[Drug treatment of Alzheimer's dementia : Status quo and perspectives]. / Pharmakologische Therapie der Alzheimer-Demenz : Aktueller Stand und Perspektiven.

Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system. AD is characterized by progressive impairments of memory as well as other cognitive functions and an increasing loss of autonomy in everyday life. This review article provides an overview of the current state-of-the-art (symptomatic) pharmacological treatment of Alzheimer's disease, specifics in the context of concomitant neuropsychiatric symptoms in multimorbid patients, and drugs currently under development that have a potentially causal (disease modifying) effect are also mentioned.

Differential expression of presynaptic genes in a rat model of postnatal hypoxia: relevance to schizophrenia.

Obstetric complications play a role in the pathophysiology of schizophrenia. However, the biological consequences during neurodevelopment until adulthood are unknown. Microarrays have been used for expression profiling in four brain regions of a rat model of neonatal hypoxia as a common factor of obstetric complications. Animals were repeatedly exposed to chronic hypoxia from postnatal (PD) day 4 through day 8 and killed at the age of 150 days. Additional groups of rats were treated with clozapine from PD 120-150. Self-spotted chips containing 340 cDNAs related to the glutamate system ("glutamate chips") were used. The data show differential (up and down) regulations of numerous genes in frontal (FR), temporal (TE) and parietal cortex (PAR), and in caudate putamen (CPU), but evidently many more genes are upregulated in frontal and temporal cortex, whereas in parietal cortex the majority of genes are downregulated. Because of their primary presynaptic occurrence, five differentially expressed genes (CPX1, NPY, NRXN1, SNAP-25, and STX1A) have been selected for comparisons with clozapine-treated animals by qRT-PCR. Complexin 1 is upregulated in FR and TE cortex but unchanged in PAR by hypoxic treatment. Clozapine downregulates it in FR but upregulates it in PAR cortex. Similarly, syntaxin 1A was upregulated in FR, but downregulated in TE and unchanged in PAR cortex, whereas clozapine downregulated it in FR but upregulated it in PAR cortex. Hence, hypoxia alters gene expression regionally specific, which is in agreement with reports on differentially expressed presynaptic genes in schizophrenia. Chronic clozapine treatment may contribute to normalize synaptic connectivity.

mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity.

Formation and extinction of aversive memories in the mammalian brain are insufficiently understood at the cellular and molecular levels. Using the novel metabotropic glutamate receptor 7 (mGluR7) agonist AMN082, we demonstrate that mGluR7 activation facilitates the extinction of aversive memories in two different amygdala-dependent tasks. Conversely, mGluR7 knockdown using short interfering RNA attenuated the extinction of learned aversion. mGluR7 activation also blocked the acquisition of Pavlovian fear learning and its electrophysiological correlate long-term potentiation in the amygdala. The finding that mGluR7 critically regulates extinction, in addition to acquisition of aversive memories, demonstrates that this receptor may be relevant for the manifestation and treatment of anxiety disorders.

Carbachol injections into the nucleus accumbens disrupt acquisition and expression of fear-potentiated startle and freezing in rats.

The nucleus accumbens is involved in different types of emotional learning, ranging from appetitive instrumental learning to Pavlovian fear conditioning. In previous studies, we found that temporary inactivation of the nucleus accumbens blocked both the acquisition and expression of conditioned fear. This was not due to altered dopaminergic activity as we have also found that intra-nucleus accumbens infusions of the dopamine agonist amphetamine do not affect either the acquisition or the expression of conditioned fear. Therefore, in the present study we examined whether cholinergic activity in the nucleus accumbens is involved in the acquisition and expression of conditioned fear. Specifically, the effect of intra-nucleus accumbens infusions of the unselective cholinergic agonist carbachol on the acquisition and expression of conditioned fear was assessed. Across several experiments, we measured fear to visual and acoustic conditioned stimuli and to the experimental context. Further, two different measures of conditioned fear were recorded: fear potentiation of startle and freezing. Intra-nucleus accumbens carbachol infusions disrupted acquisition as well as expression of conditioned fear, regardless of the modality of the fear-eliciting stimulus or of the specific measure of conditioned fear. This disruption of conditioned fear was not simply a by-product of enhanced motor activity which also occurred after intra-nucleus accumbens carbachol infusions. Interestingly, despite the substantial effect of intra-nucleus accumbens carbachol on expression of conditioned fear, the results of the final experiment suggest that these rats extinguish similarly to control rats. Taken together, the present results indicate that acetylcholine within the nucleus accumbens is important for the learning and retrieval of conditioned fear.

