Mesolimbic

Acnte Drag Action/Drng Reinforcement and the Mesolimbic Dopamine System... 

In 1954, experiments by Olds and Milner revealed that the brain has specialized centers for reward functions. In these studies electrical stimulation of certain brain sites was found to be highly rewarding in the sense that rats operantly respond for electrical stimulation of these brain sites, often to the exclusion of any other activity. A neurotransmitter system that is particularly sensitive to electrical self-stimulation is the mesolimbic dopamine projection that originates in the ventral tegmental area and projects to structures closely... 

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. 

The main target of action of methylphenidate, the most widespread clinically used psychostimulant, is the dopamine transporter (DAT) its inhibition increases intrasynaptic dopamine concentrations. The subcortical dopamine system (mesolimbic and nigrostriatal parts) mediates the unconditioned and conditioned responses toward reinforcement. 

Nicotine is the main psychoactive ingredient of tobacco and is responsible for the stimulant effects and abuse/ addiction that may result form tobacco use. Cigarette smoking rapidly (in about 3 sec ) delivers pulses of nicotine into the bloodstream. Its initial effects are caused by its activation of nicotinic acetylcholine (nACh) receptors. nACh receptors are ligand-gated ion-channels and pre- and postsynaptically located. Reinforcement depends on an intact mesolimbic dopamine system (VTA). nACh receptors on VTA dopamine neurons are normally activated by cholinergic innervation from the laterodorsal tegmental nucleus or the pedunculopontine nucleus. 

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. 

As with many neurons (e.g. NA) there are presynaptic autoreceptors on the terminals of dopamine neurons whose activation attenuate DA release. Although most of these receptors appear to be of the D2 type, as found postsynaptically, D3 receptors are also found. It is possible that in addition to the short-term control of transmitter release they may also be linked directly to the control of the synthesising enzyme tyrosine hydroxylase. It seems that autoreceptors are more common on the terminals of nerves in the nigrostriatal (and possibly mesolimbic) than mesocortical pathway. 

Initiation of behaviour Mesolimbic pathway to nucleus accumbens from VTA (AIO) Mesocortical pathways to prefrontal cortex from VTA (AIO) Animals Increases locomotor activity and intracranial self-stimulation Humans Hallucinations, psychoses (reward, reinforcement) Animals Decreases activity and self-stimulation Humans Reduces positive symptoms of schizophrenia D2 ... 

This peptide itself has no selectivity for the two CCK receptors, CCK-A and B, which have so far been established to stimulate IP3/DAG while, like substance P, can close potassium channels to increase neuronal activity. The CCK-B receptor is thought to predominate in the CNS but species differences may make this interpretation difficult. It has a wide distribution in the CNS but is also found in the gut whereas the CCK-A receptor is more restricted but is found in the hypothalamus, hippocampus and in the brainstem. There are high levels of the natural peptide, CCK-8 in cortex, hippocampus, hypothalamus, ventral tegmentum, substantia nigra, brainstem and spinal cord. CCK is one of the most abundant peptides in the brain and CCK co-exists with dopamine, substance P, 5-HT and vasopressin. Interestingly, in the dopamine areas, CCK co-exists in the mesolimbic pathways but in the nigrostriatal projections, the peptide and... 

The localisation of a particular peptide to a particular brain area and possibly associated with a particular transmitter (e.g. CCK with dopamine in mesolimbic pathways) has often prompted a prediction of function (e.g. CCK may have a role in schizophrenia). Animal studies in which the peptide has been injected into the appropriate brain area or tested on slices taken from the brain area have sometimes been taken to confirm such hypotheses. These approaches have lined up the peptides for a whole range of potential roles, some of which are listed in Table 12.4. Whether these predictions are realities will depend on the availability of chemical agents and their evaluation, not only in animals but also in humans. 

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. 

The mesolimbic from the ventral tegmentum (VTA, AlO) to the nucleus accumbens, olfactory tubercule, amygdala and pyriform cortex... 

Although there is no evidence that the DA afferents to DLPFC are damaged in schizophrenics, if the cortical pathology does reduce the ability of DA to function there, this would be equivalent to deafferentation and, as in the experimental studies, lead to increased subcortical mesolimbic activity and positive symptoms (Fig. 17.3). Unfortunately there is no good evidence that the nucleus accumbens is more active in schizophrenics or is even the origin of positive symptoms (but see Animal models ). Nevertheless it is a useful working hypothesis. 

A DA antagonist could certainly counter the increased mesolimbic activity and the positive symptoms. On the other hand, they would not be expected to reduce negative symptoms if these arise through an already inadequate DA influence. This fits with clinical experience because most of the neuroleptics are ineffective in treating negative symptoms. In fact if the negative symptoms do result from loss of the actual cortical neurons, rather than input to them, they will be difficult to reverse and much will depend on the precise role of DA in the DLPFC (see later). 

There is certainly evidence that whereas typical neuroleptics are equally active in mesolimbic/cortical areas as well as the striatum, the atypical drugs are much less effective in the latter. This has been shown by (1) increased DA turnover through DOPAC and HVA production in vitro, (2) augmented DA and DOPAC release by microdialysis in vivo and (3) increased c-fos- ike, expression. 

The mechanism by which 5-HT2 antagonism could ameliorate schizophrenic symptoms and what effect 5-HT has on mesolimbic and mesocortical pathways through A10 neurons is even less certain. It is more likely that 5-HT s action occurs postsynaptically in the limbic system or PFC. The probability that neuroleptics benefit from a particular balance of DA and 5-HT2A antagonism is developed later. 

Many of the neuroleptics are a-adrenoceptor antagonists. Some, like chlorpromazine, block d postsynaptic receptors while clozapine (and risperidone) are as potent at 2 as D2 receptors. There is no evidence that either of these actions could influence striatal or mesolimbic function but NA is considered important for function of the prefrontal cortex and any increase in its release, achieved by blocking a2-mediated autoinhibition, might contribute to a reduction in negative symptoms and provide a further plus for clozapine (see Nutt et al. 1997). Centrally, however, most a2-receptors are found postsynaptically and their function, and the effect of blocking them, is uncertain. 

Figure 17.9 Schematic representation of the proposed activity profile of an ideal neuroleptic. The figure shows DA pathways to the prefrontal cortex, mesolimbic nucleus accumbens and striatum the effects required for an ideal drug on the DA influence and symptoms there and to what extent they are met by most typical and atypical neuroleptics and by clozapine. Note that while all atypical neuroleptics induce few extrapyramidal w side-effects (EPSs) few of them, apart from clozapine, have much beneficial effect in overcoming negative symptoms of schizophrenia ...

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. 

---