Um aspecto marcante do mercado brasileiro de medicamentos benzodiazepínicos é o largo emprego das associações medicamentosas de venda livre conhecidas genericamente como \"antidistônicos\". Sua composição só difere daquela dos ansiolíticos e hipnóticos de venda controlada pelo acréscimo de pequenas doses anticolinárgico e/ou antiespasmódico; as razões da ausência de controle sobre suas vendas são essencialmente não-médicas. Assim, quando se discute o consumo de benzodiazepínicos no Brasil, deve-se fazer distinçã entre os ansiolíticos e hipnóticos de venda livre ou controlada. No período de 1970 a 1985 a tendência do consumo de benzodiazepinas no mercado brasileiro - medida através do número de doses médias diárias consumidas por 1000 habitantes de 15 ou mais anos de idade apresentou três fases. Entre 1970 e 1976 observou-se um crescimento da ordem de 22 por cento ao ano, devido, em sua maior parte, aos antidistônicos que cresceram a uma taxa média anual de 54 por cento . Entre 1976 e 1980 estas taxas de crescimento continuaram sendo positivas, mas seus valores cairam significativamente (4,4 por cento e 4,7 por cento respectivamente). A partir de 1980, inverte-se a tendência; até 1984 observaram-se taxas negativas (-2 por cento e -3,6 por cento , respectivamente). Popularizados a partir do fim da década de 60, os antidistônicos representam, hoje em dia, 47 por cento do consumo de todas as benzodiazepinas. Entre 1970 e 1985 o consumo de ansiolíticos variou de 4,1 a 7,9 DMD/1000hab/dia; o consumo de hipnóticos variou 1,7 a 2,1 DMD/10000hab/dia e o de antidistônicos de 1,5 a 9,7 DMD/1000hab/dia. Nesse período as preferências têm recaído sobre os derivados benzodiazepínicos que hoje em dia representam 97 por cento do consumo de tranquilizantes menores. Os baixos valores do consumo de hipnóticos devem-se, em grande parte, ao fato de, o fenobarbital, largamente empregado como hipnótico no Brasil, estar classificado no grupo de medicamentos anticonvulsivantes; o consumo dos demais barbitúricos é insignificante. Utilizando como parâmetro da expansão dos serviços de assistência a evolução do consumo de alguns grupos de medicamentos cujo emprego se faz sempre sob supervisão médica, verificamos que o crescimento do consumo de benzodiazepinas, entre 1970 e 1980, foi maior do que aquele que poderia ser esperado se eles acompanhassem as tendências gerais do setor saúde. As maiores restrições impostas, a partir de 1984, à prescrição de tranquilizantes menores resultou numa redução do consumo de benzodiazepinas controladas e um concomitante aumento das vendas de antidistônicos. No período de 1980 a 1983 todo o mercado brasileiro de medicamentos esteve retraído coincidindo com o período de recessão econômica. A retomada do crescimento de vendas começou a ocorrer a partir de 1984 na maioria dos grupos estudados. Não é possível concluir se a persistência da queda do consumo de benzodiazepinas foi primariamente devida às mudanças da legislaçio sanitária ou se ela indica uma tendência à redução mais definitiva do largo emprego dessas drogas. / One of the distinctive features in the brazilian market of benzodiazepines is the large use of hidden-psychotropics sold over-the counter (generally known as \"antidistonics\"). The only difference they have as related to the controlled preparations of benzodiazepines are the small doseS of anticholinergic agents; there are nonmedical reasons to explain why \"antidistonics\" have their use not controlled. Therefore, to discuss the consumption of benzodiazepines in Brazil, one should make a distinction between \"free\" and \"controlled\" minor tranquilizers. Between 1970 and 1985 the trends in the consumption of benzodiazepines in Brazil - as measured through the \"medium daily dosis\" per 1000 persons over 15 years - showed three phases. Between 1970 and 1976 a 22 per cent annual increase, greatly due to the \"antidistonics\" which increased at a 54 per cent annul rate. Between 1976 and 1980 those rates were still positives, but significantly smaller (4.4 per cent and 4.7 per cent ) As from 1980, until 1984 there was downward trend (-2.0 per cent and -3.6 per cent ). Very popular since the end of sixties, \"antidistonics\" nowadays represent 47 per cent of the whole use of benzodiazepines. Between 1970 and 1985 the consumption of controlled antianxiety drugs increased from 4.1 to 7.9 DMD/1000/day; consumption figures for hypnotics increased from 1.7 to 2.1 DMD/1000/day and for \"antidistonics\", from 1.5 to 9.7 DMD/100/day. In the last 15 years benzodiazepinas became the most widely used antianxiety and hypnotic agents; presently they represent 97 per cent of the consumption of minor tranquilizers. Low figures for consumption of hypnotics is largely due to the fact that fenobarbital, largely used as an hypnotic in Brazil, is classified among the antiepileptic drugs; the consumption of other barbiturates is not significant. When we take the consumption of drugs used on strict medical supervision as a parameter of the extent of medical care services, we conclude that the growth of the consumption of benzodiazepines between 1970 and 1980 was bigger than one might expect if they followed the general trends of the health sector. Increased restriction on minor tranquilizers\' prescriptions set in 1984, provoked a decrease in the consumption of \"controlled\" benzodiazepines and an increased in \"free\" diazepines sales. Between 1980 and 1983 the whole pharmaceutical market was inhibited by economic recession. Most of the groups included in this study had their sales recovered in 1984. Benzodiazepines sales continued to decline; it is impossible to conclude whether this decrease has due to the new regulations of if they represent a more definite trend.