Injections of the NMDA receptor antagonist aminophosphonopentanoic acid into the lateral nucleus of the amygdala block the expression of fear-potentiated startle and freezing.

NMDA receptors within the amygdala play an important role in the acquisition and expression of conditioned fear. Because amygdaloid injections of NMDA receptor antagonists did not block the expression of every behavioral sign of fear, a discussion arose as to whether amygdaloid NMDA receptors play different roles in different kinds of fear-conditioning tasks. To clarify the exact role of amygdaloid NMDA receptors, the present study measured the effects of amygdaloid NMDA receptor blockade on the two major animal models of conditioned fear. An experimental design was used that allowed simultaneous measurement of fear-potentiated startle and freezing during the same test session after animals had undergone identical training procedures. The present study clearly demonstrates that injections of the NMDA receptor antagonist AP-5 into the lateral nucleus of the amygdala significantly attenuated both behavioral fear responses (i.e., the amygdaloid NMDA receptors are necessary for the expression of fear-potentiated startle and freezing). The present results together with others from the literature indicate that NMDA receptors within the lateral amygdala are critically involved in normal synaptic transmission. It appears then that NMDA receptor antagonists may block the acquisition of fear conditioning by directly interfering with normal synaptic transmissions in the amygdala. Possible reasons for some discrepant results in earlier studies are also discussed.

Fox urine exposure induces avoidance behavior in rats and activates the amygdalar olfactory cortex.

Predator odors represent a group of biologically-relevant chemosignals called kairomones. Kairomones enable prey animals to recognize potential predatory threats in their environment and to initiate appropriate defensive responses. Although the behavioral repertoire of anti-predatory responses (e.g. avoidance, freezing, risk assessment) has been investigated extensively, our knowledge about the neural network mediating these innate fear responses is rather limited. In the present study, the GABAA agonist muscimol was bilaterally injected (2.6 nmol/0.3 µl) into the amygdalar olfactory cortex (AOC), a brain area that receives massive olfactory input from both olfactory systems and is strongly interconnected with the medial hypothalamic defense circuit. Temporary inactivation of the AOC substantially disrupted avoidance behavior of rats to fox urine that is strongly avoided under control conditions (saline injections). Taken together, these results demonstrate that the AOC is critically involved in fox urine-induced fear behavior. This suggests that the AOC is part of a brain fear circuit that mediates innate fear responses toward predatory odors.

Expression of freezing and fear-potentiated startle during sustained fear in mice.

Fear-potentiated acoustic startle paradigms have been used to investigate phasic and sustained components of conditioned fear in rats and humans. This study describes a novel training protocol to assess phasic and sustained fear in freely behaving C57BL/6J mice, using freezing and/or fear-potentiated startle as measures of fear, thereby, if needed, allowing in vivo application of various techniques, such as optogenetics, electrophysiology and pharmacological intervention, in freely behaving animals. An auditory Pavlovian fear conditioning paradigm, with pseudo-randomized conditioned-unconditioned stimulus presentations at various durations, is combined with repetitive brief auditory white noise burst presentations during fear memory retrieval 24 h after fear conditioning. Major findings are that (1) a motion sensitive platform built on mechano-electrical transducers enables measurement of startle responses in freely behaving mice, (2) absence or presence of startle stimuli during retrieval as well as unpredictability of a given threat determine phasic and sustained fear response profiles and (3) both freezing and startle responses indicate phasic and sustained components of behavioral fear, with sustained freezing reflecting unpredictability of conditioned stimulus (CS)/unconditioned stimulus (US) pairings. This paradigm and available genetically modified mouse lines will pave the way for investigation of the molecular and neural mechanisms relating to the transition from phasic to sustained fear.

