Indiana University-Purdue University Indianapolis (IUPUI) / Although marijuana and alcohol are two of the most commonly used drugs in the United States, relatively little is understood about how these drugs interact to effect drug use, cognitive behaviors, and neurophysiological changes. Specific drug use patterns such as simultaneous use may produce differential effects for consumption and other behaviors in addition to unique neurobiological changes compared to singular drug use. In order to better understand the effects of simultaneous alcohol and marijuana (SAM) use, we used the selectively bred crossed High Alcohol Preferring mice to examine consummatory, cognitive, and neurobiological changes following chronic alcohol and THC self-administration. We hypothesized that SAM mice would consume more drug than animals exposed to either substance alone. We used an operant behavioral flexibility paradigm to assess cognitive impairments believing that drug-exposed animals would show deficits relative to Control animals, with SAM mice being the most impaired of all drug conditions. Finally, we assessed CB1 receptor changes in the dorsal striatum, as this region is critical for behavioral flexibility (Bissonette & Powell, 2012; Ragozzino, 2007), CB1 receptors are the primary target of THC and these receptors are involved in numerous alcohol related behaviors (Maldonado et al., 2006; Pava & Woodward, 2012). Contrary to our hypothesis, SAM animals did not consume higher levels of drug compared to mice exposed to only THC or alcohol. Interestingly, female THC consumption was robust when THC was consumed alone but was reduced when simultaneous access to alcohol was available. Surprisingly, although we speculated that drug-exposed mice would be impaired compared to Control animals, and that SAM animals would likely be more compromised than THC and alcohol for Reversal Learning and Attentional Set-Shifting respectively, behavioral flexibility deficits were absent in our paradigm. Finally, alterations to dorsal striatal CB1 receptor expression were observed following a Short Abstinence period. Despite an absence of cognitive behavioral effects, this research contributes to furthering our understanding of co-drug use for consummatory and neurobiological changes, both of which are critically necessary given the evolving landscape surrounding simultaneous alcohol and recreational marijuana use.

Alzheimer¿s disease is associated with aging and is characterised by a progressive cognitive decline. Its onset in women coincides with the abrupt depletion of ovarian steroids prompting the investigation of utilising oestrogen replacement therapy as restoration or a preventative measure. Gonadal steroids have also recently been implicated in other disease states, particularly schizophrenia. In addition to the cognitive decline, sufferers of Alzheimer¿s disease and schizophrenia display anxiety related behaviour which gonadal steroids have also been shown to ameliorate. In this thesis several paradigms were used to investigate the effects of oestradiol benzoate (EB) on cognition and anxiety, utilising the NMDA receptor antagonist PCP, the muscarinic receptor antagonist scopolamine and the dopamine releasing agent amphetamine to induce a cognitive deficit in rats by different pharmacological mechanisms. The thesis also investigated the effects of EB on a delay dependent cognitive deficit model of forgetfulness in natural aging. Results showed that subchronic PCP dosing failed to induce a significant deficit in the novel object recognition task. Locomotor activity tests demonstrated that the PCP treated rats were sensitised to the treatment suggesting that the PCP dosing regimen was successful. There was no significant effect of oestrogen in the reversal learning model or in the plus maze task designed to explore EB¿s effects on anxiety. However, in the latter task there was a trend towards an anxiogenic effect of EB. Results from the delay dependent model of forgetfulness in natural aging demonstrated that EB could enhance recognition memory, but not spatial memory. The results are discussed in the context of the role of gonadal steroids especially oestrogen in combating the cognitive decline seen in schizophrenia, neurodegenerative disease and natural aging.

