Mesolimbic system and

It is generally felt that a substance is more likely to be a NT if it is unevenly distributed in the CNS although if it is widely used it will be widely distributed. Certainly the high concentration (5-10 pmol/g) of dopamine, compared with that of any other monoamine in the striatum or with dopamine in other brain areas, was indicative of its subsequently established role as a NT in that part of the CNS. This does not mean it cannot have an important function in other areas such as the mesolimbic system and parts of the cerebral cortex where it is present in much lower concentrations. In fact the concentration of the monoamines outside the striatum is very much lower than that of the amino acids but since the amino acids may have important biochemical functions that necessitate their widespread distribution, the NT component of any given level of amino acid is difficult to establish. 

Addiction is a prominent problem with cocaine use. Cocaine is highly reinforcing to both animals and humans, probably through inhibition of dopamine reuptake in mesolimbic systems and stimulation of brain areas known to subserve behavioral reinforcement (Kiyatkin and Stein 1995 Woolverton and Johnson 1992 Ritz et al. 1987). Although sensitization to the stimulant effects occurs in animals, humans do not sensitize to the euphoric effects of cocaine but develop a tolerance (O Brien 1996). In animals and humans alike, self-administration often follows a binge pattern, consisting of repeated use over a period of hours or days until the supply is used up. 

By means of immunofluorescence analyzed in the adjacent sections incubated with antibodies to CCK and TH, respectively, in combination with fluorescent retrograde tracing, Hokfelt and coworkers (1980b) could establish also the coexistence of TH and CCK in terminal fiber networks in the NAc and other targets of the mesolimbic system, and could determine that VTA neurons which contain both CCK and DA project to the caudal and medial portions of the NAc. 

DiChiara G, Imperato A Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Nad Acad Sci U S A 85 5274-5278, 1988 Dinwiddie SH, Cottier L, Compton W, et al Psychopathology and HIV risk behaviors among injection drug users in and out of treatment. Drug Alcohol Depend 43 1 — 11, 1996... 

There is some loss (40-60%) of DA in the nucleus accumbens of the mesolimbic system in the ventral tegmentum (AlO) and cortex at post-mortem but nowhere is it as marked as in the striatum. Some loss of NA, 5-HT, CCK and the enkephalins and of the markers GAD and ChAT (for GABA and ACh) have been reported in the striatum, SN and other areas but these rarely exceed 50% and could be secondary to DA loss. 

It appears that an ideal neuroleptic may need to reduce DA activity in the mesolimbic system (nucleus accumbens) to counter the positive symptoms of schizophrenia, increase it in the prefrontal cortex to overcome negative symptoms and have little or possibly no effect on it in the striatum so EPSs do not arise (Fig. 17.9). No wonder we still await the ideal drug. 

QUESTION How can you dissociate the locomotor effects from the reinforcing effects It has been agreed that lesions of the mesolimbic system affect locomotor activity and shown by Eberson with respect to the dopaminergic system. How do you know you don t have a rat that is motorically compromised and can t press the lever to get the cocaine How can you dissociate that from the reinforcement efficacy ... 

Additional studies in rats in vivo and in rat tissues or cells in vitro have focused on potential relationships between the effects of lead on neurotransmitter systems and neurobehavioral function. Lead exposure decreased dopamine binding sites, suggesting excess dopamine availability. The decreased dopamine binding was localized in the nucleus accumbens (mesolimbic dopamine system) but not the dorsal... 

Schizophrenia is a chronic, complex psychiatric disorder affecting approximately 1% of the population worldwide. The chronic nature of the illness, in addition to the early age of onset, results in direct and indirect health care expenditures in the U.S., which amount to approximately 30 to 64 billion dollars per year [4]. It is perhaps the most devastating of psychiatric disorders, with approximately 10% of patients committing suicide. The dopamine hypothesis of schizophrenia postulates that overactivity at dopaminergic synapses in the central nervous system (CNS), particularly the mesolimbic system, causes the psychotic symptoms (hallucinations and delusions) of schizophrenia. Roth and Meltzer [5] have provided a review of the literature and have concluded a role for serotonin as well in the pathophysiology and treatment of schizophrenia. The basic premise of their work stems from the known interaction between the serotonergic and dopaminergic systems. 

Shippenberg, T. S., Bals-Kubik, R., and Herz, A., Examination of the neurochemical substrates mediating the motivational effects of opioids Role of the mesolimbic dopamine system and D-l vs. D-2 dopamine receptors, J. Pharmacol. Exp. Ther., 265, 53, 1993. 

Viggiano, D., Grammatikopoulos, G., and Sadile, A. G. (2002) A morphometric evidence for a hyperfunctioning mesolimbic system in an animal model of ADHD. Behav. Brain Res. 130,181-189. 

In the central nervous system (CNS) of guinea-pigs and rats, 5-HT4 receptors are expressed in two anatomical and functional structures the extrapyramidal motor system and the mesolimbic system [6,7]. In human brain, the presence of 5-HT4 receptors has been shown in basal ganglia and in the caudate putamen nuclei, where the density is the highest [8]. 

Cronan T, Conrad J, et al (1985) Effects of chronically administered nicotine and sahne on motor activity in rats. Pharmacol Biochem Behav 22(5) 897-899 Curtis L, Buisson B, et al (2002) Potentiation of human alpha4beta2 neuronal nicotinic acetylcholine receptor by estradiol. Mol Pharmacol 61(1) 127-135 Dalton JC, Vickers GJ, et al (1986) Increased self-administration of cocaine following haloperidol sex-dependent effects of the antiestrogen tamoxifen. Pharmacol Biochem Behav 25(3) 497-501 Damsma G, Day J, et al (1989) Lack of tolerance to nicotine-induced dopamine release in the nucleus accumbens. Eur J Pharmacol 168(3) 363-368 Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85(14) 5274-5278... 

Willner (1995) provides evidence from many sources that increases or decreases of dopaminergic activity in the mesolimbic system may underpin the pathophysiology of mania and depression respectively. A key area involved may be the subgenual prefrontal cortex which receives extensive reciprocal dopaminergic projections from the ventral tegmental area and substantia nigra and influences dopamine release in the nucleus accumbens (Drevets et al., 1997 see Chapter 16). 

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