David S. Segal - US grants

DESCRIPTION: (Applicant's Abstract) The addictive and psychogenic effects of stimulants in humans are most commonly associated with a pattern of repeated "binge" exposures preceded by progressively escalating loses (ED) of the drug. To simulate these conditions, we exposed rats to multiple stimulant binges, preceded by relatively long-term, intermittent or ED. Rats treated with amphetamine (AMPH), methamphetamine, or cocaine, gradually developed a unique behavioral profile which consisted of a decrease in the continuous stereotypy component, a pronounced increase in the magnitude of locomotion, and a qualitative change in the ambulation. Furthermore, with multiple high dose AMPH binges, the caudate-putamen extracellular dopamine (DA) response, but not the nucleus accumbens DA response, developed a profound tolerance/tachyphylaxis to the drug-induced increase in extracellular transmitter. Similar results were obtained with serotonin, whereas the hippocampus and frontal cortex norepinephrine responses were increased. Our proposed research is designed to further examine the neurochemical and behavioral processes associated with ED/Binges. We will use microdialysis to further characterize the relationship between the regional DA response shift and the expression of the emergent behavioral profile (EBP). Lower AMPH doses as well as other stimulants will be used to determine the generality of this relationship and the persistence of the behavioral and neurochemical changes. Possible molecular mechanisms underlying the regional DA response shift, and the role of other DA systems in the behavioral response will also be examined. Behavioral (startle and noise paradigms) and neuroendocrine measures (CRF, corticosterone, ACTH, prolactin) will be used to test our hypothesis that the EBP reflects a highly aroused or stressed state. Additional studies are aimed at further assessing the roles of noradrenergic, serotonergic, and glutamatergic systems in the EBP. Elucidation of the neurobiological processes underlying the behavioral changes associated with the ED/Binge treatment may have implications for understanding stimulant addiction and relapse, and the persistent hypersensitivity to the psychotoxic effects of high dose stimulant abuse.

This application for renewal of renewal of salary support by the research Scientist Award outlines a five-year program of research to study the neuropsychopharmacology of stimulants. Studies are designed to characterize the acute (Section 1) and chronic (Section II) effects of stimulants on the various behavioral components and dimensions we have identified. Particular emphasis will be directed at the investigation of transitional doses where individual differences in patterns of responsiveness may be more readily categorized into subgroups. Evaluation of behavior on the basis of differential response profiles has proven to be important in determining the relationship between the various behavioral components and the neurochemical systems and mechanisms underlying the AMPH effects. The generality of these results will be further examined by detailed assessment of other amphetamine-like stimulants including cocaine, methylphenidate and apomorphine and by comparison of these agents with other psychomotor stimulants such as caffeine. In addition to a systematic evaluation of the role of monoamine systems in the various components of the stimulant response, specific experiments will address the hypothesized mechanisms subserving the behavioral dimensions (Section III). Experiments are also designed to assess the alleged role of stress in the stimulant response. Initial studies will further characterize the effects of noise stimulation and amphetamine on various behavioral, neurochemical, neuroendocrine and immunological measures in order to provide a basis for evaluating possible mechanisms underlying stressor-stimulant interactions. The fourth section describes our research using in vivo microdialysis procedures in freely moving animals to extend and refine our preliminary characterization of stimulant induced changes in striatal DA, 5HT, and Ach dynamics. In vitro techniques will be used to examine further the relationship of D1 and D2 DA receptor activation to the appearance of specific components of the stereotyped response. These in vivo and in vitro approaches will be extended to the mesolimbic DA system to determine how the relationship between mesostriatal and mesolimbic DA activation contributes to the AMPH behavioral profile. Finally, we will examine the effects of repeated AMPH pretreatment to determine whether neurochemical changes implicated in the acute response contribute to the behavioral augmentation resulting from repeated AMPH administration. The results of these studies should enhance our understanding of specific behavioral-neurochemical relation- ships involved in the acute and chronic effects of stimulants.

