F. Scott Hall

Negative affective states and cognitive impairments in nicotine dependence

Smokers have substantial individual differences in quit success in response to current treatments for nicotine dependence. This observation may suggest that different underlying motivations for continued tobacco use across individuals and nicotine cessation may require different treatments in different individuals. Although most animal models of nicotine dependence emphasize the positive reinforcing effects of nicotine as the major motivational force behind nicotine use, smokers generally report that other consequences of nicotine use, including the ability of nicotine to alleviate negative affective states or cognitive impairments, as reasons for continued smoking. These states could result from nicotine withdrawal, but also may be associated with premorbid differences in affective and/or cognitive function. Effects of nicotine on cognition and affect may alleviate these impairments regardless of their premorbid or postmorbid origin (e.g., before or after the development of nicotine dependence). The ability of nicotine to alleviate these symptoms would thus negatively reinforce behavior, and thus maintain subsequent nicotine use, contributing to the initiation of smoking, the progression to dependence and relapse during quit attempts. The human and animal studies reviewed here support the idea that self-medication for pre-morbid and withdrawal-induced impairments may be more important factors in nicotine addiction and relapse than has been previously appreciated in preclinical research into nicotine dependence. Given the diverse beneficial effects of nicotine under these conditions, individuals might smoke for quite different reasons. This review suggests that inter-individual differences in the diverse effects of nicotine associated with self-medication and negative reinforcement are an important consideration in studies attempting to understand the causes of nicotine addiction, as well as in the development of effective, individualized nicotine cessation treatments.

Memory Impairment and Reduced Exploratory Behavior in Mice after Administration of Systemic Morphine

In the present study, the effects of morphine were examined on tests of spatial memory, object exploration, locomotion, and anxiety in male ICR mice. Administration of morphine (15 or 30 mg/kg, intraperitoneally (i.p.)) induced a significant decrease in Y-maze alternations compared to saline vehicle-treated mice. The reduced Y-maze alternations induced by morphine were completely blocked by naloxone (15 mg/kg) or β-funaltrexamine (5 mg/kg) but not by norbinaltorphimine (5 mg/kg) or naltrindole (5 mg/kg), suggesting that the morphine-induced spatial memory impairment was mediated predominantly by jl-opioid receptors (MOPs). Significant spatial memory retrieval impairments were observed in the Morris water maze (MWM) in mice treated with morphine (15 mg/kg) or scopolamine (1 mg/kg), but not with naloxone or morphine plus naloxone. Reduced exploratory time was observed in mice after administration of morphine (15 mg/kg), in a novel-object exploration test, without any changes in locomotor activity. No anxiolytic-like behavior was observed in morphine-treated mice in the elevated plus maze. A significant reduction in buried marbles was observed in morphine-treated mice measured in the marble-burying test, which was blocked by naloxone. These observations suggest that morphine induces impairments in spatial short-term memory and retrieval, and reduces exploratory behavior, but that these effects are not because of overall changes in locomotion or anxiety.

Reverse Translational Implications of Genome-Wide Association Studies for Addiction Genetics

Abstract In recent years genome-wide association studies (GWAS) have transformed thinking about the genetics of addiction. Prior to the advent of these sorts of studies there were two primary problems in addiction genetics, which was based in large part on candidate gene studies: failure to replicate findings, and a priori expectation as the primary basis of hypotheses. GWAS overcame many of these problems, and has changed our view of the genetics of addiction. As discussed in this review, a substantial degree of replication began to emerge as these studies progressed, particularly as sample sizes increased, marker density increased, and we became more sensitive to issues of marker and genomic heterogeneity between different human populations. GWAS for addiction, like GWAS for most other common disorders, found that the genetic causes of such conditions were best explained by the contribution of a large number of allelic variants of small effect. Moreover, the genes identified by GWAS were quite different from those considered to be important for drug dependence based on candidate gene studies or studies of genetically modified mice, including a very large proportion of cell adhesion molecule genes. The current challenge for studies in genetically modified mice is to examine these genes, e.g., the reverse translational implications of the results of GWAS, thought to contribute to liability for drug dependence in humans.

