Ida Fredriksson

The glucagon-like peptide 1 analogue Exendin-4 attenuates alcohol mediated behaviors in rodents

Development of alcohol use disorders largely depends on the effects of alcohol on the brain reward systems. Emerging evidence indicate that common mechanisms regulate food and alcohol intake and raise the possibility that endocrine signals from the gut may play an important role for alcohol consumption, alcohol-induced reward and the motivation to consume alcohol. Glucagon-like peptide 1 (GLP-1), a gastrointestinal peptide regulating food intake and glucose homeostasis, has recently been shown to target central brain areas involved in reward and motivation, including the ventral tegmental area and nucleus accumbens. Herein we investigated the effects of the GLP-1 receptor agonist, Exendin-4 (Ex4), on various measures of alcohol-induced reward as well as on alcohol intake and alcohol seeking behavior in rodents. Treatment with Ex4, at a dose with no effect per se, attenuated alcohol-induced locomotor stimulation and accumbal dopamine release in mice. Furthermore, conditioned place preference for alcohol was abolished by both acute and chronic treatment with Ex4 in mice. Finally we found that Ex4 treatment decreased alcohol intake, using the intermittent access 20% alcohol two-bottle-choice model, as well as alcohol seeking behavior, using the progressive ratio test in the operant self-administration model, in rats. These novel findings indicate that GLP-1 signaling attenuates the reinforcing properties of alcohol implying that the physiological role of GLP-1 extends beyond glucose homeostasis and food intake regulation. Collectively these findings implicate that the GLP-1 receptor may be a potential target for the development of novel treatment strategies for alcohol use disorders.

Ghrelin Receptor (GHS-R1A) Antagonism Suppresses Both Alcohol Consumption and the Alcohol Deprivation Effect in Rats following Long-Term Voluntary Alcohol Consumption

Alcohol dependence is a heterogeneous disorder where several signalling systems play important roles. Recent studies implicate that the gut-brain hormone ghrelin, an orexigenic peptide, is a potential mediator of alcohol related behaviours. Ghrelin increases whereas a ghrelin receptor (GHS-R1A) antagonist decreases alcohol consumption as well as operant self-administration of alcohol in rodents that have consumed alcohol for twelve weeks. In the present study we aimed at investigating the effect of acute and repeated treatment with the GHS-R1A antagonist JMV2959 on alcohol intake in a group of rats following voluntarily alcohol consumption for two, five and eight months. After approximately ten months of voluntary alcohol consumption the expression of the GHS-R1A gene (Ghsr) as well as the degree of methylation of a CpG island found in Ghsr was examined in reward related brain areas. In a separate group of rats, we examined the effect of the JMV2959 on alcohol relapse using the alcohol deprivation paradigm. Acute JMV2959 treatment was found to decrease alcohol intake and the effect was more pronounced after five, compared to two months of alcohol exposure. In addition, repeated JMV2959 treatment decreased alcohol intake without inducing tolerance or rebound increase in alcohol intake after the treatment. The GHS-R1A antagonist prevented the alcohol deprivation effect in rats. There was a significant down-regulation of the Ghsr expression in the ventral tegmental area (VTA) in high- compared to low-alcohol consuming rats after approximately ten months of voluntary alcohol consumption. Further analysis revealed a negative correlation between Ghsr expression in the VTA and alcohol intake. No differences in methylation degree were found between high- compared to low-alcohol consuming rats. These findings support previous studies showing that the ghrelin signalling system may constitute a potential target for development of novel treatment strategies for alcohol dependence.

Evaluation of guanfacine as a potential medication for alcohol use disorder in long-term drinking rats: behavioral and electrophysiological findings.

