Cocaine self-administration punished by i.v. histamine in rat models of high and low drug abuse vulnerability: Effects of saccharin preference, impulsivity, and sex

Abstract

A key feature of substance use disorders is continued drug consumption despite aversive consequences. This has been modeled in the animal laboratory by pairing drug self-administration with electric shock, thereby punishing drug intake (Deroche-Gamonet et al. 2004). In the present experiments, we examined the effects of punishment on i.v. cocaine self-administration by adding histamine to the cocaine solution in three different animal models of high and low vulnerability to drug abuse: rats selectively bred for high (HiS) and low (LoS) saccharin consumption, rats selected for high (HiI) and low (LoI) impulsivity, and sex differences. Animals were allowed to self-administer cocaine (0.4 mg/kg/infusion) to establish a baseline of operant responding. Histamine (4.0 mg/kg/infusion) was then added directly into the cocaine solution and its consequent effects on self-administration were compared to baseline. The histamine + cocaine solution was then replaced with a cocaine-only solution, and the rats' operant responding was again measured and compared to baseline. Concurrent histamine exposure was effective in reducing cocaine consumption in all groups of rats; however, LoS and female rats took longer to return to baseline levels of cocaine consumption after histamine was removed compared to HiS and male rats. These data suggest the reduction of drug self-administration by aversive consequences may differ in groups that vary in drug use vulnerability, and these results may inform pharmacological strategies that enhance the negative aspects of drug consumption.

Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases

“…Another two H3R antagonists, namely GSK-189254 and GSK-239512, have been described as potent, selective, and highly brain penetrant antagonists with proven effectiveness in a number of animal experiments, including attentional and memory models (Figure 10, Table 1) [53,59,[91][92][93][94][95][96][97]. Interestingly, GSK-239512 has completed phase 1 clinical trial, and the results suggest a modest efficacy in mild-moderate AD patients (ClinicalTrials.gov trial registration number: NCT00675090).…”

Intracranial self-stimulation reward thresholds during morphine withdrawal in rats bred for high (HiS) and low (LoS) saccharin intake

“…Furthermore, we have shown that LoS (vs. HiS) rats are more sensitive to the effects of i.v. histamine punishment on cocaine self administration (Holtz et al, 2013), suggesting a more general link between phenotypic sensitivity to aversive events and addiction vulnerability.…”

Cocaine-, caffeine-, and stress-evoked cocaine reinstatement in high vs. low impulsive rats: Treatment with allopregnanolone

“…For example, animals selected for low impulsivity (LoI vs. HiI), low saccharin intake (LoS vs. HiS), as well as adults (vs. adolescents), and males (vs. females) not only exhibit less drug seeking than their counterparts, but they also exhibit more sensitivity to punishment by histamine, greater signs of withdrawal from drugs of abuse, greater taste aversion, greater response to anxiogenic stimuli, and greater acoustic startle (Carroll et al, 2009; Carroll and Holtz, 2014; Holtz et al, 2013, 2014b; Holtz and Carroll, 2014; McLaughlin et al, 2011; Radke et al, 2014, but see Radke et al, 2013), while their counterparts (HiI, HiS, adolescents, and females, respectively) have greater response to positive aspects of drugs (i.e., greater drug-seeking and drug-taking behaviors, see review by Carroll et al, 2009). This raises the question of to what extent are individual differences in drug seeking understood based on differential reactions to positive or negative aspects of drugs.…”

“…To date, there have been very few preclinical animal studies that have addressed negative aspects of drugs of abuse in terms of the development and treatment of drug abuse, and there are even fewer studies in humans (Anker and Carroll, 2012; Carroll and Holtz, 2014; Holtz et al, 2013; Holtz and Carroll, 2011, 2014). In terms of prevention, it is particularly important to know how positive vs. negative aspects of drugs will affect relapse in groups that differentially administer drugs.…”

“…Allopregnanolone has been used in previous rat studies to reduce cocaine- (Anker et al, 2009; Anker and Carroll, 2010a) and methamphetamine- (Holtz et al, 2014b) induced reinstatement of drug seeking in rats. Since ALLO, progesterone, and their precursor, pregnenolone have been show to have anxiolytic effects (Anker and Carroll, 2010a, 2011; Anker et al, 2007; Concas et al, 2000; Llaneza and Frye, 2009; Schneider and Popik, 2007), it was hypothesized that it may produce a greater reduction of stress-induced (e.g., YOH and a high dose of CAFF priming injections) responding in LoI vs. HiI animals, since LoI rats may be more sensitive to anxiogenic stimuli or other negative aspects of drugs (Holtz et al, 2013; Holtz and Carroll, 2011, 2014). Female rats were used in this study, as they show a greater difference between HiI and LoI measures of cocaine seeking than male rats (Perry et al, 2008); thus, they would provide a higher baseline of reinstatement for reduction by ALLO.…”