The neuroanatomical and neurochemical basis of conditioned fear.

After a few pairings of a threatening stimulus with a formerly neutral cue, animals and humans will experience a state of conditioned fear when only the cue is present. Conditioned fear provides a critical survival-related function in the face of threat by activating a range of protective behaviors. The present review summarizes and compares the results of different laboratories investigating the neuroanatomical and neurochemical basis of conditioned fear, focusing primarily on the behavioral models of freezing and fear-potentiated startle in rats. On the basis of these studies, we describe the pathways mediating and modulating fear. We identify several key unanswered questions and discuss possible implications for the understanding of human anxiety disorders.

The metabotropic glutamate receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) blocks fear conditioning in rats.

Glutamate receptors play an essential role in fear-related learning and memory. The present study was designed to assess the role of the group I metabotropic glutamate receptor (mGluR) subtype 5 in the acquisition and retrieval of conditioned fear in rats. The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) was applied systemically (0.0, 0.3, 3.0, 30.0 mg/kg per os) 60 min before the acquisition training and before the expression of conditioned fear, respectively, in the fear-potentiated startle paradigm. MPEP dose-dependently blocked the acquisition of fear. This effect was not due to state-dependent learning. MPEP also prevented the expression of fear at a dose of 30.0 mg/kg. As a positive control for these effects, we showed that the benzodiazepine anxiolytic compound diazepam (1.25 mg/kg intraperitoneally) also blocked acquisition and expression of fear potentiated startle. MPEP did not affect the baseline startle magnitude, short-term habituation of startle, sensitisation of startle by footshocks or prepulse inhibition of startle. These data indicate a crucial role for mGluR5 in the regulation of fear conditioning. In the highest dose MPEP might exert anxiolytic properties.

Amygdaloid N-methyl-D-aspartate and gamma-aminobutyric acid(A) receptors regulate sensorimotor gating in a dopamine-dependent way in rats.

Sensorimotor gating can be measured as prepulse inhibition of the startle response in humans and rats. Since prepulse inhibition is impaired in schizophrenics there is considerable interest in understanding the neuronal basis of prepulse inhibition. Neuropathological findings indicate a dysfunction of the glutamatergic and GABAergic system in cortico-limbic areas in schizophrenics. We tested whether blockade of N-methyl-D-aspartate or GABA(A) receptors in the basolateral amygdala affects prepulse inhibition in rats. Local infusion of the N-methyl-D-aspartate receptor antagonist dizocilpine (0, 6.25 microg/0.5 microl), or of the GABA(A) receptor antagonist picrotoxin (0, 5.0, 10.0 ng/0.5 microl) reduced prepulse inhibition. The prepulse inhibition-disrupting effect of 6.25 microg dizocilpine or 10.0 ng picrotoxin was reversed by systemic co-administration of the dopamine antagonist haloperidol (0.1mg/kg i.p.). These data indicate that sensorimotor gating is regulated in a dopamine-dependent way by N-methyl-D-aspartate and GABA(A) receptors in the basolateral amygdala. Our findings are discussed with respect to neuropathological findings in schizophrenics.

Anxiogenic-like effects of opiate withdrawal seen in the fear-potentiated startle test, an interdisciplinary probe for drug-related motivational states.

