Cocaine, dopamine and the endogenous opioid system

Cocaine addiction and opiate addiction are both major health problems in the United States today. Prospective studies from our Laboratory, which were able to detect the advent of the HIV-1 epidemic in parenteral drug abusers in New York City beginning around 1978, also showed that, from the beginning of the AIDS epidemic, cocaine abuse was a very important co-factor significantly increasing the risk for developing cocaine dependency. Fundamental studies from many laboratories including our own have shown that cocaine has profound effects on dopaminergic function, primarily from its well-established primary action of blocking the reuptake of dopamine from the synaptic cleft, an action of cocaine directed at the specific dopamine transporter. It has also been well-established by others that cocaine similarly blocks the reuptake of serotonin and norepinephrine. However, recent studies from our laboratory have shown that chronic cocaine administration profoundly disrupts the endogenous opioid system. Extensive studies have been conducted using an animal model which we have developed in our laboratory, the "binge" pattern cocaine administration model. Findings from these studies have led us to recognize the profound disruption of both dynorphin gene expression and kappa opioid receptor gene expression in a setting of chronic cocaine administration and, in turn, have led us to question a possible role of disruption of this system in the acquisition and persistence of cocaine addiction. These findings may have significance for the development of new pharmacotherapeutic agents which may be directed to specific components of the endogenous opioid system and, in particular, possibly the kappa opioid receptor system. Therefore, we have initiated studies to examine further the role of the dynorphin peptide-kappa opioid receptor system in normal physiologic function in humans.     

Cyclooxygenases and the central nervous system

Prostaglandins (PGs) were first described in the brain by Samuelsson over 30 years ago (Samuelsson, 1964). Since then a large number of studies have shown that PGs are formed in regions of the brain and spinal cord in response to a variety of stimuli. The recent identification of two forms of cyclooxygenase (COX; Kujubu et al., 1991; Xie et al., 1991; Smith and DeWitt, 1996), both of which are expressed in the brain, along with superior tools for mapping COX distribution, has spurred a resurgence of interest in the role of PGs in the central nervous system (CNS). In this review we will describe new data in this area, focusing on the distribution and potential role of the COX isoforms in brain function and disease.     

Aging and the central nervous system

This review of the literature on aging and the central nervous system attempts to cover the basic perameters investigated at both human and infrahuman levels for the better part of the last century. The results have indicated that there is a rather considerable lack of consistency in the data both within the frame of reference of a single species, and with regard to intraspecies comparisons. We have suggested that possible reasons for the contradictory findings would rest upon variability in techniques employed but, perhaps more importantly, on the failure of investigators in this area to standardize terminology. It is suggested that such a standardization might well be one of the more useful things to be accomplished in order to facilitate the interpretation of future work. The literature review first dealt with gross, i.e., macroscopic changes in brain morphology that could correlate with age, and then covered changes at the microscopic level. Finally, a brief review of the literature with regard to the biochemistry of aging was carried out. Implications of the data were noted where appropriate.     

Renin and nervous system

The renin release is controlled mainly by 3 mechanisms which are mutually not exclusive. The mechanisms can work together or 1 mechanism may play an important role than the other 2. The 3 mechanisms are the sympathetic nervous system, intrarenal baroreceptors, and the macula densa. In this paper, the renin release by electrical stimulation of brain stem, renin release by beta-adrenergic receptor, renin release by catecholamine infusion and angiotensin=sensitive site in brain are reported and discussed.     

Purinoceptors in the nervous system

The purine nucleoside adenosine and the purine nucleotide ATP play different roles in the nervous system. Adenosine acts on a family of G protein coupled receptors, collectively called adenosine receptors or P1 purinoceptors. Four members of this family have been cloned and pharmacologically characterized: A1, A2A, A2B and A3. Their distribution, pharmacology and biological roles are briefly discussed. In particular, the evidence that adenosine acting at A1 receptors regulates the release of several neurotransmitters and that adenosine acting at A2A receptors modulates dopaminergic transmission is summarized. ATP acts on receptors called P2 purinoceptors, which appear to fall into at least two main families--G protein coupled receptors and intrinsic ion channels. Their subclassification is becoming clearer as receptors are cloned and new selective agonists and/or antagonists are becoming available. There is an interesting potential for development of drugs targeted at purines or their receptors.     