Um aspecto marcante do mercado brasileiro de medicamentos benzodiazepínicos é o largo emprego das associações medicamentosas de venda livre conhecidas genericamente como \"antidistônicos\". Sua composição só difere daquela dos ansiolíticos e hipnóticos de venda controlada pelo acréscimo de pequenas doses anticolinárgico e/ou antiespasmódico; as razões da ausência de controle sobre suas vendas são essencialmente não-médicas. Assim, quando se discute o consumo de benzodiazepínicos no Brasil, deve-se fazer distinçã entre os ansiolíticos e hipnóticos de venda livre ou controlada. No período de 1970 a 1985 a tendência do consumo de benzodiazepinas no mercado brasileiro - medida através do número de doses médias diárias consumidas por 1000 habitantes de 15 ou mais anos de idade apresentou três fases. Entre 1970 e 1976 observou-se um crescimento da ordem de 22 por cento ao ano, devido, em sua maior parte, aos antidistônicos que cresceram a uma taxa média anual de 54 por cento . Entre 1976 e 1980 estas taxas de crescimento continuaram sendo positivas, mas seus valores cairam significativamente (4,4 por cento e 4,7 por cento respectivamente). A partir de 1980, inverte-se a tendência; até 1984 observaram-se taxas negativas (-2 por cento e -3,6 por cento , respectivamente). Popularizados a partir do fim da década de 60, os antidistônicos representam, hoje em dia, 47 por cento do consumo de todas as benzodiazepinas. Entre 1970 e 1985 o consumo de ansiolíticos variou de 4,1 a 7,9 DMD/1000hab/dia; o consumo de hipnóticos variou 1,7 a 2,1 DMD/10000hab/dia e o de antidistônicos de 1,5 a 9,7 DMD/1000hab/dia. Nesse período as preferências têm recaído sobre os derivados benzodiazepínicos que hoje em dia representam 97 por cento do consumo de tranquilizantes menores. Os baixos valores do consumo de hipnóticos devem-se, em grande parte, ao fato de, o fenobarbital, largamente empregado como hipnótico no Brasil, estar classificado no grupo de medicamentos anticonvulsivantes; o consumo dos demais barbitúricos é insignificante. Utilizando como parâmetro da expansão dos serviços de assistência a evolução do consumo de alguns grupos de medicamentos cujo emprego se faz sempre sob supervisão médica, verificamos que o crescimento do consumo de benzodiazepinas, entre 1970 e 1980, foi maior do que aquele que poderia ser esperado se eles acompanhassem as tendências gerais do setor saúde. As maiores restrições impostas, a partir de 1984, à prescrição de tranquilizantes menores resultou numa redução do consumo de benzodiazepinas controladas e um concomitante aumento das vendas de antidistônicos. No período de 1980 a 1983 todo o mercado brasileiro de medicamentos esteve retraído coincidindo com o período de recessão econômica. A retomada do crescimento de vendas começou a ocorrer a partir de 1984 na maioria dos grupos estudados. Não é possível concluir se a persistência da queda do consumo de benzodiazepinas foi primariamente devida às mudanças da legislaçio sanitária ou se ela indica uma tendência à redução mais definitiva do largo emprego dessas drogas. / One of the distinctive features in the brazilian market of benzodiazepines is the large use of hidden-psychotropics sold over-the counter (generally known as \"antidistonics\"). The only difference they have as related to the controlled preparations of benzodiazepines are the small doseS of anticholinergic agents; there are nonmedical reasons to explain why \"antidistonics\" have their use not controlled. Therefore, to discuss the consumption of benzodiazepines in Brazil, one should make a distinction between \"free\" and \"controlled\" minor tranquilizers. Between 1970 and 1985 the trends in the consumption of benzodiazepines in Brazil - as measured through the \"medium daily dosis\" per 1000 persons over 15 years - showed three phases. Between 1970 and 1976 a 22 per cent annual increase, greatly due to the \"antidistonics\" which increased at a 54 per cent annul rate. Between 1976 and 1980 those rates were still positives, but significantly smaller (4.4 per cent and 4.7 per cent ) As from 1980, until 1984 there was downward trend (-2.0 per cent and -3.6 per cent ). Very popular since the end of sixties, \"antidistonics\" nowadays represent 47 per cent of the whole use of benzodiazepines. Between 1970 and 1985 the consumption of controlled antianxiety drugs increased from 4.1 to 7.9 DMD/1000/day; consumption figures for hypnotics increased from 1.7 to 2.1 DMD/1000/day and for \"antidistonics\", from 1.5 to 9.7 DMD/100/day. In the last 15 years benzodiazepinas became the most widely used antianxiety and hypnotic agents; presently they represent 97 per cent of the consumption of minor tranquilizers. Low figures for consumption of hypnotics is largely due to the fact that fenobarbital, largely used as an hypnotic in Brazil, is classified among the antiepileptic drugs; the consumption of other