This study evaluated the effects of chronic olanzapine treatment on cognitive performance and neurochemical function in a rodent model of schizophrenia. Animals were neonatally treated with quinpirole, a dopamine D2 receptor agonist, or saline. Quinpirole treatment produces an increase of dopamine D2 receptor sensitivity that extends into adulthood, known as D2 receptor priming, similar to a phenomenon that occurs in schizophrenia. These same rats were treated in adulthood for 28 days with olanzapine, an atypical antipsychotic, or saline. Dopamine D2- primed rats demonstrated significant deficits on a cognitive task that were alleviated by olanzapine treatment. Brain tissue analysis revealed that D2-primed animals demonstrated a significant decrease in the neurotrophins nerve growth factor (NGF) in the hippocampus and brain-derived neurotrophic factor (BDNF) in the frontal cortex. Olanzapine treatment alleviated the decrease in NGF. The results suggest that olanzapine eliminates cognitive impairment and may have neuroprotective properties in the hippocampus of D2-primed rats.

No description available.

Caffeine is the most consumed psychoactive substance in the world, and most caffeine consumption in coffee and energy drinks is intended to produce a psychoactive effect. However, caffeine is not a primary reinforcer in preclinical paradigms – non-human species do not reliably take the drug to produce a psychoactive effect. However, caffeine is a ‘reinforcement enhancer’ in preclinical models; the effects of caffeine increase the motivation to obtain other non-drug reinforcers. The overall goal of this project was to determine if these reinforcement enhancing effects of caffeine could promote caffeine self-administration and to subsequently investigate the behavioral and neurochemical underpinnings of this effect. We hypothesized reliable caffeine self-administration would occur by adventitious pairing of caffeine with saccharin, a primary reinforcer. Second, we hypothesized that caffeine enhances reinforcement by increasing the salience of incentive stimuli, which are stimuli that come to evoke approach behaviors through associative learning (e.g., Pavlovian conditioning). Finally, incentive salience is moderated by dopamine release in the nucleus accumbens (NAc), an area highly involved in reward-learning and substance dependence. Therefore, we hypothesized that if caffeine enhanced control of approach behavior by incentives, then it would increase the ability of incentive stimuli to evoke dopamine in the NAc. These studies show that intravenous delivery of caffeine with oral saccharin increases operant relative to control groups responding for intravenous caffeine or oral saccharin. The effect was also dose-dependent, confirming that the psychoactive effects of caffeine increased behavior. We also extended this effect to an oral model of caffeine self-administration, which included a simple sweetener (saccharin) or a complex oral vehicle (saccharin with decaffeinated coffee) to mask the bitter taste of caffeine. Presenting caffeine with oral saccharin promoted self-administration, relative to saccharin alone and did not depend on the nature of the complexity of the vehicle. Caffeine also dose-dependently increased approach to an incentive stimulus and this effect was associated with increased extracellular dopamine in the NAc. These findings suggest caffeine enhances incentive motivation and that this effect may result from increases in CS-evoked striatal dopamine.

Although it is well-established that animals will self-stimulate electric current to various diverse brain structures, the neural substrate of brain stimulation reward (BSR) has eluded identification since its discovery more than a half-century ago. We show that GABA neurons in the midbrain, hypothalamus and thalamus express connexin-36 (Cx36) gap junctions and couple electrically with dopamine application or by stimulation of the internal capsule (IC), which also supports self-stimulation. The threshold for responding for self-stimulation of the IC is the threshold for coupling between these GABA neurons, the degree of responding for IC ICSS is proportional to the magnitude of electrical coupling between these GABA neurons, and GJ blockers, including the Cx36 blocker mefloquine, increase the threshold for IC self-stimulation without affecting performance. Thus, electrical coupling between this network of GABA neurons fits the prevailing model for the elusive integrator of BSR.

The purpose of this project was to investigate the mechanism of action of acupuncture on a critical neural substrate involved in alcoholism. Specifically, this study evaluated the effects of stimulation of the acupuncture Shenmen (HT7) point on inhibitory GABA neurons in the ventral tegmental area (VTA), a midbrain structure implicated in drug and alcohol abuse, and ethanol self-administration. In addition, the role of opioid receptors (ORs) in ethanol and acupuncture effects was explored. Using electrophysiological methods in mature rats, we evaluated the effects of HT7 stimulation and opioid antagonists on the VTA GABA neuron firing rate. With behavioral paradigms, we also assessed those effects on ethanol self-administration, using a modification of the sucrose fading procedure. We found that HT7 stimulation produced a biphasic modulation of VTA GABA neuron firing rate characterized by transient enhancement at the onset of stimulation followed by a prolonged inhibition and subsequent recovery in 5 min. HT7 stimulation blocked the typical suppression of VTA GABA neuron firing rate produced by a moderately intoxicating dose of ethanol. The late inhibition produced by HT7 stimulation as well as HT7 reversal of ethanol's effects on GABA neuron firing rate was blocked by the non-selective opioid receptor antagonist, naloxoneIn addition, HT7 acupuncture reduced ethanol self-administration without affecting sucrose consumption. More important, systemic administration of the δ-opioid receptor (DOR) antagonist, naltrindole blocked ethanol suppression of VTA GABA neuron firing rate and significantly reduced ethanol self-administration without affecting sucrose consumption. These findings suggest that DOR-mediated opioid modulation of VTA GABA neurons may be related to the role of acupuncture in modulating mesolimbic DA release and suppressing the reinforcing effects of ethanol. We confirmed that acupuncture stimulation may have a significant impact on the inhibitory neuron activity in the VTA and that acupuncture may serve as an effective adjunct to OR antagonist therapy for alcoholism.