no / Rationale Phencyclidine (PCP), a glutamate/N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to induce a range of symptoms similar to those of patients with schizophrenia, while d-amphetamine induces predominantly positive symptoms. Previous studies in our laboratory have shown that PCP can selectively impair the performance of an operant reversal-learning task in the rat. Furthermore, we found that the novel antipsychotic ziprasidone, but not the classical antipsychotic haloperidol, could prevent the PCP-induced deficit. Objectives The aim of the present study was to validate the model further using the atypical antipsychotic clozapine and then to investigate the effects of lamotrigine, a broad-spectrum anticonvulsant that is known to reduce glutamate release in vitro and is able to prevent ketamine-induced psychotic symptoms in healthy human volunteers. A further aim was to compare effects of PCP and d-amphetamine in the test and investigate the effects of the typical antipsychotic haloperidol against the latter. Methods Female hooded-Lister rats were food deprived and trained to respond for food in a reversal-learning paradigm. Results PCP at 1.5 mg/kg and 2.0 mg/kg and d-amphetamine at 0.5 mg/kg significantly and selectively impaired performance in the reversal phase of the task. The cognitive deficit induced by 1.5 mg/kg PCP was attenuated by prior administration of lamotrigine (20 mg/kg and 30 mg/kg) or clozapine (5 mg/kg), but not haloperidol (0.05 mg/kg). In direct contrast, haloperidol (0.05 mg/kg), but not lamotrigine (25 mg/kg) or clozapine (5 mg/kg), prevented a similar cognitive impairment produced by d-amphetamine (0.5 mg/kg). Conclusions Our findings provide further data to support the use of PCP-induced disruption of reversal learning in rodents to investigate novel antipsychotic drugs. The results also provide evidence for different mechanisms of PCP and d-amphetamine-induced disruption of performance in the test, and their different sensitivities to typical and atypical antipsychotic drugs.

No

Yes / Rationale: Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Aim: To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987. Methods: Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle i.p. twice daily for seven days, followed by 7-days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20 mg/kg; s.c.) or vehicle and were tested in the reversal learning task. In cohort 2, PCP-treated rats received PNU-282987 (10 mg/kg; s.c.) or saline for 15 days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance. Results: Sub-chronic PCP produced significant deficits in both cognitive tasks (P<0.01-0.001). PNU-282987 attenuated the PCP-induced deficits in reversal learning at 10 mg/kg (P<0.01) and 20 mg/kg (P<0.001), and in novel object recognition at 10 mg/kg on day 1 (P<0.01) and on day 15 (P<0.001). Conclusions: These data show that PNU-282987 has efficacy to reverse PCP-induced deficits in two paradigms of relevance to schizophrenia. Results further suggest that 15 day daily dosing of PNU-282987 (10 mg/kg s.c.) does not cause tolerance in rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia. / SL McLean was supported by a joint University of Bradford–GSK postgraduate studentship.

Yes / Rationale: 5-HT receptor mechanisms have been suggested to mediate improvements in cognition in schizophrenia. Aim: To investigate the involvement of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in female rats, a task of relevance to schizophrenia. Methods: Adult female hooded-Lister rats were trained to perform an operant reversal learning task and then received sub-chronic PCP (2 mg/kg) or vehicle i.p. twice daily for seven days, followed by 7-days washout. Rats then received an acute dose of the 5-HT7 receptor antagonist SB-269970A (1.0, 3.0, 10.0 mg/kg; i.p.) or vehicle. In experiment 2, PCP-treated rats received the selective 5-HT2C receptor antagonist, SB-243213A acutely (1.0, 3.0, 10.0 mg/kg; i.p.) or vehicle. In experiment 3, PCP-treated rats received the 5-HT1A receptor partial agonist, buspirone (0.15625, 0.3125, 0.625 mg/kg, i.p.) in combination with the selective 5-HT1A receptor antagonist WAY-100635 (0.3, 1.0 mg/kg). Results: In all experiments sub-chronic PCP significantly impaired reversal phase performance (P<0.01-0.001), with no effect in the initial phase. SB-269970A at 3.0 and 10.0 mg/kg significantly improved the PCP-induced deficit (P<0.05). SB-243213A also significantly attenuated the deficit at 10 mg/kg (P<0.05). In experiment 3, buspirone attenuated the deficit with significant effects at 0.3125 mg/kg and 0.625 mg/kg (P<0.05). WAY-100635 at 0.3 and 1.0 mg/kg produced a partial attenuation of buspirone’s effect as buspirone (0.3125 mg/kg) in the presence of WAY-100635 did not significantly reverse the PCP-induced deficit. Conclusions: These studies implicate the role of 5-HT7, 5-HT2C and 5-HT1A receptors in the improvement of cognitive dysfunction of relevance to schizophrenia.