barbiturates is not significant. When we take the consumption of drugs used on strict medical supervision as a parameter of the extent of medical care services, we conclude that the growth of the consumption of benzodiazepines between 1970 and 1980 was bigger than one might expect if they followed the general trends of the health sector. Increased restriction on minor tranquilizers\' prescriptions set in 1984, provoked a decrease in the consumption of \"controlled\" benzodiazepines and an increased in \"free\" diazepines sales. Between 1980 and 1983 the whole pharmaceutical market was inhibited by economic recession. Most of the groups included in this study had their sales recovered in 1984. Benzodiazepines sales continued to decline; it is impossible to conclude whether this decrease has due to the new regulations of if they represent a more definite trend.

Benzodiazepines (Benzos) and ketamine (K) are compounds that have been encountered in Drug-Facilitated Sexual Assault (DFSA) cases. Due to the intimate nature of these crimes, evidence collection is often postponed due to delays and/or reluctance in reporting these crimes. Further delays in analysis may be encountered in laboratories with large caseloads and/or backlogs. Drug identification in biological samples is important to determine whether victims knowingly or unknowingly took an impairing substance, however, the results could be negative due to chemical degradation over a long storage period. The purpose of this project was to study if degradation could be prevented with a new preservation method at the time of collection. Urine samples were prepared by the addition of K and metabolites and selected benzos and metabolites that were subjected to different sample pre-treatment techniques, and were analyzed after storage at room temperature (25°C), refrigerator (4°C) and freezer (-20°). The samples were either pre-treated with preservative (0.5% toluene) or filtration sterilization (sterile filter kit) within two hours after sample collection, and a control group with no pre-treatment was incorporated into the study for comparison. The changes in concentrations over 50 days (Benzos group) and 210 days (K group) were evaluated between different pre-treated methods and different temperature conditions. Sample that were treated with 0.5% toluene showed the most degradation: 44% of oxazepam and 96% of diazepam degraded over 10 days, and 80% of dehydronorketamine degraded after storage of 150 days regardless the temperature conditions. Clonazepam and flunitrazepam concentrations were reduced by 80% of the original concentration when stored at room temperature for 10 days. The major benzodiazepines evaluated in this study were stable when stored in the freezer. In K group, ketamine and norketamine that were stored at room temperature and refrigerated over 210 days were stable, however, degradation was observed after 150 days when the samples were stored in the freezer. There was no statistically different change observed among the samples pre-treated with or without filtration sterilization. Each sample pH was measured and it was determined that those stored at room temperature had an average pH of 8.5, while samples stored in the refrigerator and freezer had an average pH of 6.7 and 6.5, respectively. This finding revealed that pH could be the major factor affecting compound degradation rather than the bacterial contamination with high pH contributing to degradation, and low pH potentially preventing sample lost.

The prevalence of drugged driving has increased in the United States, and some prescription medications (e.g., zolpidem) cause impairment after the predicted duration of therapeutic action has elapsed. The aim of this study is to determine if bedtime administration of alprazolam similarly impacts driving performance the following day. Volunteers were 14 healthy adults (6 males) who completed a double-blind, double-dummy within-subjects design study examining the effects of alprazolam (0.5, 1, & 2mg), zolpidem (10mg), and placebo administered at bedtime on driving performance the following day. The positive control condition was alprazolam (1mg) administered on the test morning. Driving simulator measures, cognitive and psychomotor tasks, and questionnaires querying drug effects were collected the afternoon before drug administration and for 5.5 hours the next day and analyzed using symmetry and mixed-model approaches. The positive control was robustly impairing. Driving impairment equivalent to that seen with alcohol at the legal limit was observed up to 12.5hr after bedtime alprazolam 2mg and for 8.5hr after bedtime zolpidem 10mg. Volunteers were not fully aware of their own level of impairment. These results suggest that alprazolam used before bed may pose an as yet unrecognized public safety risk in the form of next-day drugged-driving.

