Lindsay H. Burns

Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intra-accumbens infusions of D-amphetamine.

The experiments reported here have investigated the impact on reward-related processes of lesioning the basolateral amygdala, ventral subiculum and prelimbic cortex which represent the major limbic sources of afferents to the ventral striatum. The results showed that, while lesions of the prelimbic cortex were without effect on the approach to a CS predictive of sucrose reinforcement and the acquisition of a new response with conditioned reinforcement, lesions of the other two structures significantly impaired both responses. However, there were important differences between the effects of basolateral amygdala and ventral subiculum lesions. Thus, lesions of the ventral subiculum completely abolished the locomotor response to intra-accumbens infusions of D-amphetamine, in addition to blocking the potentiative effect of the same treatment on responding with conditioned reinforcement. Lesions of the basolateral amygdala, by contrast, reduced the control over behaviour by a conditioned reinforcer, but not the potentiation of that control by intra-accumbens D-amphetamine except at the highest dose. Moreover, the locomotor response to D-amphetamine-induced increases in dopamine in the nucleus accumbens was unaffected by amygdala lesions over the dose range blocked by ventral subiculum lesions. The results suggest a rather selective effect of amygdala-ventral striatal interactions on processes subserving conditioned reinforcement and a more fundamental influence of ventral subiculum-ventral striatal interactions in mediating the psychomotor stimulant effects of D-amphetamine.

Effects of lesions to amygdala, ventral subiculum, medial prefrontal cortex, and nucleus accumbens on the reaction to novelty: implication for limbic-striatal interactions.

The effects of bilateral excitotoxic lesions of 3 major sources of afferents to the ventral striatum (nucleus accumbens) were compared on an open field test of food neophobia allowing the choice between familiar and novel food. Whereas lesions of the basolateral amygdala and ventral subiculum had qualitatively similar effects to reduce food neophobia (although not affecting the latency to eat), amygdala lesions increased and the ventral subiculum decreased locomotor activity. In contrast, damage to the ventromedial prelimbic prefrontal cortex only affected initial food choice and latency measures. By comparison, excitotoxic lesions of the nucleus accumbens itself and intra-accumbens infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist AP5 increased activity and attenuated food neophobia. Results are discussed in terms of the role of limbic and prefrontal neuronal networks converging in the nucleus accumbens to control different aspects of the behavioral response to novelty.

Glutamate-dopamine interactions in the ventral striatum: role in locomotor activity and responding with conditioned reinforcement

Previous evidence suggests that glutamatergic limbic afferents participate in the potentiation of responding with conditioned reinforcement produced by intra-accumbens d-amphetamine. The present experiments were designed to investigate glutamate-dopamine interactions in the ventral striatum in both conditioned reinforcement and locomotor activity. Glutamate receptor agonists and antagonists were infused into the nucleus accumbens both alone and in combination with 3 µg d-amphetamine, and the effects of these interactions on responding with conditioned reinforcement and locomotor activity were measured. The glutamate receptor agonists NMDA, AMPA and quisqualate (agonists at the NMDA, AMPA and metabotropic glutamate receptor subtypes, respectively) and the antagonists AP5 and CNQX, (antagonists at the NMDA and AMPA receptor subtypes, respectively) were used in these investigations. These compounds were used in a dose range of 0.3 to 3 nmol, except CNQX, which was used in 0.2 to 2 nmol doses. While all agonists and antagonists increased locomotor activity when administered alone, the antagonists attenuated the locomotor response to d-amphetamine. In contrast, the agonists AMPA and quisqualate enhanced d-amphetamine-induced locomotor activity, although NMDA interfered with the effects of d-amphetamine. In the conditioned reinforcement paradigm, both the agonists and the antagonists abolished amphetamines potentiation of responding with conditioned reinforcement, suggesting that the glutamatergic transmission of information about the conditioned reinforcer could be blocked by glutamate receptor antagonists and disrupted by administration of the agonists. The dissociation between the effects of these excitatory amino acids on amphetamine-induced locomotor activity versus their effects on amphetamines potentiation of responding with conditioned reinforcement provides insight into the nature of the reward enhancement by accumbens dopamine versus its locomotor stimulant effects.

Intra-amygdala infusion of the N-methyl-d-aspartate receptor antagonist AP5 impairs acquisition but not performance of discriminated approach to an appetitive CS

The present experiments investigated the effects of blocking glutamate transmission in the amygdala on the learning and subsequent performance of a discriminated approach response to food, as well as on locomotor activity and a test of neophobia to food. In the appetitive conditioning experiment, three separate groups of rats received intra-amygdala infusions of PBS (phosphate-buffered saline) or 1.0 or 3.0 nmol of AP5, an antagonist at the NMDA glutamate receptor subtype, immediately before each conditioning session. The effects of AP5 on the performance of the discriminated approach response were tested in a fourth group of animals. AP5 dose-dependently impaired the discriminated approach response during the acquisition of the stimulus-reward association but had no effect on the performance of this response after this association was learned. These results suggest that glutamate transmission in the amygdala at the NMDA glutamate receptor subtype is important in the learning process. In separate experiments, intra-amygdala AP5 increased locomotor activity and attenuated the neophobia to food in a novel environment by increasing approaches to the food. Together, these findings parallel the effects of lesions to the basolateral amygdala. In addition, the specific effects on learning are consistent with the hypothesis that NMDA-receptor-mediated LTP underlies specific forms of learning within the amygdala.