No description available.

Identification of the pathways that could be targeted to alleviate ageing-related cognitive decline is of prime importance. One of the most promising target mechanisms is connected to healthy dopaminergic ageing. Extant research suggest that women may exhibit less ageing-related dopamine (DA) decline compared to men, implicating that women may suffer less from dopamine-related cognitive decline. However, to date, shortage of empirical investigations limit firm conclusions of sex differences. In the present work it is hypothesized that: (i) women as compared to men exhibit less aging-related DA losses, and (ii) less aging-related decline of episodic memory (EM), and that (iii) sex differences in episodic memory might be mediated by differences in DA integrity. To that end, sex-related differences in D1-type dopamine receptor (D1DR) integrity and episodic memory were investigated in a healthy cohort of young to old participants (age 20 – 80, n = 180, 50% women) through whole-brain voxel-wise analysis and linear regression models. Firstly, the dorsal caudate was identified as the main region of the EM-D1DR interrelation. Secondly, a significant female advantage was found for EM and D1DR in ageing. Finally, no mediation effect by D1DR on the sex-EM interaction was found. These results indicate the presence of correlational relationships between sex, cognition and D1DR, in ageing. However, D1DR was not found to be the mediating factor in the observed correlations. Future research, preferably using longitudinal design, should further investigate the underpinnings of sex differences in D1DR and EM.

Rhythmic oscillations in neuronal activity display variations in amplitude (power) over a range of frequencies. Attention and cognitive performance correlate with increases in cortical gamma oscillations (40-70Hz) that are generated by the coordinated firing of glutamatergic pyramidal neurons and GABAergic interneurons, and are modulated by dopamine. In the medial prefrontal cortex (mPFC) of rats, gamma power increases during treadmill walking, or after administration of an acute subanesthetic dose of the NMDA receptor antagonist ketamine. Ketamine is also used to mimic symptoms of schizophrenia, including cognitive deficits, in healthy humans and rodents. Additionally, the ability of a drug to modify ketamine-induced gamma power has been proposed to predict its pro-cognitive therapeutic efficacy. However, the mechanism underlying ketamine-induced gamma oscillations is poorly understood. We hypothesized that gamma oscillations induced by walking and ketamine would be generated by a shared mechanism in the mPFC and one of its major sources of innervation, the mediodorsal thalamus (MD). Recordings from chronically implanted electrodes in rats showed that both treadmill walking and ketamine increased gamma power, firing rates, and spike-gamma LFP correlations in the mPFC. By contrast, in the MD, treadmill walking increased all three measures, but ketamine decreased firing rates and spike-gamma LFP correlations while increasing gamma power. Therefore, walking- and ketamine-induced gamma oscillations may arise from a shared circuit in the mPFC, but different circuits in the MD. Recent work in normal animals suggests that dopamine D4 receptors (D4Rs) synergize with the neuregulin/ErbB4 signaling pathway to modulate gamma oscillations and cognitive performance. Consequently, we hypothesized that drugs targeting the D4Rs and ErbB receptors would show pro-cognitive potential by reducing ketamine-induced gamma oscillations in mPFC. However, when injected before ketamine, neither the D4R agonist nor antagonist altered ketamine’s effects on gamma power or firing rates in the mPFC, but the pan-ErbB antagonist potentiated ketamine’s increase in gamma power, and prevented ketamine from increasing firing rates. This indicates that D4Rs and ErbB receptors influence gamma power via distinct mechanisms that interact with NMDA receptor antagonism differently. Our results highlight the value of using ketamine-induced changes in gamma power as a means of testing novel pharmaceutical agents.

Decision making – committing to a single action from a plethora of viable alternatives – is a necessity for all motile creatures, each moving a single body to many possible destinations. Some decisions are better than others. For example, to a rat deciding between one path that will bring it to a piece of cheese and another that will bring it to the jaws of a cat, there is a clear reason for the rat to prefer one choice over the other. Two criteria for adjusting decision making for optimal outcome are to make decisions as accurately as possible – choose the course of action most likely to result in the preferred outcome – but also to decide as fast as possible. Because these criteria often conflict, decision making has an inherent “speed-accuracy tradeoff”. Presented here is a computational neural model of decision making, which incorporates neurobiological design principles that optimize this tradeoff via reward-guided transfers of control between two sensory processing systems with different speed/accuracy characteristics. This model incorporates anatomical and physiological evidence that dopamine, the key neurotransmitter in reinforcement learning, has varying effects in different sub-regions of the basal ganglia, a subcortical structure that interfaces with the neocortex to control behavior. Based on the observed differences between these sub-regions, the model proposes that gradual adaptations of synaptic links by reinforcement learning signals lead to rapid changes in the speed and accuracy of decision making, by assigning control of behavior to alternative cortical representations. Chapter one draws conceptual links from experimental data to the design of the proposed model. Chapter two applies the model to speed-accuracy tradeoffs and habit formation by simulating forced-choice paradigms. Several robust behavioral phenomena are replicated. By isolating reinforcement learning factors that control the speed and depth of habit formation, the model can help explain why all substances that strongly and synergistically affect such factors share a high potential for habit formation, or habit abatement. To illustrate such potential applications of the current model, chapter three investigates effects of varying model parameters in accord with the known neurochemical effects of some major habit-forming substances, such as cocaine and ethanol.

No description available.