Infections of the nervous system

Epidemiologic trends causing infections of the nervous system remain a significant source of morbidity and mortality one half-century after the introduction of penicillin. This article outlines common causes of bacterial meningitis, aseptic meningitis syndrome, encephalitis, abscess, spinal cord syndromes, and cranial and peripheral nerve problems. Recommendations for diagnostic evaluation and both empiric and definitive antimicrobial therapy are offered; controversial management issues are also discussed. The protean manifestations of varicella-zoster virus and Lyme diseases are outlined. In addition, special considerations in the immunocompromised host, including organ transplant recipients, cancer patients, and HIV-positive persons are explained, and antimicrobial therapy is discussed.     

Activation and repression in the nervous system

Corrosion castings of 60 human hearts were used to demonstrate that the point of origin of the posterior interventricular artery (PIA), in relation to the crux cordis, is responsible for its subsequent course with respect to the posterior interventricular vein (PIV). In seven cases (12%), the PIA appeared as the continuation of the left circumflex, descending rightwards and on a deeper level of the PIV. In 53 cases (88%), the PIA arose from the right coronary artery (RCA) and 50 of these were selected to be classified into three groups, according to the PIAs origin and course. In group A (29 cases, 58%) and B (seven cases, 14%), the PIA emerged before the crux cordis and descended to the right or left of the PIV, respectively. In group C (14 cases, 28%), it originated at, or beyond, the crux cordis and descended along the left side of the PIV. Among the 50 cases, the PIA was found to be long in 34 (68%), large in 32 (64%), and long and large in 29 cases (58%). In 18 of the latter 29 cases (62%) or 36% of the 50 cases in total, the PIA arose as a continuation of the RCA (group A) and therefore these cases were easily accessible to interventional cardiologists and also to surgeons, since the PIA lay on the same or on a superficial level in relation to the PIV. This work describes and explains the variations of the PIA and concludes that at least 36% of these may be helpful in coronary artery angioplasty and bypass surgery.     

Remyelination of the central nervous system

The three typical stages in the clinical course of multiple sclerosis (relapse, persistent disability and progression) can be explained on the basis of inflammation, demyelination and failure of repair leading to axon degeneration and astrocytosis. Strategies are being evaluated for limiting the inflammatory process using immunological treatments and these may have unexpected dividends in promoting endogenous remyelination. Increasing knowledge on glial lineages and axon-glial interactions needed for stable myelination also offer the prospect for enhancing remyelination through growth factor therapy and cell implantation.     

Tumors of the central nervous system

Neoplasia of the central nervous system (CNS) can be divided into two main categories: nonpituitary CNS neoplasia and pituitary adenomas. Nonpituitary CNS neoplasias are generally compressive in nature, although some are also invasive. The majority of reported CNS tumors are secondary with only a few originating from nervous tissue. Pituitary adenomas predominantly occur in the pars intermedia of the older horse. Clinical signs, diagnostic testing, and possible treatments are discussed.     

Paraneoplastic syndromes affecting the nervous system

Paraneoplastic syndromes can affect virtually any portion of the nervous system. Most paraneoplastic syndromes are believed to be caused by an autoimmune reaction to an "onconeural" antigen shared by the cancer and the nervous system. The immune reaction may retard growth of the cancer, but it also damages the nervous system. Specific autoantibodies found in some individual paraneoplastic syndromes are usually associated with specific tumors. Neurological disorders, clinically and pathologically identical to paraneoplastic syndromes, may occur in some patients without cancer, but paraneoplastic antibodies are not found in these patients. The diagnosis of a paraneoplastic syndrome is based on its increased incidence in patients with cancer, the occasional response of the neurological syndrome to treatment of the underlying cancer, or the presence of specific autoantibodies. Some paraneoplastic syndromes respond to treatment of the underlying cancer or to immunosuppression but, for most syndromes, no effective treatment exists.