RATIONALE: Anxiety-like effects may be universal to withdrawal from drugs of abuse. The study of withdrawal would benefit from the acoustic startle response (ASR), a discrete, cross-species reflex which is increased by fear-related states. However, existing reports of opiate-related effects on baseline ASR have not validated ASR as a measure of drug-related motivation. OBJECTIVE: The effects of opiate treatment and withdrawal were examined using fear-potentiated startle, a startle test more sensitive to fear than baseline changes. METHODS: Fear-conditioned rats were treated with Alzet osmotic pumps delivering 0.25 mg/kg per day fentanyl or placebo pumps. Experiment I examined changes before and during opiate treatment on locomotor activity and baseline, prepulse inhibition, and fear-potentiated startle. Experiment 2 examined the same responses during withdrawal precipitated after 4-7 days of treatment using IV naloxone. RESULTS: Experiment 1 revealed an attenuated fear-potentiated startle on the first test after the start of fentanyl treatment (4 h); this was not seen on subsequent tests and suggested tolerance to this acute effect. Experiment 2 found an enhancement of fear-potentiated startle precipitated in fentanyl-treated rats after injection of 0.025 and 0.16 mg/kg naloxone; this was not seen at 1 mg/kg naloxone, even though more physical withdrawal signs were most prevalent at this dose. In neither experiment did locomotor activity, baseline ASR, or prepulse inhibition of the ASR show any treatment effect. CONCLUSIONS: Fear-potentiated startle may provide a specific and valid measure of anxiety-like effects of drug withdrawal. Discussed were conditions needed to see this effect and the relevance of the findings for different mechanisms of withdrawal discomfort.

Sensitization of prepulse inhibition deficits by repeated administration of dizocilpine.

RATIONALE: Repeated administration of psychoactive drugs results in a progressive enhancement of the behavioral effects of these compounds, a phenomenon termed sensitization. OBJECTIVE: We tested whether repeated administration of the non-competitive NMDA receptor antagonist dizocilpine (MK-801) induces sensitization of the disruptive effects of this compound on prepulse inhibition (PPI) of startle. METHODS: Rats received nine daily i.p. injections of 0.1 mg/kg MK-801 in the startle cage and were tested for PPI, startle in the absence of prepulses and motor activity in the startle cage. Another group of rats received MK-801 in the home cage on 9 days without daily testing. Controls were injected with saline and tested daily, while a separate group of rats received saline in the home cage without daily testing. On day 10, all rats received saline injections and were tested. On day 11, all rats were injected with 0.1 mg/kg MK-801 and tested again. On day 12, all rats received 1 mg/kg dl-amphetamine i.p. and were tested for PPI, to assess a possible cross-sensitization. RESULTS: MK-801 had no effect on day 1 of testing but induced a PPI deficit after 6-9 days of daily treatment and testing in those rats that received the drug in the startle cage, but not in the home cage. Motor activity was increased after repeated treatment and testing. There was also a trend towards sensitization of enhancement of the startle magnitude by MK-801 in these rats. dl-Amphetamine reduced PPI in those rats that received daily MK-801 injections in the startle cage to a similar extent as saline injections. CONCLUSIONS: Since PPI is considered as a measure of sensorimotor gating, our data indicate that sensorimotor gating deficits induced by MK-801 are subject to a sensitization process. These findings may be relevant for current hypotheses relating schizophrenic symptoms to sensitization.

Brain stem circuits mediating prepulse inhibition of the startle reflex.

RATIONALE: Prepulse inhibition (PPI) of the startle reflex occurs when brief, non-startling tactile, acoustic or visual stimuli are presented 20-500 ms before the startling stimulus. OBJECTIVE: To review information about PPI-mediating brain stem circuits and transmitters, and their functions. RESULTS: Midbrain systems are most critical for the fast relay of these PPI stimuli. Acoustic prepulses for PPI are relayed through the inferior colliculus (IC). The superior colliculus (SC) is important for acoustic PPI, and may be important for the mediation of tactile and visual prepulses. This collicular activation for PPI is quickly relayed through the pedunculopontine tegmental nucleus (PPTg), with lesser contributions to PPI from the laterodorsal tegmental nucleus (LDTg) and substantia nigra, pars reticulata (SNR). The transient activation of midbrain nuclei by PPI stimuli is converted into long-lasting inhibition of the giant neurons of the caudal pontine reticular nucleus (PnC). We propose that muscarinic and GABA(B) inhibitory receptors (both metabotropic receptors) on PnC giant neurons combine to produce the long-lasting inhibition of startle. Activation of mesopontine cholinergic neurons leads to cortical arousal, turning and exploratory approach responses. CONCLUSION: PPI is mediated by a circuit involving the IC, SC, PPTg, LDTg, SNR and PnC. By reducing startle, PPI allows the execution of approach responses and perceptual processing following salient stimuli.

