Mesolimbic system

The nucleus accumbens is part of the limbic system. It receives dopaminergic input through the mesolimbic system that originates from cell bodies in the ventral segmental area (A 10 cell group). This mesolimbic dopaminergic pathway is part of the reward pathways. Drugs of abuse (cocaine, amphetamine, opiates or nicotine) have been shown to increase the level of dopamine release in these neurons. 

Mesolimbic System/Reward System Metabolic Syndrome Metabotropic Glutamate Receptors Metabotropic Receptor Metalloprote(in)ases Methicillin-resistant Staphylococci iV-Methyl D-aspartate Receptors Methylating Agents... 

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... 

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. 

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 ... 

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. 

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]. 

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. 

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). 

The results of these studies implicate dysfunctions in presynaptic storage, release, reuptake, and metabolic mechanisms in dopamine mesolimbic systems (Davis and Lieberman, 2000). 

Current research is directed toward discovering atypical antipsychotic compounds that are either more selective for the mesolimbic system (to reduce their effects on the extrapyramidal system) or have effects on central neurotransmitter receptors—such as those for acetylcholine and excitatory amino acids—that have been proposed as new targets for antipsychotic action. 

The classification of NMDA antagonists as nonaddictive drugs was based on early assessments, which, in the case of PCP, have recently been questioned. In fact, animal research shows that PCP can increase mesolimbic dopamine concentrations and has some reinforcing properties in rodents. Concurrent effects on both thalamocortical and mesolimbic systems also exist for other addictive drugs. Psychosis-like symptoms can be observed with cannabinoids, amphetamines, and cocaine, which may reflect their effects on thalamocortical structures. For example, cannabinoids, in addition to their documented effects on the mesolimbic dopamine system, also enhance excitation in cortical circuits through presynaptic inhibition of GABA release. 

All addicting drugs, which produce augmented hedonic tone, have one major commonality They augment DA function as a final common neu pharmacological action (via different specific sites and mechanisms of action), particularly in the VTA-MFB-Acb DA mesolimbic system so important in reward (Koob and Bloom 1988 Gardner 1997). 

Dopamine Concentrations in the Mesolimbic System of Freely Moving Rats." Proceedings of the National Academy United States if America 85 5274-78. 

Kalivas, Peter W., Erik Widerlov, Donald Stanley, George Breese, and Arthur J. Prange. 1983. "Enkephalin Action on the Mesolimbic System A Dopamine-Dependent and a Dopamine Independent Increase in Locomotor Activity." Journal of Pharmacology and Experimental Therapeutics 227 229-37. 

Puglisi-Allegra, Stephano, Assunta Imperato, Luciano Angelucci, and Simona Cabib. 1991. "Acute Stress Induces Time Dependent Responses in Dopamine Mesolimbic System." Brain Research 554 217-22. 

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