientific experimentation, both at the preclinical and clinical levels. It is known that methadone prevents abstinence symptoms, prevents drug hunger or craving, blocks euphorogenic effects of other opiates, and prevents relapse to illicit use of opiates. It is known that the site of action of methadone is at specific opioid receptors. Research to date suggests that there is no demonstrable down-regulation or up-regulation of opioid receptors during chronic opioid agonist perfusion, although chronic administration of the opioid antagonist naltrexone does appear to up-regulate opioid receptors. Clinical studies show that chronic use of methadone allows normalization of release and peripheral levels of one of the classes of endogenous opioids, beta-endorphin, and the related peptides derived from POMC released and processed from the anterior pituitary in humans. Also levels of beta-endorphin in cerebrospinal fluid become normal during chronic maintenance treatment, reflecting apparently normal processing and release of beta-endorphin at brain or hypothalamic sites of POMC production. Available data from studies of beta-endorphin indicate that there is a [table; see text] normalization, rather than disruption, of the endogenous opioid system in general during steady state administration of methadone, as contrasted with intermittent dosing and then abrupt withdrawal of short-acting opiates such as heroin. Although there is still much to be learned about the neurobiology of opiate addiction, at this time we do know a great deal about the effects of opiates and opioids.(ABSTRACT TRUNCATED AT 400 WORDS)