One of the main treatment challenges in alcohol use disorder (AUD) is the high rate of craving in combination with decreased cognitive functioning including impaired decision making and impulse control that often lead to relapse. Recent studies show that guanfacine, an α-2-adrenoceptor agonist and FDA-approved ADHD medication, attenuates stress-induced relapse of several drugs of abuse including alcohol. Here we evaluated guanfacine’s effects on voluntary alcohol intake, the alcohol deprivation effect (ADE), alcohol seeking behavior, and cue/priming-induced reinstatement in Wistar rats that had voluntarily consumed alcohol for at least 2 months before treatment. In addition, guanfacine’s ability to regulate glutamatergic neurotransmission was evaluated through electrophysiological recordings in medial prefrontal cortex (mPFC) slices prepared from long-term drinking rats (and alcohol-naive controls) that had received three daily guanfacine (0.6 mg/kg/day) or vehicle injections in vivo. Guanfacine decreased alcohol intake in high, but not low, alcohol-consuming rats and the effects were generally more long lasting than that of the AUD medication naltrexone. Repeated guanfacine treatment induced a long-lasting decrease in alcohol intake, persistent up to five drinking sessions after the last injection. In addition, guanfacine attenuated the ADE as well as alcohol seeking and cue/priming-induced reinstatement of alcohol seeking. Finally, subchronic guanfacine treatment normalized an alcohol-induced dysregulated glutamatergic neurotransmission in the mPFC. These results support previous studies showing that guanfacine has the ability to improve prefrontal connectivity through modulation of the glutamatergic system. Together with the fact that guanfacine appears to be clinically safe, these results merit evaluation of guanfacine’s clinical efficacy in AUD individuals.

The monoamine stabilizer (−)‐OSU6162 counteracts downregulated dopamine output in the nucleus accumbens of long‐term drinking Wistar rats

We recently established that the monoamine stabilizer (−)‐OSU6162 (OSU6162) decreased voluntary alcohol‐mediated behaviors, including alcohol intake and cue/priming‐induced reinstatement, in long‐term drinking rats, while blunting alcohol‐induced dopamine output in the nucleus accumbens (NAc) of alcohol‐naïve rats. Therefore, we hypothesized that OSU6162 attenuates alcohol‐mediated behaviors by blunting alcohols rewarding effects. Here, we evaluated the effects of long‐term drinking and OSU6162 treatment (30 mg/kg, sc) on basal and alcohol‐induced (2.5 g/kg, ip) NAc dopamine outputs in Wistar rats after 10 months of intermittent access to 20% alcohol. The results showed that basal and alcohol‐induced NAc dopamine outputs were significantly lower in long‐term drinking rats, compared with alcohol‐naïve rats. In the long‐term drinking rats, OSU6162 slowly increased and maintained the dopamine output significantly elevated compared with baseline for at least 4 hours. Furthermore, OSU6162 pre‐treatment did not blunt the alcohol‐induced output in the long‐term drinking rats, a finding that contrasted with our previous results in alcohol‐naïve rats. Finally, OSU6162 did not induce conditioned place preference (CPP) in either long‐term drinking or alcohol‐naïve rats, indicating that OSU6162 has no reinforcing properties. To verify that the CPP results were not due to memory acquisition impairment, we demonstrated that OSU6162 did not affect novel object recognition. In conclusion, these results indicate that OSU6162 attenuates alcohol‐mediated behaviors by counteracting NAc dopamine deficits in long‐term drinking rats and that OSU6162 is not rewarding on its own. Together with OSU6162s beneficial side‐effect profile, the present study merits evaluation of OSU6162s clinical efficacy to attenuate alcohol use in alcohol‐dependent patients.

Prior Exposure to Alcohol Has No Effect on Cocaine Self-Administration and Relapse in Rats: Evidence from a Rat Model that Does Not Support the Gateway Hypothesis

The gateway hypothesis posits that initial exposure to legal drugs promotes subsequent addiction to illicit drugs. However, epidemiological studies are correlational and cannot rule out the alternative hypothesis of shared addiction vulnerability to legal and illegal drugs. We tested the gateway hypothesis using established rat alcohol exposure procedures and cocaine self-administration and reinstatement (relapse) procedures. We gave Wistar or alcohol-preferring (P) rats intermittent access to water or 20% alcohol in their homecage for 7 weeks (three 24-h sessions/week). We also exposed Wistar rats to air or intoxicating alcohol levels in vapor chambers for 14-h/day for 7 weeks. We then tested the groups of rats for acquisition of cocaine self-administration using ascending cocaine doses (0.125, 0.25, 0.5, 1.0 mg/kg/infusion) followed by a dose–response curve after acquisition of cocaine self-administration. We then extinguished lever pressing and tested the rats for reinstatement of drug seeking induced by cocaine-paired cues and cocaine priming (0, 2.5, 5, 10 mg/kg, i.p.). Wistar rats consumed moderate amounts of alcohol (4.6 g/kg/24 h), P rats consumed higher amounts of alcohol (7.6 g/kg/24 h), and Wistar rats exposed to alcohol vapor had a mean blood alcohol concentration of 176.2 mg/dl during the last week of alcohol exposure. Alcohol pre-exposure had no effect on cocaine self-administration, extinction responding, and reinstatement of drug seeking. Pre-exposure to moderate, high, or intoxicating levels of alcohol had no effect on cocaine self-administration and relapse to cocaine seeking. Our data do not support the notion that alcohol is a gateway drug to cocaine.