Pretreatment or Posttreatment with Aripiprazole Attenuates Methamphetamine-induced Stereotyped Behavior in Mice

Aripiprazole is a third-generation atypical antipsychotic and a dopamine D2 receptor partial agonist. In the present study, we investigated whether a single administration of aripiprazole to mice, either as a pretreatment or as a posttreatment, would affect stereotypy induced by methamphetamine (METH). Pretreatment of male ICR mice with aripiprazole (1 or 10 mg/kg, i.p.) attenuated the incidence of METH-induced stereotypical behavior in a dose-dependent manner. Pretreatment of mice with 1 mg/kg aripiprazole produced an increase in the locomotor activity in mice treated with METH compared with mice treated with vehicle plus METH and with 10 mg/kg aripiprazole plus METH. This increase in locomotion is indicative of a rightward shift in the dose-response curve for METH, consistent with a shift in the type of stereotypical behavior observed from biting to sniffing. Aripiprazole posttreatment, after METH-induced stereotypical behavior, was fully expressed and also significantly attenuated overall stereotypy in an aripiprazole dose-dependent manner. These data suggest that the antagonism of METH effects by aripiprazole should be investigated as a potential treatment for acute METH overdose.

The role of 5-HT2c receptor on corticosterone-mediated food intake

Corticosterone plays an important role in feeding behavior. However, its mechanism remains unclear. Therefore, the present study aimed to investigate the effect of corticosterone on feeding behavior. In this study, cumulative food intake was increased by acute corticosterone administration in a dose‐dependent manner. Administration of the 5‐HT2c receptor agonist m‐chlorophenylpiperazin (mCPP) reversed the effect of corticosterone on food intake. The anorectic effects of mCPP were also blocked by the 5‐HT2c receptor antagonist RS102221 in corticosterone‐treated mice. Both corticosterone and mCPP increased c‐Fos expression in hypothalamic nuclei, but not the nucleus of the solitary tract. RS102221 inhibited c‐Fos expression induced by mCPP, but not corticosterone. In addition, mCPP had little effect on TH and POMC levels in the hypothalamus. Furthermore, mCPP antagonized decreasing effect of the leptin produced by corticosterone. Taken together, our findings suggest that 5‐HT2c receptors and leptin may be involved in the effects of corticosterone‐induced hyperphagia.

Brain Histamine N-Methyltransferase As a Possible Target of Treatment for Methamphetamine Overdose

Stereotypical behaviors induced by methamphetamine (METH) overdose are one of the overt symptoms of METH abuse, which can be easily assessed in animal models. Currently, there is no successful treatment for METH overdose. There is increasing evidence that elevated levels of brain histamine can attenuate METH-induced behavioral abnormalities, which might therefore constitute a novel therapeutic treatment for METH abuse and METH overdose. In mammals, histamine N-methyltransferase (HMT) is the sole enzyme responsible for degrading histamine in the brain. Metoprine, one of the most potent HMT inhibitors, can cross the blood-brain barrier and increase brain histamine levels by inhibiting HMT. Consequently, this compound can be a candidate for a prototype of drugs for the treatment of METH overdose.

Tetrabenazine, a vesicular monoamine transporter-2 inhibitor, attenuates morphine-induced hyperlocomotion in mice through alteration of dopamine and 5-hydroxytryptamine turnover in the cerebral cortex

