Prefrontal cortex

Youngren KD, Inglis FM, Pivirotto PJ et al (1999) Clozapine preferentially increases dopamine release in the rhesus monkey prefrontal cortex compared with the caudate nucleus. Neuropsychopharmacology 20 403-12... 

CRH (Corticotropin releasing hormone) is expressed in the nucleus paraventricularis of the hypothalamus and drives the stress hormone system by activating synthesis and release of corticotropin at the pituitary and in turn corticosteroid from the adrenal cortex. CRH is also expressed at many other brain locations not involved in neuroendocrine regulation, e.g. the prefrontal cortex and the amygdala. Preclinical studies have shown that CRH also coordinates the behavioral adaptation to stress (e.g. anxiety, loss of appetite, decreased sleepiness, autonomic changes, loss of libido). 

The frontal cortex consists of three main structures (i) motoric regions (including the Broca area and ocular areas), (ii) the prefrontal cortex, and (iii) the orbital cortex. The prefrontal cortex is associated with attention, arousal, and expectation, the orbital cortex with motivation. 

In summary, main structures involved in the action of psychostimulants can be divided into cortical (mainly prefrontal cortex) and subcortical (basal ganglia and related structures, LC and cerebellum) ones. Figure 1 gives a schematic overview of the connections between these structures, omitting the cerebellum due to lack of precise information. 

Other bone-growth syndromes Schizophrenia (reduced levels in prefrontal cortex) ... 

Ahmad K Asia grapples with spreading amphetamine abuse. Lancet 361 1878—1879,2003 Almodovar-Fabregas LJ, Segarra O, Colon N, et al Effects of cocaine administration on VTA cell activity in response to prefrontal cortex stimulation. Ann N Y Acad... 

Figure 7.5 Rate recording of the dose-dependent inhibitory effects of apomorphine (pg/kg) on the spontaneous activity of a neuron in the medial prefrontal cortex of the halothane anaesthetised rat and its antagonism by haloperidol (HAL, 0.5mg/kg). Time scale is 50 min intervals. Reproduced by permission from Dailey (1992)...

In other brain areas which receive a DA input, such as the nucleus accumbens and prefrontal cortex, it appears to be inhibitory and predominently D2-mediated. This is clear from Fig. 7.5 which shows inhibition by apomorphine (mixed D2, Di agonists) of the firing of neurons in the medial prefrontal cortex of the anaesthetised rat and its antagonism by the D2 antagonist haloperidol. 

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 ... 

To some extent, this proposal is supported by microdialysis studies of changes in 5-HT efflux in the terminal fields of 5-HT neurons. For instance, increased 5-HT efilux in the striatum, induced by immobilisation of rats, occurs only during the period of increased motor activity that follows the animals release (Takahashi et al. 1998). A single swim stress also fails to increase 5-HT efflux in the medial prefrontal cortex of rats. 

Yoshioka, M, Matsumoto, M, Togashi, H and Saito, H (1995) Effects of conditioned fear stress on 5-HT release in the rat prefrontal cortex. Pharmacol. Biochem. Behav. 51 515-519. 

The prefrontal cortex (PFQ and in particular the dorsal lateral part (DLPFQ appear to be particularly important in schizophrenia (Kerwin 1992). Lesions there are known to produce functional defects in humans reminiscent of many of the negative symptoms of schizophrenia, such as attention and cognitive defects and withdrawal. Despite this, no specific pathology is seen in the DLPFC in schizophrenics although there is some atrophy and neuronal loss which are normally old and could be congenital. That being so, it is necessary to explain why the symptoms become apparent only in adolescence. 

The injection of 6-OHDA into the rat nucleus accumbens produces the expected proliferation of DA receptors and resulting supersensitivity so that doses of apomorphine lower than normal produce a significant attenuation of PPI. This is not seen after the production of supersensitivity by toxin lesions of the substantia nigra and prefrontal cortex. The effects of amphetamine were also mainly modified by accumbens lesions. Thus as DA agonists primarily augment the positive symptoms such findings link these with the accumbens. 

While there are some reports of increased NMDA and non-NMDA receptor number in various cortical regions of schizophrenics including the prefrontal cortex, there are also indications of impaired glutamate innervation, such as reduction in its neuronal uptake sites (Ishimaru, Kurumaji and Torn 1994). Also it has been found that levels of the mRNA for the NRI subunit of the NMDA receptor in the hippocampus and its D-aspartate binding sites in the temporal cortex are both reduced more on the left than right side in schizophrenic brain. This is another indication of greater malfunction on the left side of the brain and the possibility that some schizophrenic symptoms arise from an imbalance between cross-cortical activity. 