Role of mu, but not delta or kappa, opioid receptors in context-induced reinstatement of oxycodone seeking

Relapse to non‐medical use of prescription opioids often occurs after exposure to places previously associated with drug use. Here, we describe a rat model of context‐induced reinstatement of oxycodone seeking after repeated cycles of drug self‐administration and extinction‐induced abstinence. We also determined the role of mu, delta and kappa opioid receptors (MOR, DOR, KOR) in this reinstatement. We trained rats to self‐administer oxycodone for 6 h/day in context A; lever pressing was paired with a discrete cue. Next, we extinguished the lever pressing in the presence of the discrete cue in context B and then tested the rats for reinstatement of oxycodone seeking in both contexts. We retrained rats to self‐administer oxycodone in context A, re‐extinguished their lever pressing in context B and retested them for reinstatement in both contexts. Prior to testing, we injected the rats with vehicle or antagonists of MOR (naltrexone; 0.5 or 1.0 mg/kg), DOR (naltrindole; 7.5 or 15 mg/kg) or KOR (LY2456302; 5 or 10 mg/kg). We also tested the effect of naltrexone, naltrindole and LY2456302 on oxycodone self‐administration under fixed‐ratio‐1 (FR1) and progressive ratio (PR) reinforcement schedules. We observed context‐induced reinstatement of oxycodone seeking after repeated cycles of drug self‐administration and extinction. Naltrexone, but not naltrindole or LY2456302, injections decreased this reinstatement. Additionally, naltrexone increased oxycodone self‐administration under the FR1 schedule and decreased oxycodone self‐administration under the PR schedule; naltrindole and LY2456302 were ineffective. Results demonstrate a critical role of MOR, but not DOR or KOR, in context‐induced reinstatement of oxycodone seeking and oxycodone self‐administration.

The monoamine stabilizer (−)-OSU6162 prevents the alcohol deprivation effect and improves motor impulsive behavior in rats: OSU6162-impulse control

Alcohol craving, in combination with impaired impulse control, often leads to relapse. The dopamine system mediates the rewarding properties of alcohol but is also involved in regulating impulsive behavior. The monoamine stabilizer (−)‐OSU6162 (OSU6162) has the ability to stabilize dopamine activity depending on the prevailing dopaminergic tone and may therefore normalize the dopaminergic transmission regulating both alcohol use disorder and impulsivity. We have recently showed that OSU6162 attenuates voluntary alcohol consumption, operant alcohol self‐administration, alcohol withdrawal symptoms and cue‐induced reinstatement of alcohol seeking in rats. Here, we evaluated OSU6162s effects on motor impulsivity in Wistar rats that had voluntarily consumed alcohol or water for 10 weeks. The five‐choice serial reaction time task was used to measure motor impulsivity, and a prolonged waiting period (changed from 5 to 7 seconds) was applied to induce premature responses. OSU6162‐testing was conducted twice a week (Tuesdays and Fridays), every other week with regular baseline training sessions in between. We also tested OSU6162s effects on the alcohol deprivation effect in long‐term alcohol drinking Wistar rats. The results showed that OSU6162 (30 mg/kg) pre‐treatment significantly improved motor impulsivity in the five‐choice serial reaction time task in both alcohol and alcohol‐naïve rats. Moreover, OSU6162 (30 mg/kg) pre‐treatment prevented the alcohol deprivation effect, i.e. relapse‐like drinking behavior after a forced period of abstinence in long‐term drinking rats. In conclusion, our results provide further support for OSU6162 as a novel treatment for alcohol use disorder. The results further indicate that improvement of motor impulse control might be one mechanism behind OSU6162s ability to attenuate alcohol‐mediated behaviors.