Studies on repeated exposure to opioids have been carried out for decades yet the mechanisms for certain phenomena such as tolerance are still not fully understood. Furthermore, different medications, such as frequently prescribed benzodiazepines, or different disease states, such as HIV, have their own effects and interactions with chronic opioid exposure that are not fully understood. The overall objective of this dissertation was to investigate the complexities of chronic opioid exposure and how different disease states and medications may modulate the effects of chronic opioids. Our findings demonstrate that the administration of diazepam, at doses that are not antinociceptive or have any motor effects, reverse both antinociceptive and locomotor tolerance to orally active opioids. These doses of diazepam did not potentiate the acute effects of these prescription opioids. We also found that HIV-1 Tat expression significantly attenuated the antinociceptive potency of acute morphine in non-tolerant mice while not significantly altering the antinociceptive tolerance to morphine. Consistent with this, Tat attenuated withdrawal symptoms among morphine-tolerant mice. Pretreatment with maraviroc, a CCR5 antagonist blocked the effects of Tat, reinstating morphine potency in non-tolerant mice and restoring withdrawal symptomology in morphine-tolerant mice. Protein array analyses revealed only minor changes to cytokine profiles whether morphine was administered acutely or repeatedly; however, 24 h post repeated morphine administration, the expression of several cytokines was greatly increased. Tat further elevated levels of several cytokines and maraviroc pretreatment attenuated these effects. With the understanding that gap junctions may be involved in both HIV-Tat effects on opioid antinociception as well as tolerance, we investigated the role of gap junctions in opioid antinociceptive tolerance. We observed that carbenoxolone, a gap junction inhibitor, administered systemically attenuated the development of opioid antinociceptive tolerance. Furthermore, we observed a small percentage of carbenoxolone in brain tissue compared to the amount found in blood, suggesting a peripheral site of action. Finally, we show preliminary evidence that in vivo administration of carbenoxolone is able to attenuate tolerance to morphine in DRG neurons.

Doctor of Philosophy (PhD) / Abstract Olfactory tasks are used very often with laboratory animals in studies of the neurobiology of learning and memory. Rats and mice are extremely sensitive in their detection and discrimination of odours, learn olfactory tasks rapidly, and can display higher order cognitive functions in olfactory tasks. This cognitive capacity may rival the ability of primates to learn analogous tasks with visual cues and most likely reflects strong anatomical connections between the olfactory bulbs and higher brain regions such as the piriform cortex, orbitofrontal cortex and hippocampus. The current thesis explored olfactory discrimination learning and performance in rats and had two principal aims. The first part of the thesis was oriented around odour masking phenomena in rats: the ability of one odour in a mixture to suppress detection of a second odour in that mixture. A specialized behavioural paradigm was developed to allow the study of odour masking in the rat. The second part of the thesis was pharmacological and determined whether the acquisition, reversal and performance of olfactory discriminations, and analogous auditory discriminations, are affected by two commonly used classes of drugs (benzodiazepines and cannabinoids). Together, these studies attempt to gain a better understanding of the nature of olfactory discrimination learning in rats, by using both psychophysical and pharmacological approaches, and to develop behavioural paradigms which may be used in future psychophysical and pharmacological studies. Following an introduction and review of olfactory and auditory studies in rat (Chapter 1), odour masking phenomena were studied in Chapter 2. The aliphatic aldehydes butanal (C4) and heptanal (C7) were used in the study. Aldehydes were of interest as this class of odorants abound in nature and may be important for rodents’ species-specific communication. Thirsty rats were initially trained to discriminate C4 and C7 in the olfactometer, using a go/no-go olfactory discrimination task. This involved rats learning to nose poke in an odour port and to lick a tube for a water reward on presentation of the rewarded component S+, while withholding licking at the tube when the other, unrewarded, aldehyde (S-) was presented. Odour mixtures (C4C7 or C7C4) were then introduced into the task as an additional non-rewarded condition (mixture S-). The concentration of the non-rewarded aldehyde in the mixture was then systematically decreased, while the concentration of the rewarded aldehyde was kept constant. When the non-rewarded aldehyde reached a critical low level in the mixture, rats