Yes / The ability to either erase or update the memories of a previously learned spatial task is an essential process that is required to modify behaviour in a changing environment. Current evidence suggests that the neural representation of such cognitive flexibility involves the balancing of synaptic potentiation (acquisition of memories) with synaptic depression (modulation and updating previously acquired memories). Here we demonstrate that the p38 MAPK/MAPK-activated protein kinase 2 (MK2) cascade is required to maintain the precise tuning of long-term potentiation and long-term depression at CA1 synapses of the hippocampus which is correlated with efficient reversal learning. Using the MK2 knockout (KO) mouse, we show that mGluR-LTD, but not NMDAR-LTD, is markedly impaired in mice aged between 4 and 5 weeks (juvenile) to 7 months (mature adult). Although the amplitude of LTP was the same as in wildtype mice, priming of LTP by the activation of group I metabotropic receptors was impaired in MK2 KO mice. Consistent with unaltered LTP amplitude and compromised mGluR-LTD, MK2 KO mice had intact spatial learning when performing the Barnes maze task, but showed specific deficits in selecting the most efficient combination of search strategies to perform the task reversal. Findings from this study suggest that the mGluR-p38-MK2 cascade is important for cognitive flexibility by regulating LTD amplitude and the priming of LTP. / Professor Richard Greene at the University of Bradford - startup fund to setup electrophysiological facility and Wellcome Trust 200646/Z/16/Z to S.A.L.C.

No description available.

<div><div><div><p>Although marijuana and alcohol are two of the most commonly used drugs in the United States, relatively little is understood about how these drugs interact to effect drug use, cognitive behaviors, and neurophysiological changes. Specific drug use patterns such as simultaneous use may produce differential effects for consumption and other behaviors in addition to unique neurobiological changes compared to singular drug use. In order to better understand the effects of simultaneous alcohol and marijuana (SAM) use, we used the selectively bred crossed High Alcohol Preferring mice to examine consummatory, cognitive, and neurobiological changes following chronic alcohol and THC self-administration. We hypothesized that SAM mice would consume more drug than animals exposed to either substance alone. We used an operant behavioral flexibility paradigm to assess cognitive impairments believing that drug-exposed animals would show deficits relative to Control animals, with SAM mice being the most impaired of all drug conditions. Finally, we assessed CB1 receptor changes in the dorsal striatum, as this region is critical for behavioral flexibility (Bissonette & Powell, 2012; Ragozzino, 2007), CB1 receptors are the primary target of THC and these receptors are involved in numerous alcohol related behaviors (Maldonado et al., 2006; Pava & Woodward, 2012). Contrary to our hypothesis, SAM animals did not consume higher levels of drug compared to mice exposed to only THC or alcohol. Interestingly, female THC consumption was robust when THC was consumed alone but was reduced when simultaneous access to alcohol was available. Surprisingly, although we speculated that drug- exposed mice would be impaired compared to Control animals, and that SAM animals would likely be more compromised than THC and alcohol for Reversal Learning and Attentional Set-Shifting respectively, behavioral flexibility deficits were absent in our paradigm. Finally, alterations to dorsal striatal CB1 receptor expression were observed following a Short Abstinence period. Despite an absence of cognitive behavioral effects, this research contributes to furthering our understanding of co-drug use for consummatory and neurobiological changes, both of which are critically necessary given the evolving landscape surrounding simultaneous alcohol and recreational marijuana use.</p></div></div></div>

Yes / Neuronal activity regulates the transcription and translation of the immediate-early gene Arc/Arg3.1, a key mediator of synaptic plasticity. Proteasomedependent degradation of Arc tightly limits its temporal expression, yet the significance of this regulation remains unknown. We disrupted the temporal control of Arc degradation by creating an Arc knockin mouse (ArcKR) where the predominant Arc ubiquitination sites were mutated. ArcKR mice had intact spatial learning but showed specific deficits in selecting an optimal strategy during reversal learning. This cognitive inflexibility was coupled to changes in Arc mRNA and protein expression resulting in a reduced threshold to induce mGluR-LTD and enhanced mGluR-LTD amplitude. These findings show that the abnormal persistence of Arc protein limits the dynamic range of Arc signaling pathways specifically during reversal learning. Our work illuminates how the precise temporal control of activity-dependent molecules, such as Arc, regulates synaptic plasticity and is crucial for cognition. / Open access funded by Biotechnology and Biological Sciences Research Council