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. 

Negative symptoms. These may be reduced because either clozapine antagonises appropriate receptors in the prefrontal cortex or it does not act as an antagonist there. This apparently stupid statement is prompted by the lack of knowledge of what is required to reduce negative symptoms. D4 and Di receptors are found in the prefrontal cortex and only clozapine among current neuroleptics is more active at both of these than the D2 receptor. Thus on this basis it is well placed to block DA s... 

Unfortunately although much is known about the pathways and receptors involved in extrapyramidal activity and the mechanism of the EPSs that follow neuroleptic therapy and even the possible origin of negative symptoms in the prefrontal cortex, the precise site of origin and NT involvement in the overriding positive symptoms is less clear. Until that is corrected, permutations of NT antagonisms are likely to multiply with the neuroleptics. 

Measuring the expression of the early-immediate gene c-fos supports the striatal role of neuroleptics in the induction of EPSs because although all neuroleptics induce such expression in both the nucleus accumbens and striatum, the atypical neuroleptics do so more in the accumbens while clozapine, but not risperidone, also achieve it in the prefrontal cortex (Robertson, Matsumura and Fibiger 1994). How this arises is uncertain but since risperidone is a more potent 5-HT2 antagonist than clozapine, it cannot be through that mechanism. 

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 ...

Whether the amelioration of negative symptoms results from an action in the cortex and, in particular, the prefrontal cortex requires further study. The fact that clozapine, the atypical drug that is currently most effective in this respect, has actions there which are not shown by other compounds is encouraging even though the precise mechanism by which it works remains to be elucidated. 

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. 

Dailey, JW and Webster, RA (1993) Dopamine-like effects of clozapine on spontaneously active neurons in the rat prefrontal cortex. J. Psychopharm. 1 A7. 

Knoble, MB and Weinberger, DR (1997) Dopamine, the prefrontal cortex and schizophrenia. J. 

Nutt, DJ, Lalies, MD, Lione, LA and Hudson, AL (1997) Noradrenergic mechanisms in the prefrontal cortex. J. Psychopharm. 11 163-168. 

One problem with both these theories is that disruption of noradrenergic transmission by selective adrenoceptor antagonists has little impact on the development of escape deficits. However, such antagonists do prevent the reversal of learned helplessness by antidepressants (reviewed by Stanford 1995). Also, it would be most unlikely that a deficit in only one neurotransmitter system fully accounts for learned helplessness. Indeed, there is plenty of evidence for a role for 5-HT in learned helplessness for instance, this behaviour is reversed by microinjection of 5-HT into the prefrontal cortex (Davis et al. 1999). Finally, it is clear that opioid, GABAergic and cholinergic systems (among others) are all linked with this behavioural deficit and even dihydropyridine antagonists of Ca + channels prevent its development. 

Both amphetamine and cocaine have also been reported to support intracranial self-administration in the mesolimbic/mesocortical dopaminergic system. Rats will self-administer cocaine into the medial prefrontal cortex (Goeders and Smith 1983). while amphetamine is self-administered into the orbitofrontal cortex of rhesus monkeys (Phillips and Rolls 1981) and the nucleus accumbens of rats (Hoebel et al. 1983 Monaco et al. 1981). These data indicate that the mesolimbic/mesocortical dopaminergic system is involved in the initiation of stimulant reinforcement processes, and this work suggests that the region of the nucleus accumbens, more specifically the mesolimbic dopamine system, may be an important substrate for reinforcing properties of several psychomotor stimulant drugs. 

O Virtually all abused substances appear to activate the same brain reward pathway. Key components of the reward pathway are the dopamine (DA) mesocorticolimbic system that projects from the ventral tegmental area (VTA) and the nucleus accumbens (NA) to the prefrontal cortex, the amygdala, and the olfactory tubercle (Figs. 33-3 and 33-4).5 Animal studies... 

The average increase in rCMR after THC administration was less in marijuana users than in controls, and users had lower cerebellar metabolism than the controls at baseline [8]. Thus the cerebellum shows the greatest metabolic increase in response to acute THC and responds to chronic marijuana exposure with a decrease in baseline CMR. Habitual users but not controls responded to THC administration with increased rCMR in prefrontal cortex, orbitofrontal cortex, and basal ganglia. In contrast to the robust effects of THC on relative rCMR, changes in global CMR in response to THC were quite variable, with increases, decreases, and no changes seen in equal numbers of subjects. There was also variability in subjective effects, which were pleasurable for most subjects but either minimal or unpleasant (anxiety or paranoia) for others. 

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