started to make responses to the non-rewarded mixture (false alarms) showing that the S+ odour was suppressing the S- odour in the mixture, so the mixture was being responded to in the same manner as the S+ odour presented alone. Results also showed asymmetric suppression in the mixture condition, such that butanal suppressed detection of heptanal at a much lower concentration than vice versa. A second experiment demonstrated that when both butanal and heptanal were present in a binary mixture at the same concentration (10-6 volume %), rats responded to the mixture as if only butanal was present. Our findings are in agreement with human studies showing component interactions in binary mixtures of aldehydes. The molecular feature of carbon chain length appears to be a critical factor in determining the outcome of interactions between aldehydes at peripheral olfactory receptors, with smaller chain aldehydes better able to compete for receptor occupancy. Subsequent chapters explored the effects of two classes of commonly used drugs - benzodiazepines and cannabinoids - on olfactory and auditory discrimination in rats. Animal models such as the radial arm maze, Morris water maze and object recognition test are routinely used to test adverse and facilitatory effects of drugs on cognition in rodents. However, comparatively few pharmacological studies employ olfactory or auditory go/no-go paradigms. Thus, an important part of the present thesis was to assess the viability of using such paradigms in detecting pharmacological effects, and to identify whether such effects may be modality specific (i.e. whether a drug has a greater effect on olfactory or auditory tasks). In Chapter 3, the effects of benzodiazepines on olfactory discrimination tasks were explored. Rats were injected with the benzodiazepine drugs midazolam or diazepam and tested on discrimination tasks involving either the auditory and olfactory modality. Results showed that midazolam (0.5–2 mg/kg sc) did not affect the performance of a well-learned two-odour olfactory discrimination task, and moderately facilitated the performance of a go/no-go auditory discrimination task. On the contrary, midazolam (1 mg/kg) impaired the acquisition of a novel go/no-go olfactory discrimination task, as well as the reversal of a previously well-learned olfactory discrimination. However, midazolam did not affect the acquisition or reversal of an equivalent auditory discrimination task. The olfactory bulb and the piriform cortex are intimately involved in associative learning and behavioural aspects of olfactory performance, and have high concentrations of benzodiazepine receptors. These may therefore be possible neural substrates for the disruptive effects of benzodiazepines on olfactory learning. Findings from Chapter 4 indicated that the prototypical cannabinoid agonist delta-9-tetrahydrocanabinol (Δ9 THC) (0.3, 1 and 3 mg/kg) impairs auditory discrimination performance, but had no effect on equivalent olfactory discriminations. This is in marked contrast to the effects of benzodiazepines. Residual effects were observed, such that auditory discrimination performance was still impaired on the day following Δ9 THC administration. Delta-9-tetrahydrocanabinol effects were prevented by co-administration of the cannabinoid antagonist rimonabant (3 mg/kg). In addition, the anandamide hydrolysis inhibitor URB597 (0.1 and 0.3 mg/kg), which boosts levels of endogenous cannabinoids in the synapse, also impaired auditory discrimination performance, and this effect was also reversed by rimonabant. This study also assessed the effects of Δ9 THC (0.3, 1 and 3 mg/kg) and URB597 (0.1 and 0.3 mg/kg) on acquisition and reversal of novel olfactory discriminations. Results showed that Δ9 THC impairs olfactory reversal learning without affecting acquisition of the original discrimination. It is argued that this reversal deficit may be part of a wider capacity for cannabinoids to impair cognitive flexibility. The final Chapter (General Discussion) discusses the relevance and implications of the combined findings. The results add significantly to our current understanding of perceptual, learning and memory processes involving the olfactory modality in rats. With respect to olfactory perception, this thesis introduced a new behavioural paradigm, which can be used to assess component suppression in mixtures, and may be of use in future psychophysical studies involving rodents or other species. With respect to learning and memory, the thesis provides novel information on the disruptive effects of benzodiazepines and cannabinoids on olfactory and auditory tasks. It is concluded that go/no-go olfactory and auditory discrimination tasks in rats can provide a useful platform for assessing the disruptive and modality-specific effects of drugs on learning, performance and cognitive flexibility. Future studies might expand the range of drugs tested on these paradigms and might consider chronic as well as acute drug effects.

