Animal Models

There are few experimental models. Even if appropriate lesions could be produced it will always be difficult to tell if an animal is experiencing hallucinations. Neuroleptics

Figure 17.3 Effect of lesions in the prefrontal cortex on the activity of the dopamine mesolimbic pathway. DA neurons from the ventral tegmentum (A10 nucleus) not only innervate the prefrontal cortex (PFC) and limbic areas and in particular the nucleus accumbens (NucAcc) but are influenced by descending projections to them from the prefrontal cortex. Under normal circumstances the system appears to be balanced (a). Experimental lesions of the DA pathway to prefrontal cortex in rats (i) disturbs the balance and appears to increase the activity of VTA neurons and DA input to the limbic system (Pycock, Kerwin and Carter 1980), possibly through a change in cortico-limbic or cortico-VTA activity (b). While there is no evidence for such a lesion in the schizophrenic brain the general pathology found in the PFC could reduce the influence of DA there (ii) and so be equivalent to deafferentation. This could then result in a change in cortical influence on the limbic system and VTA resulting in increased activity in the DA mesolimbic pathway. Such increased mesolimbic activity is thought to mediate the positive symptoms of schizophrenia (see Weinberger 1987)

Figure 17.3 Effect of lesions in the prefrontal cortex on the activity of the dopamine mesolimbic pathway. DA neurons from the ventral tegmentum (A10 nucleus) not only innervate the prefrontal cortex (PFC) and limbic areas and in particular the nucleus accumbens (NucAcc) but are influenced by descending projections to them from the prefrontal cortex. Under normal circumstances the system appears to be balanced (a). Experimental lesions of the DA pathway to prefrontal cortex in rats (i) disturbs the balance and appears to increase the activity of VTA neurons and DA input to the limbic system (Pycock, Kerwin and Carter 1980), possibly through a change in cortico-limbic or cortico-VTA activity (b). While there is no evidence for such a lesion in the schizophrenic brain the general pathology found in the PFC could reduce the influence of DA there (ii) and so be equivalent to deafferentation. This could then result in a change in cortical influence on the limbic system and VTA resulting in increased activity in the DA mesolimbic pathway. Such increased mesolimbic activity is thought to mediate the positive symptoms of schizophrenia (see Weinberger 1987)

block DA-induced stereotypy or locomotor activity but this merely reflects their DA antagonism and restricts the discovery of new neuroleptics to those which antagonise DA. They are little better than in vitro binding studies.

More recently animal models based on the startle response have been developed which do in fact reflect some of the behavioural changes seen in schizophrenia (Geyer et al. 1990). It is believed that schizophrenics cannot adequately process (filter) incoming sensory information, become inundated with it and show cognitive impairment. The startle reflex is a motor response to sensory input (sensorimotor reflex) which is common to both animals and humans. The whole body reaction of rats to a sound or tactile (air-puff) stimulus can be monitored in a special chamber (stabilimeter) while in humans eyelid movements or electromyograms from the facial muscles can be monitored. In both species, if a smaller subthreshold stimulus (the pre-pulse) is presented some time (100-1000 ms) before the actual startle inducing stimulus (pulse) is given, then the response to the standard pulse is inhibited. Such pre-pulse inhibition (PPI) is attenuated in schizophrenics and in rats in which DA activity has been supplemented by giving apomorphine or amphetamine; although in neither case is the response to the actual pulse altered. This DA-increased inhibition of PPI in rats is counteracted by neuroleptics as is the attenuation of PPI in schizophrenics.

Based just on these results, PPI could simply be just another index of DA function but phencyclidine, an NMDA rather than DA receptor antagonist, which exacerbates schizophrenic symptoms and induces such symptoms when abused, also inhibits PPI (Bashki, Swerdlow and Geyer 1994). In contrast with DA augmentation, which initiates only positive symptoms in humans, phencyclidine also produces negative symptoms and its inhibition of PPI in rats is not affected by DA antagonists. Thus PPI may be one model that is not solely dependent on DA, although phencyclidine does enhance DA release in the mesolimbic system.

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.

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