Converging evidence suggests that endogenons opioid systems (EOS) may play an important role in modulating behavioral responsiveness to stressful situations. However, further progress is limited, in part, because of inadequate or incomplete behavioral characterization of various opioid and stress treatments. In addition, comparison of these effects would be greatly facilitated if the behavioral characterization was carried out under similar experimental conditions. Our behavioral system has been specifically designed for the continuous and concurrent monitoring of a broad spectrum of behavioral responses including various measures of arousal, environmental interaction, and ingestive behaviors. The proposed research represents a systematic progression of studies designed to assess the role of EOS in the various behavioral components associated with different types and degress of stress. The acute and chronic behavioral profiles of putative mu (morphine, methadone), kappa- (ketocyclazocine, ethylcyclazocine), sigma- ((+NANM, PCP), and delta- (D-Ala2-Met5-enkephalinamide) opiate receptor agonists will be characterized in the RACs as will the relatively pure opiate antagonists naloxone, naltrexone, and diprenorphine. Under identical experimental conditions, the effects of restraint, noise, and exposure to a novel environment will be determined. Acute interactions and cross-tolerance/sensitization between opioid and stress effects will be examined to determine the extent to which similar behaviors induced by these treatments are mediated by common underlying mechanisms. Stress-opioid interactions will also be examined with the use of our multicompartment chamber and behavioral pattern monitor, and with startle and social interaction paradigms. We will also assess further the effects of NE dorsal bundle lesions on the response to representative opioid and stress treatments. In addition to the conventional stressors, the role of EOS in the alleged stress component of the acute and chronic response to amphetamine and in the apparent susceptibility of spontaneously hypertensive rats to stress will also be examined. The detailed acute and chronic behavioral characterization of exogenously administered opioids and various stressors should enhance our understanding of the role of EOS in the regulation of responsiveness to stress. The potential clinical value of this research is indicated by the accumulating evidence that stress may be significantly implicated in the pathogenesis of major forms of psychopathology including depression and schizophrenia. In addition, individual differences in responsiveness to stress may be involved in determining predisposition to drug abuse.

This application is for renewal of salary support by the Research Scientist Award and outlines a 5-year program of research to study the neuropsychopharmacology of stimulants. Repeated administration of amphetamine (AMPH) results in a multiphasic spectrum of behavioral changes which include sensitization and a post-stimulant withdrawal syndrome (PSWS) in rodents. The patterns of these effects vary profoundly as a function of dose, chronicity, and withdrawal interval. Although dopamine (DA) has been implicated in these changes, our results suggest that sensitization and the PSWS reflect a sequence of time-dependent mechanisms in which DA effects represent only one aspect of a spectrum of changes. Therefore we propose several interrelated lines of research which focus on the various behavioral phases and the potential DA and non-DA changes associated with each. Studies are designed to systematically characterize the DA response correlates of the various patterns of sensitization development and persistence following different chronic AMPH regimens. Similar evaluation of the PSWS will emphasize DA mechanisms underlying the development and apparent sensitization of post-stimulant depression. Predisposing factors for the range of individual differences in responsiveness will be examined with particular emphasis on the role of stress reactivity. Potential processes contributing to the time-related changes in EC DA response to AMPH will be evaluated, including DA release in somatodendritic regions, changes in the uptake carrier, indices of postsynaptic DA receptor function, and the possible role of glutamatergic mechanisms. We will also extend our previous studies to determine the role of NE and 5HT systems in the various phases of sensitization and the PSWS. Finally, the generality of the stimulant effects will be examined through studies of other AMPH-like drugs. Further elucidation of the mechanisms underlying the behavioral changes associated with chronic AMPH may have implications for understanding the factors which contribute to stimulant addiction and relapse, and the persistent hypersensitivity to the psychotoxic effects of these drugs.

Methamphetamine abuse has significantly increased over the past decade and the availability of relatively pure, high potency forms of the drug has led to more chronic, high dose exposure patterns. Converging evidence suggests that profound neurochemical and neuropsychiatric changes can result from methamphetamine abuse and that alterations in striatal dopamine transmission may be implicated in many of these effects. However, it is unclear whether these changes reflect neurodegeneration or adaptational adjustments, nor if functional recovery occurs after discontinuation of drug. Such information is a critical prerequisite to the rational development of effective therapeutic interventions. The proposed research will use a newly developed methamphetamine treatment paradigm that closely simulates, in rats, the drug exposure conditions associated with a high dose, maintenance pattern of methamphetamine abuse, in order to characterize the temporal changes of a broad spectrum of neurochemical and behavioral indices associated with striatal dopamine neuronal transmission. The specific studies are designed to test our hypotheses that: (1) repeated multiple daily administration of methamphetamine will produce profound neurochemical (striatal dopamine nerve terminal markers) and behavioral (spontaneous activity, behavioral organization, and short-term memory) impairments in the absence of dopamine neuronal degeneration; (2) the changes in dopamine transmission (including measures of the dopamine transporter and the vesicular monoamine transporter, as well as extracellular dopamine) and related behavioral deficits will exhibit complete recovery over time; (3) during the late stages of methamphetamine treatment, a spectrum of behaviors associated with the development of paranoid psychosis in stimulant abusers (hyperarousal, increased aggressivity and responsiveness to stress) will gradually emerge, corresponding to a shift in the relative caudate-putamen and nucleus accumbens dopamine responses; and, (4) both the altered behavioral and dopamine effects in response to acute methamphetamine challenge will exhibit gradual recovery over time after discontinuation of chronic treatment. The results of these studies should provide greater insight into the mechanisms and processes contributing to the behavioral and neurochemical consequences associated with a common pattern of methamphetamine abuse.