Pilot Study: a) 21 Generalised Anxiety Disorder (GAD) patients were treated double-blind with either diazepam or placebo for 6 weeks. This active treatment period was preceded by one-week single-blind placebo 'wash-in', and followed by two-week single-blind 'washout'. Results showed that diazepam used in moderate doses for 6 weeks produced anxiety recurrence and withdrawal symptoms. b) 10 GAD patients were randomly allocated to Cognitive-Behaviour Therapy (CBT) and compared with the above diazepam and placebo groups. All treatments were balanced for degree of Psychologist/patient contact. At cessation of active treatment CBT superiority was indicated. Post-Study psychotropic prescription and psychological treatment were assessed at 12 months follow-up. The CBT group had the lowest incidence of subsequent treatment interventions. Main Study : 101 GAD patients were randomly allocated to diazepam, placebo, CBT, CBT + diazepam, and CBT + placebo, and treated over 10 weeks. Outcome measures at end of treatment and at 6 months follow-up revealed the superiority of all CBT treatments; especially CBT alone, and CBT + diazepam. Diazepam was more effective than placebo. CBT + diazepam, and diazepam groups showed no anxiety recurrence during graded withdrawal. Secondary Study : 205 long-term benzodiazepine users were matched for age and sex with controls. Inspection of medical case notes showed that benzodiazepine users had higher rates of previous physical illness, GP attendance, and non-psychotropic drug prescription. Differences emerged between anxiolytic, hypnotic, and anxiolytic + hypnotic benzodiazepine users in age, history of physical illness, and previously prescribed medication. Tertiary Study : 44 long-term benzodiazepine users were interviewed. The incidence of psychological ill-health and social problems was lower than expected. Patients were dependent on medication, and reported concern if their medication were to be stopped. Nevertheless 40% considered stopping benzodiazepines. Results from the above studies are discussed in relation to clinical management of GAD, and current concerns about benzodiazepine dependence and withdrawal.

Misuse of prescription anxiolytic and sedative medication is a widespread phenomenon in Canada and a topic of increasing concern among health care providers. While anxiolytics and sedatives have important therapeutic uses in the treatment of anxiety and insomnia, these substances have psychoactive properties that render them vulnerable to misuse. Understanding the correlates and contexts of misuse is essential for developing targeted treatment and prevention strategies. This dissertation is comprised of a series of four studies conducted with adults in the Halifax Regional Municipality, recruited from the community and from a local substance use disorder treatment program. Study 1 investigated misuse of anxiolytics and sedatives among currently prescribed users of these medications in the general community. Misuse and diversion were associated with a more extensive history of other substance use and with personality dimensions, including hopelessness and impulsivity. Study 2 investigated motives for misuse among non-prescribed anxiolytic and sedative users recruited from the community. This study also included non-prescribed stimulant medication users to facilitate comparisons across differing classes of psychiatric medications. Non-therapeutic motives were associated with substance use history and, for anxiolytics and sedatives, with the personality dimension sensation-seeking. Study 3 involved an analysis of prescription regimens and misuse among all participants of Studies 1 and 2 who had ever held a prescription for an anxiolytic or sedative. Misuse of benzodiazepine anxiolytics and sedatives was more frequent than that of non-benzodiazepines, but was unrelated to prescription regimen. Study 4 examined the misuse of quetiapine, an atypical antipsychotic medication with anxiolytic and sedative effects, among clients of a methadone maintenance program. Misuse of quetiapine was widespread, but was typically associated with therapeutic motives. Quetiapine misuse was linked with a history of misusing other anxiolytic and sedative drugs. Collectively, these studies provide evidence that anxiolytic and sedative misuse is a heterogeneous phenomenon encompassing varying patterns of use and motives for misuse. Furthermore, these investigations suggest that anxiolytic and sedative misuse is linked to individual-level and medication-related variables. By providing a more comprehensive characterization of this important public health issue, these findings have practical implications in both clinical and research contexts.