Sensorimotor gating deficit after lesions of the superior colliculus.

The superior colliculus (SC) is important for the processing of sensory information of different modalities and for the mediation of adequate motor responses in mammals. The present study investigated the effects of excitotoxic lesions of the SC on two different modulations of the acoustic startle response (ASR) in rats. Modulations of the ASR (i.e. increase or decrease of the response strength) represent useful models for the study of sensorimotor integration phenomena. Lesions of the SC decreased the prepulse inhibition of the ASR without affecting the baseline startle amplitude or the enhancement of the ASR by footshock sensitization. These results suggest a crucial role of the SC in the prepulse inhibition of the ASR, a model of sensorimotor gating.

Cholecystokinin enhances the acoustic startle response in rats.

The present study examined the effects of the neuropeptide cholecystokinin (CCK) on neurones of the caudal pontine reticular nucleus (PnC), which mediates the acoustic startle response (ASR) in rats. Electrophysiological experiments revealed an excitatory effect of CCK on acoustically responsive neurones in the PnC. On the behavioural level, CCK also enhanced the ASR. Since the PnC is not only an obligatory relay station of the brain circuit mediating the ASR, but also receives modulatory input from brain areas involved in the expression of fear and anxiety, the enhancement of the ASR by CCK could be interpreted as an anxiogenic-like effect of this peptide.

Lesions of the central gray block conditioned fear as measured with the potentiated startle paradigm.

The amplitude of the acoustic startle response (ASR) in rats is increased in the presence of a cue which has previously been paired with an electric footshock. This phenomenon is termed fear-potentiated startle and is a useful model to investigate the neural systems underlying fear and anxiety. A series of studies have shown, that the amygdaloid complex is necessary for the acquisition and the expression of conditioned fear. Further experiments have delineated an efferent amygdalofugal pathway to the primary startle circuit, at the level of the caudal pontine reticular formation, which mediates the expression of conditioned fear [10]. Yet it was unclear, whether this amygdaloreticular pathway directly transfers the effects of conditioned fear from the amygdala to the primary startle circuit or whether there exist one or more relay nuclei within this pathway or even additional parallel circuits. Based on our previous finding that the midbrain central gray (CG) is involved in the mediation of the facilitatory effects on the ASR of unconditioned aversive events, the present study tested the hypothesis that the CG is important for the potentiation of the ASR by conditioned fear. Therefore, we lesioned the CG before and after fear-conditioning and examined the effects of these lesions on fear-potentiated startle. Pre- and post-training lesions of the CG totally blocked the potentiation of the ASR amplitude by conditioned fear, which was seen in sham-lesioned rats, indicating that CG lesions affected the expression of conditioned fear. The baseline ASR amplitude was not influenced by CG lesions. We discuss possible pathways and mechanisms underlying the expression of conditioned and unconditioned fear in rats.

Role of the substantia nigra pars reticulata in sensorimotor gating, measured by prepulse inhibition of startle in rats.

