Journal of Drug and Alcohol Research最新文献

Inhalants are distinguished as a class primarily based upon a shared route of administration. Grouping inhalants according to their abuse-related in vivo pharmacological effects using the drug discrimination procedure has the potential to provide a more relevant classification scheme to the research and treatment community. Mice were trained to differentiate the introceptive effects of the trichloroethylene vapor from air using an operant procedure. Trichloroethylene is a chlorinated hydrocarbon solvent once used as an anesthetic as well as in glues and other consumer products. It is now primarily employed as a metal degreaser. We found that the stimulus effects of trichloroethylene were similar to those of other chlorinated hydrocarbon vapors, the aromatic hydrocarbon toluene and the vapor anesthetics methoxyflurane and isoflurane. The stimulus effects of trichloroethylene overlapped with those of the barbiturate methohexital, to a lesser extent the benzodiazepine midazolam and to ethanol. NMDA antagonists, the kappa opioid agonist U50,488 and the mixed 5-HT agonist mCPP largely failed to substitute for trichloroethylene. These data suggest that stimulus effects of chlorinated hydrocarbon vapors are mediated at least partially by GABA_A receptor positive modulatory effects.

Toluene is a representative member of a class of inhaled solvents that are voluntarily used by adolescents and adults for their euphorigenic effects. Research into the mechanisms of action of inhaled solvents has lagged behind that of other drugs of abuse despite mounting evidence that these compounds exert profound neurobehavioral and neurotoxicological effects. Results from studies carried out by the authors and others suggest that the neural effects of inhalants arise from their interaction with a discrete set of ion channels that regulate brain activity. Of particular interest is how these interactions allow toluene and other solvents to engage portions of an addiction neurocircuitry that includes midbrain and cortical structures. In this review, we focus on the current state of knowledge regarding toluene's action on midbrain dopamine neurons, a key brain region involved in the initial assessment of natural and drug-induced rewards. Findings from recent studies in the authors' laboratory show that brief exposures of adolescent rats to toluene vapor induce profound changes in markers of glutamatergic plasticity in VTA DA neurons. These changes are restricted to VTA DA neurons that project to limbic structures and are prevented by transient activation of the medial prefrontal cortex prior to toluene exposure. Together, these data provide the first evidence linking the voluntary inhalation of solvents to changes in reward -sensitive dopamine neurons.

It has long been known that individuals will engage in voluntary inhalation of volatile solvents for their rewarding effects. However, research into the neurobiology of these agents has lagged behind that of more commonly used drugs of abuse such as psychostimulants, alcohol and nicotine. This imbalance has begun to shift in recent years as the serious effects of abused inhalants, especially among children and adolescents, on brain function and behavior have become appreciated and scientifically documented. In this review, we discuss the physicochemical and pharmacological properties of toluene, a representative member of a large class of organic solvents commonly used as inhalants. This is followed by a brief summary of the clinical and pre-clinical evidence showing that toluene and related solvents produce significant effects on brain structures and processes involved in the rewarding aspects of drugs. This is highlighted by tables highlighting toluene's effect on behaviors (reward, motor effects, learning, etc.) and cellular proteins (e.g. voltage and ligand-gated ion channels) closely associated the actions of abused substances. These sections demonstrate not only the significant progress that has been made in understanding the neurobiological basis for solvent abuse but also reveal the challenges that remain in developing a coherent understanding of this often overlooked class of drugs of abuse.

Chronic cocaine use produces long-lasting changes in reward circuits that may underlie the transition from casual to compulsive patterns of drug use. Although strong neuroadaptations within the mesocorticolimbic system are known to occur, the specific role of these drug-induced plasticities on sensitization remains to be elucidated. Here we investigate whether PKMζ, a protein involved in maintaining long-term potentiation (LTP), plays a role in these cocaine-induced changes in synaptic strengthening. We performed whole-cell voltage clamp recordings of putative ventral tegmental area (VTA) dopamine (DA) cells 24 hours after five days of 15 mg/kg i.p. cocaine or isovolumetric saline injections. We observed that superfusion of 5µM ZIP (PKMζ inhibitory peptide) decreased AMPA currents and AMPA/NMDA ratios only in cocaine sensitized rats. In vivo ZIP microinfusions (10 nmol) into the VTA after cocaine sensitization decreased locomotor activity on a subsequent cocaine challenge only if given ZIP is given before the withdrawal period. On the other hand, ZIP microinfusions into the nucleus accumbens (NAc) core after a seven days withdrawal period disrupt the expression of locomotor sensitization. The present data provide a potentially relevant region, and time-specific PKMζ-dependent brain mechanism that enables sensitization. Our results support the vision that addiction involves a pathological learning process. They imply that if this synaptic strengthening is reversed, changes in the behavioral response may also be overturned.