Mental health disorders such as depression and insomnia are prevalent in the community; the use of antidepressants and benzodiazepines is therefore common. However if these medications are not prescribed and used appropriately issues relating to safety and/or efficacy can occur. There is also some concern about the misuse of benzodiazepines by the injecting drug user (IDU) community. The overall aim of this PhD was to perform international utilization comparison studies and analyze national prescribing data to understand and describe factors influencing the use of prescription medicines, in particular antidepressants and benzodiazepines, and to develop some ideas and initiatives to improve future use. Comparisons in the prescribing of benzodiazepines and antidepressants between Nova Scotia, Canada and Australia were undertaken. Dispensing data for all publicly subsidized benzodiazepines and related compounds and antidepressant classes of medications and utilization was compared from 2000-2003, using the World Health Organisation ATC/ DDD system. Australian dispensing data were also used to examine changes in the utilization of antidepressants and benzodiazepines between different age groups within Australia from 2003-2006. Dispensing data and numerical data derived from reports from Australia’s Illicit Drug Reporting System (IDRS) were used to estimate benzodiazepine use by those who inject heroin, in areas with high proportion of persons who inject heroin in Sydney, Melbourne and Brisbane. To determine a strategy aimed at improving the use of benzodiazepines, the literature was searched and the latest interventions, solely focusing on increasing appropriate prescribing and reducing long term use of benzodiazepines worldwide were retrieved and analyzed. The comparison studies showed the use of benzodiazepines increased at a steady but comparable rate in both Australia and Nova Scotia, although overall use was much higher in Nova Scotia than Australia (123 and 48 DDD/1000 beneficiaries/day, respectively). However, the use of antidepressants in Nova Scotia increased at a higher rate than Australia. The variations between the two jurisdictions may be due to the more limited range of benzodiazepines available in Australia, or perhaps different initiatives to control. The differences may also be due to increased exposure to marketing, promotion, education or different prescribing practices in Nova Scotia compared to Australia. From 2003 to 2006, the use of antidepressants increased with age, with those over 65 years having the greatest use (86.9 and 97.7DDD/1000 population/day, respectively). Differences were also seen in the antidepressant most utilized, with the elderly using more tricyclic antidepressants than those who were younger. The utilization of benzodiazepines decreased from 2003-2006 in the same population (66.6 and 61 DDD/1000 concession beneficiaries/day, respectively). However, those over 85 had the highest use of benzodiazepines and used more long acting benzodiazepines than those aged 35-44. This demonstrates that the elderly still account for most use per capita of benzodiazepines. Some of this use may be inappropriate (e.g. use of long-acting benzodiazepines) and hence may provide a useful target for future educational intervention. The elderly also account for the largest per capita use of antidepressants. In areas with a high proportion of heroin IDU, the utilization of benzodiazepines by the estimated IDU population decreased (4064048DDDs in 2000 to 2613100 DDDs in 2006) however the overall use of benzodiazepines in Australia continued to increase from 2000-2006. This demonstrates that the increase in benzodiazepine utilization during this period was not primarily driven by use among IDU. The review identified three main target audiences at which interventions for improving the use of benzodiazepines were aimed at. These were consumers, General Practitioners or long term care facilities. Education, audit and feedback and alerts were the 3 major intervention approaches taken in the studies. The review concluded that studies which used a multi-factorial approach had the largest and most sustained reductions in benzodiazepines use. It appears that support groups for patients, non-voluntary recruitment of GPs, and oral delivery of alerts or feedback may all improve the outcomes of interventions. Using the review findings, an intervention targeting consumers and health professionals was conducted in a rural and urban area of Australia, using informative emails, bookmarks and website over a 6 month period. The intervention showed a significant decrease in the long term use of benzodiazepines within nursing homes located in the intervention geographical areas compared to the control areas. In conclusion the utilization studies revealed the current trends in utilization of antidepressants and benzodiazepines for Australia and led to the development of an intervention, based on factors that were found to influence prescribing of benzodiazepines. The intervention aimed at various target audiences did produce a small improvement in the prescribing of benzodiazepines.

Doctor of Philosophy (PhD) / Abstract Olfactory tasks are used very often with laboratory animals in studies of the neurobiology of learning and memory. Rats and mice are extremely sensitive in their detection and discrimination of odours, learn olfactory tasks rapidly, and can display higher order cognitive functions in olfactory tasks. This cognitive capacity may rival the ability of primates to learn analogous tasks with visual cues and most likely reflects strong anatomical connections between the olfactory bulbs and higher brain regions such as the piriform cortex, orbitofrontal cortex and hippocampus. The current thesis explored olfactory discrimination learning and performance in rats and had two principal aims. The first part of the thesis was oriented around odour masking phenomena in rats: the ability of one odour in a mixture to suppress detection of a second odour in that mixture. A specialized behavioural paradigm was developed to allow the study of odour masking in the rat. The second part of the thesis was pharmacological and determined whether the acquisition, reversal and performance of olfactory discriminations, and analogous auditory discriminations, are affected by two commonly used classes of drugs (benzodiazepines