| dc.description.abstract | The acoustic startle reflex is a widespread skeletal muscle contraction in response to a sudden loud auditory stimulus. Prepulse inhibition (PPI) refers to the reduction in startle amplitude when a weak prestimulus is presented immediately before the startle-eliciting stimulus. PPI has been used as an operational measure of sensorimotor gating in the central nervous system, and studies in humans indicate that schizophrenic patients exhibit diminished PPI consistent with a deficit in their sensorimotor gating capability. PPI is reduced also in rats treated with psychotomimetic drugs, such as amphetamine (AMP) and phencyclidine (PCP). In this thesis the neuronal mechanisms involved in the modulation of PPI was studied. The overall aim of these studies was to investigate how sensory information is integrated and processed in the brain under normal or functionally impaired conditions and how malfunction of these processes may apply to the pathophysiology of schizophrenia. The present studies further confirm, from different aspects, that the dopamine (DA) neurotransmitter is involved in the modulation of PPI. The indirect DA agonist, AMP, was shown to decrease PPI. A close and time-related reverse relationship between DA overflow in the nucleus accumbens and PPI was obtained using an in vivo brain microdialysis technique allowing concomitant measurement of these parameters in awake, freely moving rats. This effect was more pronounced in AMP-treated rats compared to rats treated with equimolar doses of cocaine, which showed an increase in DA overflow but no change in PPI. In other experiments, the combined treatment with subthreshold doses of the selective DA D1 agonist, SKF 38393, and the selective DA D2 agonist, quinpirole, was also shown to decrease PPI. Finally, the selective DA D2 antagonist, raclopride, was shown to enhance PPI. It is concluded that DA neurotransmission is involved in the modulation of PPI and that the ventral part of the mesostriatal DA system may serve an important role in this modulation. Furthermore, the possibility is discussed that the discrepant results on PPI obtained with AMP and cocaine may disclose functionally relevant differences in their mechanisms of action, and that the enhancement of PPI induced by some antipsychotics in rats may signal aversive mental effects in humans.Rats repeatedly treated with AMP at three day intervals for 15 days showed sensitization to the disruptive effect of AMP on PPI. Persistent changes in brain function was indicated since an increase in disruptive effect was observed in sensitized animals also after a 22 days long drug- and test-free period. The development of sensitization was blocked by pretreatment with haloperidol, which suggests that sensitization was dependent on DA D2 receptor activation. Furthermore, the development of sensitization was blocked by adrenalectomy, which suggests that sensitization was dependent also on circulating adrenal hormones.Increased sensitivity to the disruptive effect of AMP was also obtained in rats subjected to local infusion of pertussis toxin (PTX) into the ventral tegmental area (VTA). This treatment uncouples the G protein-mediated feedback inhibition of the mesocorticolimbic DA neurons and disinhibits this neuronal system. Increased DA-ergic activity has been implicated in the pathophysiology of schizophrenia and AMP- or PTX-induced sensitization to the neuronal functions that modulate PPI may be experimental models to investigate this hypothesis. Previous studies have shown that several neuroanatomical structures and pathways in the brain are involved in the modulation of PPI. In this thesis, the functional importance of the medial geniculate body (MG) in the modulation of PPI was investigated. To this end, in vivo microdialysis probes were used to locally infuse drugs into the MG of awake, freely moving rats simultaneously with startle response and PPI measurements in the same animals. Intrageniculate infusion of the sodium channel blocker, tetrodotoxin (TTX), significantly reduced PPI. A similar effect was obtained after intrageniculate infusion of the GABAB receptor agonist, baclofen. Also intrageniculate infusion of muscimol, an agonist at the GABAA receptor complex, reduced PPI although this effect was obtained at a higher concentration of the drug compared to that of baclofen. These studies suggest that the MG is involved in the modulation of PPI and that auditory signals relayed via the MG may be subjected to an inhibitory control at this level involving GABA neurotransmission. | en |