Alcohol and nicotine are two very commonly abused legal substances. Although various hypotheses for such co-dependence have been suggested, it is not known whether the effects of alcohol and nicotine on mood behavior may also contribute to such co-abuse. Chronic exposure to high alcohol levels may lead to various neurochemical changes and precipitate depressive-like behavior. Nicotine, on the other hand, may exert an antidepressant-like effect. Here, we sought to determine whether nicotine may also block or mitigate the "depressogenic" effects of alcohol in a rat model. Moreover, since hippocampal brain-derived neurotrophic factor (BDNF) has been strongly implicated in mood regulation and effectiveness of antidepressants, the level of this neurotrophic factor in the hippocampus was also evaluated. Adult male Wistar rats were injected (i.p.) with alcohol (1.0 g/kg), nicotine (0.3 mg/kg) or their combination once daily for 14 days. Controls received saline. The behavior of these rats in open field locomotor activity (LMA), the forced swim test (FST), a measure of helplessness, and sucrose intake, a measure of anhedonia were evaluated 16-18 h after the last injection. Chronic alcohol did not affect LMA, but increased immobility in FST and decreased sucrose consumption, suggesting a "depressogenic" effect. Nicotine by itself did not affect any of the measured behavior but blocked alcohol-induced changes in FST and sucrose intake. Parallel to the behavioral changes, chronic alcohol resulted in a significant decrease in hippocampal BDNF, which was normalized by nicotine. These findings suggest that the opposing effects of alcohol and nicotine on depressive-like behavior may contribute to their co-abuse.

The present study investigated whether chronic methamphetamine (METH) would suppress METH-induced mRNA expression of immediate early genes (IEGs) in the rat brain. Rats were given METH or saline over two weeks. After an overnight withdrawal, saline- and METH-pretreated rats received an acute saline or METH challenge. The acute METH challenge increased expression of members of activator protein 1 (AP-1) and Nr4a IEG families in the nucleus accumbens (NAc) and midbrain of saline-pretreated rats. Chronic METH exposure attenuated the effects of acute METH challenge on AP-1 IEG expression in the NAc. However, chronic METH failed to attenuate acute METH-induced increases of Nr4a1 and Nr4a3 expression in the NAc. In contrast to observations in the NAc, chronic METH did not prevent acute METH-induced changes in IEG expression in the midbrain. These results suggest that these two brain regions that are implicated in neuroplastic effects of illicit substances might be differentially affected by psychostimulants.

Several laboratories have shown that methamphetamine (METH) neurotoxicity is associated with increases of nitric oxide (NO) production in striatal tissue and blockade of NO production protects from METH. Because substance P modulates NO production, we tested the hypothesis that intrinsic striatal neuropeptides such as somatostatin and neuropeptide Y (NPY) modulate striatal NO production in the presence of METH. To that end, METH (30 mg/kg, IP) was injected into adult male mice alone or in combination with pharmacological agonists or antagonists of the neurokinin-1 (substance P), somatostatin or NPY receptors and 3-nitrotyrosine (an indirect index of NO production) was assessed utilizing HPLC or a histological method. Pre-treatment with the systemic neurokinin-1 receptor antagonist WIN-51,708 significantly attenuated the METH-induced production of striatal 3-NT measured at two hours post-METH. Conversely, intrastriatal injection of NPY1 or 2 receptor agonists inhibited the METH-induced production of striatal 3-NT. Similarly, intrastriatal infusion of the somatostatin receptor agonist octreotide attenuated the METH-induced striatal production of 3-NT. Taken together, our results suggest the hypothesis that the neuropeptide substance P is pro-damage while the neuropeptides somatostatin and NPY are anti-damage in the presence of METH by targeting the production of NO.

CART (cocaine and amphetamine regulated transcript) peptide functions as both a neurotransmitter and a hormone and is found both in the central nervous system (CNS) and in the periphery. CART peptide in the nucleus accumbens (NAc) has been implicated in the regulation of cocaine-dopamine-mediated locomotion and self-administration, and amphetamine-mediated locomotion and behavior. However, there are no studies on the effect of systemic administration of CART peptide on cocaine and amphetamine-mediated locomotion. In this study, we tested if the systemic administration of CART 55-102 by the intraperitoneal (ip) route has a functional effect on psychostimulant-mediated locomotion in rats as it does when given into the brain. We determined that ip CART 55-102 attenuates psychostimulant-mediated locomotion as it does when administered into the NAc and display a biphasic dose response curve.