ABSTRACT A single administration with morphine (30 mg/kg, i.p.) induced long‐lasting hyperlocomotion in male ICR mice. Pretreatment of mice with a benzoquinolizine derivative tetrabenazine (TBZ; a reversible vesicular monoamine transporter‐2 inhibitor) (1 mg/kg, i.p.) for 30 min significantly attenuated the hyperlocomotion induced by morphine, as compared with vehicle (saline)‐pretreated mice. No significant change in locomotion was observed in mice pretreated with TBZ (1 mg/kg) alone. Mice treated with TBZ (1 mg/kg) showed an increase in immobility time in a tail suspension test, as compared with saline‐treated mice. Pretreatment with TBZ (1 mg/kg) had no effect on morphine (1–30 mg/kg)‐induced antinociception. TBZ at a dose of 1 mg/kg inhibited dopamine turnover (the ratio of 3,4‐dihydroxyphenylacetic acid/dopamine) and 5‐hydroxytryptamine turnover (the ratio of 5‐hydroxyindoleacetic acid/5‐hydroxytryptamine) in the cerebral cortex of mice challenged with morphine, as compared with saline‐pretreated mice challenged with morphine. No stereotypic behavior was observed in mice treated with morphine (30 mg/kg) in combination with TBZ (1 mg/kg), so the reduction in observed locomotion did not result from induction of stereotypical behavior. Moreover, TBZ (1 and 2 mg/kg) pretreatment had no effect on stereotyped behaviors observed in mice challenged with 10 mg/kg methamphetamine. These data support the potential antagonistic actions of TBZ on some opiate actions, and encourage further exploration of potential effects on morphine reinforcement. HighlightsIn naive mice, morphine induced a hyperlocomotion.Tetrabenazine (TBZ) pretreatment reduced the morphine‐induced hyperlocomotion.TBZ pretreatment did not affect morphine‐induced antinociception.TBZ inhibited cerebral cortical dopamine and serotonin turnovers.

The Role of Cell Adhesion Molecule Genes Regulating Neuroplasticity in Addiction

A variety of genetic approaches, including twin studies, linkage studies, and candidate gene studies, has established a firm genetic basis for addiction. However, there has been difficulty identifying the precise genes that underlie addiction liability using these approaches. This situation became especially clear in genome-wide association studies (GWAS) of addiction. Moreover, the results of GWAS brought into clarity many of the shortcomings of those early genetic approaches. GWAS studies stripped away those preconceived notions, examining genes that would not previously have been considered in the study of addiction, consequently creating a shift in our understanding. Most importantly, those studies implicated a class of genes that had not previously been considered in the study of addiction genetics: cell adhesion molecules (CAMs). Considering the well-documented evidence supporting a role for various CAMs in synaptic plasticity, axonal growth, and regeneration, it is not surprising that allelic variation in CAM genes might also play a role in addiction liability. This review focuses on the role of various cell adhesion molecules in neuroplasticity that might contribute to addictive processes and emphasizes the importance of ongoing research on CAM genes that have been implicated in addiction by GWAS.

Psychotomimetic-like behavioral effects of memantine in the mouse

A single administration of mice with memantine (1-amino-3,5-dimethyladamantane), a glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, induced stereotyped behaviors in dose- and time-dependent manners. The predominant behavioral component of the stereotypy was a continuous, exaggerated sniffing which was accompanied by persistent locomotion. In contrast, a psychostimulant methamphetamine (METH) predominantly induced a stereotyped biting and other forms of intense stationary stereotypical behaviors. Memantine-induced stereotyped sniffing was attenuated by pretreatment with haloperidol, a dopamine D2 receptor antagonist, in a dose-dependent manner. The memantine-induced stereotyped sniffing was also attenuated by pretreatment with betahistine (2-[2-(methylamino)ethyl]pyridine), an agent which increases histamine turnover and releases histamine in the brain. These observations suggest that memantine might induce stereotypies through neuronal mechanisms that are somewhat different from those of METH, but still overlap to a certain extent, since memantine-induced stereotypies can be attenuated by the mechanisms that also suppress METH-induced stereotypy. Importantly, these data suggests that the effects of memantine may be more limited to the ventral striatum including nucleus accumbens than those of METH, which is associated with dorsal striatal stimulation at high doses. In this respect memantine may also have pharmacological properties such as compartmentation (i.e. brain distribution) and neuronal mechanisms different from those of other NMDA receptor antagonists, such as ketamine, which may have important implications for therapeutic uses of these drugs.