The substantia nigra pars reticulata (SNR) is one of the major output nuclei of the basal ganglia. It connects the dorsal and ventral striatum with the thalamus, superior colliculus and pontomedullary brainstem. The SNR is therefore in a strategic position to regulate sensorimotor behavior. We here assessed the effects of SNR lesions on prepulse inhibition (PPI) of the acoustic startle response (ASR), stereotypy and locomotion in drug-free rats, as well as after systemic administration of the dopamine agonist DL-amphetamine (2 mg/kg), and the NMDA receptor antagonists dizocilpine (0.16 mg/kg) and CGP 40116 (2 mg/kg). SNR lesions reduced PPI, enhanced spontaneous sniffing and potentiated the locomotor stimulation by dizocilpine and CGP 40116. PPI was impaired by dizocilpine and CGP 40116 in controls. The ASR was enhanced in controls by dizocilpine and amphetamine. SNR lesions prevented the enhancement of the ASR by amphetamine. A second experiment tested the hypothesis that the SNR mediates PPI via a GABAergic inhibition of the startle pathway. Infusion of the GABA(B) antagonist phaclofen but not the GABA(A) antagonist picrotoxin into the caudal pontine reticular nucleus reduced PPI. Hence, lesion of the SNR reduces sensorimotor gating possibly by elimination of a nigroreticular GABAergic projection interacting with GABA(B) receptors. Moreover, destruction of the SNR enhances the motor stimulatory effects of amphetamine and of the NMDA antagonists dizocilpine and CGP 40116. We conclude that the SNR exerts a tonic GABAergic inhibition on sensorimotor behavior that is regulated by the dorsal and the ventral striatum.

The superior olivary complex is necessary for the full expression of the acoustic but not tactile startle response in rats.

The acoustic startle response (ASR) in rats is mediated by an oligosynaptic pathway from the cochlea via the brainstem to spinal and cranial motoneurons. The present study tested whether the superior olivary complex (SOC) plays a role in the mediation of the ASR. The SOC receives auditory information from the ventral cochlear nuclei and projects to the caudal pontine reticular nucleus (PnC), the sensorimotor interface of the ASR. Axon-sparing excitotoxic lesions of the SOC strongly reduced the ASR amplitude and slightly prolonged ASR onset and peak latencies. The integrity of PnC which is adjacent to the SOC was confirmed by testing the tactile startle response which was not affected by SOC lesions. We suggest that the SOC is necessary for a full expression of the ASR and discuss possible auditory input structures involved in the mediation of the ASR.

Enhancement of prepulse inhibition after blockade of GABA activity within the superior colliculus.

The present study examined the effects of local microinjections of the GABA chloride channel blocker Picrotoxin into the superior colliculus (SC) on prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats. PPI is a useful model for the investigation of the neuronal basis of sensorimotor gating which is deficient in some psychiatric disorders, such as schizophrenia. Blockade of GABA activity within the SC by Picrotoxin injections (leading to a moderate stimulation of the SC) significantly enhanced PPI without affecting the ASR baseline amplitude or the spontaneous motor activity. Based on these results we discuss the role of the SC in a hypothetical neuronal circuit mediating PPI of the ASR.

Expression and conditioned inhibition of fear-potentiated startle after stimulation and blockade of AMPA/Kainate and GABA(A) receptors in the dorsal periaqueductal gray.

Previous work showed that the dorsal periaqueductal gray is involved in the inhibition of fear-potentiated startle. The present study investigated the effects of blockade and stimulation of Kainate/AMPA and GABA(A) receptors within the dorsal periaqueductal gray on expression and conditioned inhibition of fear-potentiated startle. Blockade of the Kainate/AMPA receptors enhanced whereas stimulation of the Kainate/AMPA receptors decreased expression of fear-potentiated startle. These effects do not reflect conditioned inhibition since this modulation was not changed by injections of Kainate/AMPA receptor agonists or antagonists into the dorsal periaqueductal gray. Stimulation and blockade of GABA(A) receptors within the dorsal periaqueductal gray neither affected expression of fear-potentiated startle nor its conditioned inhibition. The present results together with findings from the literature indicate that glutamate in the dorsal periaqueductal gray is a critical substrate for the expression and modulation of fear-related behaviours.