Effects of excitotoxic lesions of the basolateral amygdala on conditional discrimination learning with primary and conditioned reinforcement

Rats with excitotoxic lesions of the basolateral amygdala (BLA) were not impaired in the acquisition of an appetitive visuospatial conditional discrimination between stimuli varying in temporal frequency that has previously been shown to be sensitive to the effects of lesions of the striatum and cingulate cortex. After asymptotic performance was attained, discrimination was reinforced according to a fixed ratio (FR) schedule under which n presentations of sucrose were provided following n correct responses; each correct response also being reinforced immediately by a light acting as a conditioned reinforcer. Under these conditions of reinforcement when FRn=5, BLA-lesioned rats initially showed transient impairments in several aspects of performance, but rapidly attained control levels over subsequent test sessions. No further impairments occurred when FRn=10/20. However, in various conditions of extinction, further differences in performance were revealed between the BLA-lesioned and control groups, notably a significantly enhanced resistance to extinction when both sucrose and conditioned reinforcement were omitted. The results are discussed in terms of limbic-striatal mechanisms in the control of discrimination learning and the possible role of the amygdala in the mediation of different aspects of conditioned reinforcement.

Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A

PTI-125 is a novel compound demonstrating a promising new approach to treating Alzheimers disease (AD), characterized by neurodegeneration and amyloid plaque and neurofibrillary pathologies. We show that the toxic signaling of amyloid-β42 (Aβ42) by the α7-nicotinic acetylcholine receptor (α7nAChR), which results in tau phosphorylation and formation of neurofibrillary tangles, requires the recruitment of the scaffolding protein filamin A (FLNA). By binding FLNA with high affinity, PTI-125 prevents Aβ42s toxic cascade, decreasing phospho-tau and Aβ aggregates and reducing the dysfunction of α7nAChRs, NMDARs, and insulin receptors. PTI-125 prevents Aβ42 signaling by drastically reducing its affinity for α7nAChRs and can even dissociate existing Aβ42–α7nAChR complexes. Additionally, PTI-125 prevents Aβ-induced inflammatory cytokine release by blocking FLNA recruitment to toll-like receptor 4, illustrating an anti-inflammatory effect. PTI-125s broad spectrum of beneficial effects is demonstrated here in an intracerebroventricular Aβ42 infusion mouse model of AD and in human postmortem AD brain tissue.

PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis

We show that amyloid-β1-42 (Aβ42) triggers a conformational change in the scaffolding protein filamin A (FLNA) to induce FLNA associations with α7-nicotinic acetylcholine receptor (α7nAChR) and toll-like receptor 4 (TLR4). These aberrant associations respectively enable Aβ42s toxic signaling via α7nAChR to hyperphosphorylate tau protein, and TLR4 activation to release inflammatory cytokines. PTI-125 is a small molecule that preferentially binds altered FLNA and restores its native conformation, restoring receptor and synaptic activities and reducing its α7nAChR/TLR4 associations and downstream pathologies. Two-month oral PTI-125 administration to triple-transgenic (3xTg) Alzheimers disease (AD) mice before or after apparent neuropathology and to 8-month wildtypes with milder neuropathologies reduced receptor dysfunctions and improved synaptic plasticity, with some improvements in nesting behavior and spatial and working memory in 3xTg AD mice. PTI-125 also reduced tau hyperphosphorylation, aggregated Aβ42 deposition, neurofibrillary tangles, and neuroinflammation. Efficacy in postmortem AD and Aβ42-treated age-matched control hippocampal slices was concentration-dependent starting at 1 picomolar (pM) concentration. PTI-125 is the first therapeutic candidate to preferentially bind an altered protein conformation and reverse this proteopathy.

Ultra-Low-Dose Naltrexone Decreases Dependence and Addictive Properties of Opioids

Ultra-low-dose opioid antagonist cotreatment was first shown parad oxically to enhance opioid analgesia and to reduce analgesic tolerance and physical dependence. In this chapter, we review data demonstrating that ultra-low-dose naloxone or naltrexone reduces several components of opioid dependence and addiction. While the reduction in opioid dependence, first demonstrated as a reduction in somatic withdrawal signs, might seem merely a correlate of the attenuation in tolerance, the data reviewed here show that ultra-low-dose naltrexone also reduces the “psychological” or negative affective aspect of acute opioid withdrawal. In addition, the acute rewarding properties of opioids are reduced by ultra-low-dose naltrexone. The attenuation of rewarding effects occurs in the same ultra-low dose ranges shown to enhance analgesia, thus dissociating the rewarding or addictive effects of opioids from their analgesic properties. Furthermore, in intravenous self-administration procedures in rats, ultra-low-dose opioid antagonists coadmin-istered with opioids reduced their rewarding potency, reduced motivation to obtain the drug, and reduced “drug-seeking” in the absence of drug availability. Finally, in a Phase III clinical trial, the ultra-low-dose naltrexone component of Oxytrex™ significantly reduced physical signs of opioid dependence after abrupt cessation of treatment, compared to withdrawal from oxycodone alone. Together, the data reviewed in this chapter suggest a reduced potential for opioid dependence and addiction by certain ultra-low-dose opioid antagonists combined with opioids, concurrent with the enhanced analgesia from these opioid agonist/antagonist cotreatments.