and cannabinoids). Together, these studies attempt to gain a better understanding of the nature of olfactory discrimination learning in rats, by using both psychophysical and pharmacological approaches, and to develop behavioural paradigms which may be used in future psychophysical and pharmacological studies. Following an introduction and review of olfactory and auditory studies in rat (Chapter 1), odour masking phenomena were studied in Chapter 2. The aliphatic aldehydes butanal (C4) and heptanal (C7) were used in the study. Aldehydes were of interest as this class of odorants abound in nature and may be important for rodents’ species-specific communication. Thirsty rats were initially trained to discriminate C4 and C7 in the olfactometer, using a go/no-go olfactory discrimination task. This involved rats learning to nose poke in an odour port and to lick a tube for a water reward on presentation of the rewarded component S+, while withholding licking at the tube when the other, unrewarded, aldehyde (S-) was presented. Odour mixtures (C4C7 or C7C4) were then introduced into the task as an additional non-rewarded condition (mixture S-). The concentration of the non-rewarded aldehyde in the mixture was then systematically decreased, while the concentration of the rewarded aldehyde was kept constant. When the non-rewarded aldehyde reached a critical low level in the mixture, rats started to make responses to the non-rewarded mixture (false alarms) showing that the S+ odour was suppressing the S- odour in the mixture, so the mixture was being responded to in the same manner as the S+ odour presented alone. Results also showed asymmetric suppression in the mixture condition, such that butanal suppressed detection of heptanal at a much lower concentration than vice versa. A second experiment demonstrated that when both butanal and heptanal were present in a binary mixture at the same concentration (10-6 volume %), rats responded to the mixture as if only butanal was present. Our findings are in agreement with human studies showing component interactions in binary mixtures of aldehydes. The molecular feature of carbon chain length appears to be a critical factor in determining the outcome of interactions between aldehydes at peripheral olfactory receptors, with smaller chain aldehydes better able to compete for receptor occupancy. Subsequent chapters explored the effects of two classes of commonly used drugs - benzodiazepines and cannabinoids - on olfactory and auditory discrimination in rats. Animal models such as the radial arm maze, Morris water maze and object recognition test are routinely used to test adverse and facilitatory effects of drugs on cognition in rodents. However, comparatively few pharmacological studies employ olfactory or auditory go/no-go paradigms. Thus, an important part of the present thesis was to assess the viability of using such paradigms in detecting pharmacological effects, and to identify whether such effects may be modality specific (i.e. whether a drug has a greater effect on olfactory or auditory tasks). In Chapter 3, the effects of benzodiazepines on olfactory discrimination tasks were explored. Rats were injected with the benzodiazepine drugs midazolam or diazepam and tested on discrimination tasks involving either the auditory and olfactory modality. Results showed that midazolam (0.5–2 mg/kg sc) did not affect the performance of a well-learned two-odour olfactory discrimination task, and moderately facilitated the performance of a go/no-go auditory discrimination task. On the contrary, midazolam (1 mg/kg) impaired the acquisition of a novel go/no-go olfactory discrimination task, as well as the reversal of a previously well-learned olfactory discrimination. However, midazolam did not affect the acquisition or reversal of an equivalent auditory discrimination task. The olfactory bulb and the piriform cortex are intimately involved in associative learning and behavioural aspects of olfactory performance, and have high concentrations of benzodiazepine receptors. These may therefore be possible neural substrates for the disruptive effects of benzodiazepines on olfactory learning. Findings from Chapter 4 indicated that the prototypical cannabinoid agonist delta-9-tetrahydrocanabinol (Δ9 THC) (0.3, 1 and 3 mg/kg) impairs auditory discrimination performance, but had no effect on equivalent olfactory discriminations. This is in marked contrast to the effects of benzodiazepines. Residual effects were observed, such that auditory discrimination performance was still impaired on the day following Δ9 THC administration. Delta-9-tetrahydrocanabinol effects were prevented by co-administration of the cannabinoid antagonist rimonabant (3 mg/kg). In addition, the anandamide hydrolysis inhibitor URB597 (0.1 and 0.3 mg/kg), which boosts levels of endogenous cannabinoids in the synapse, also impaired auditory discrimination performance, and this effect was also reversed by rimonabant. This study also assessed the effects of Δ9 THC (0.3, 1 and 3 mg/kg) and URB597 (0.1 and 0.3 mg/kg) on acquisition and reversal of novel olfactory discriminations. Results showed that Δ9 THC impairs olfactory reversal learning without affecting acquisition of the original discrimination. It is argued that this reversal deficit may be part of a wider capacity for cannabinoids to impair cognitive flexibility. The final Chapter (General Discussion) discusses the relevance and implications of the combined findings. The results add significantly to our current understanding of perceptual, learning and memory processes involving the olfactory modality in rats. With respect to olfactory perception, this thesis introduced a new behavioural paradigm, which can be used to assess component suppression in mixtures, and may be of use in future psychophysical studies involving rodents or other species. With respect to learning and memory, the thesis provides novel information on the disruptive effects of benzodiazepines and cannabinoids on olfactory and auditory tasks. It is concluded that go/no-go olfactory and auditory discrimination tasks in rats can provide a useful platform for assessing the disruptive and modality-specific effects of drugs on learning, performance and cognitive flexibility. Future studies might expand the range of drugs tested on these paradigms and might consider chronic as well as acute drug effects.