Indiana University-Purdue University Indianapolis (IUPUI) / Naltrexone (NTX) is clinically efficacious at attenuating alcohol intake in non-abstinent alcoholics and, to a lesser extent, craving, independent of intake. While generally regarded as a non-selective opioid antagonist, NTX has been shown to have concentration dependent selectivity with lower doses (< 1.0 mg/kg) selective for the mu receptor and doses exceeding 1.0 mg/kg capable of binding to delta and kappa receptors. Like the mu system, the delta receptor system has also been implicated in mediating the rewarding effects of EtOH. In contrast, the role of the kappa system is less clear though recent evidence suggests that kappa activation may mediate EtOH aversion. Thus, the present study sought to evaluate the effects of both mu-selective and non-selective doses of naltrexone, the selective delta antagonist naltrindole (NTI), and the selective kappa agonist U50,488H (U50) in a paradigm that procedurally separates the motivation to seek versus consume a reinforcer to assess whether these receptor-selective drugs differentially affects these behaviors in both selected (alcohol-preferring P rats) and non-selected (Long Evans) rats, and whether these effects are specific to EtOH. Rats were trained to complete a single response requirement that resulted in access to either 2% sucrose or 10% EtOH for a 20-min drinking session. In three separate experiments, rats were injected (using a balanced design) with either vehicle or 1 of 3 doses of drug: U50 (IP; 2.5, 5.0, or 10.0mg/kg), NTI (IP; 2.5, 5.0, or 10.0 mg/kg), low NTX (SC; 0.1, 0.3, or 1.0 mg/kg) or high NTX (SC; 1.0, 3.0, or 10.0 mg/kg) on both consummatory and appetitive treatment days. Following either a 20 (U50), 15 (NTI), or 30 minute (NTX) pretreatment, rats were placed into an operant chamber and intake (consummatory) or lever responses (appetitive) and response latencies were recorded. The results showed that overall: U50, NTI, and NTX attenuated intake and responding for sucrose and EtOH. Independent of reinforcer, LE rats were more sensitive to U50’s effects on intake while P rats were more sensitive to the effects on seeking. P rats reinforced with EtOH were more sensitive to NTI’s effects on intake and seeking than all other rat groups. P rats were more sensitive overall to lower doses of NTX than LE rats and lower doses of NTX were more selective in attenuating EtOH responding vs. sucrose. Higher doses of NTX suppressed intake and responding across both lines and reinforcers. These results demonstrate that craving and intake may be differentially regulated by the kappa, delta, and mu opioid receptor systems as a function of “family history” and suggest that different mechanisms of the same (opioid) system may differentially affect craving and intake.

Indiana University-Purdue University Indianapolis (IUPUI) / Differences in voluntary consumption of ethanol have been negatively correlated with differences in initial sensitivity and tolerance to ethanol’s pharmacological effects. From this perspective, both adolescent and adult alcohol-nonpreferring (NP) rats would be expected to be initially more sensitive to the sedative and hypothermic effects of ethanol and fail to acquire tolerance to those effects than preferring (P) rats. The first objective of this experiment was to assess alcohol-induced hypothermia and locomotor sedation in adolescent and adult P and NP rats over five consecutive daily administrations (saline, 1.5 g/kg, or 3.0 g/kg ethanol 17%v/v), testing the hypothesis that the P rats would acquire tolerance to the hypothermic response whereas the NP rats would not show changes across days. In addition, it was hypothesized that there would be age-related differences in initial sensitivity to ethanol, evident by adolescent rats displaying less ethanol-induced hypothermia and locomotor sedation than adult rats on Day 1. The second objective was to determine if conditioning was occurring between the administration environment and the hypothermic response and locomotor sedation elicited by ethanol exposure, via a sixth injection of saline. Female rats were surgically implanted with intraperitoneal Mini Mitter telemetry probes on postnatal day 25 or 85 and experimental manipulations began five days later. Data were collected every minute; temperature data were then converted to change from baseline scores and locomotor data were totaled for each session. On Day 1, maximum temperature reduction elicited by the 3.0 g/kg dose was greater in the NP rats than the P rats, regardless of age. That dose also produced greater levels of locomotor sedation in the adult rats compared to the adolescent rats, regardless of line. The 1.5 g/kg dose of ethanol produced a greater hypothermic response in adult rats compared to adolescent rats, locomotor activity was reduced equally across the groups. With repeated administrations, NP adult rats displayed sensitization to the hypothermic response elicited from the 3.0 g/kg dose; in contrast, tolerance to the hypothermic response was found within the 1.5 g/kg dose for the adolescent P, adult P, and the adult NP rats. Repeated saline administrations also resulted in tolerance to the hypothermic response associated with administration in the adult NP and adolescent P rats. On the Day 6 saline administrations, adult rats which had previously been exposed to the 3.0 g/kg dose, maintained their baseline body temperatures better than both of the other exposure groups. Adolescent rats failed to show any signs of conditioning when administered saline on Day 6. Contrary to prediction the P rats failed to acquire tolerance to the 3.0 g/kg dose for either measure; and the line difference in ethanol-induce hypothermia was due to sensitization of the hypothermic response in adult NP rats. These results also provide further support that adolescent rats are less sensitive to the initial aversive effects of ethanol at the 1.5 g/kg dose for ethanol-induced hypothermia and the 3.0 g/kg dose for locomotor activity. The current experiment provides evidence that initial sensitivity as well as the acquisition of tolerance to ethanol-induced hypothermia may be behavioral phenotypes correlated with selection for high and low alcohol drinking preference.

Indiana University-Purdue University Indianapolis (IUPUI) / Alcohol and cocaine are commonly co-abused drugs, and those meeting criteria for both cocaine and alcohol use disorders experience more severe behavioral and health consequences than those with a single disorder. Chronic alcohol (ethanol) drinking increased the reinforcing and dopamine (DA) neuronal stimulating effects of ethanol within mesolimbic regions of the central nervous system (CNS) of alcohol-preferring (P) rats. The objectives of the current study were to determine if chronic continuous ethanol drinking produced: (1) alterations in the sensitivity of the nucleus accumbens shell (AcbSh) to the reinforcing effects of cocaine, (2) changes in the magnitude and time course of the local stimulating effects of cocaine on posterior ventral tegmental area (pVTA) DA neurons, and (3) a persistence of alterations in the stimulating effects of cocaine after a period of protracted abstinence. Female P rats received continuous, free-choice access to water and 15% v/v ethanol for at least 10 wk (continuous ethanol-drinking; CE) or access to water alone (ethanol-naïve; N). A third group of rats received the same period of ethanol access followed by 30 d of protracted abstinence from ethanol (ethanol-abstinent; Ab). CE and Ab rats consumed, on average, 6-7 g/kg/d of ethanol. Animals with a single cannula aimed at the AcbSh responded for injections of cocaine into the AcbSh during four initial operant sessions. Cocaine was not present in the self-infused solution for the subsequent three sessions, and cocaine access was restored during one final session. Animals with dual ipsilateral cannulae aimed at the AcbSh and the pVTA were injected with pulsed microinfusions of cocaine into the pVTA while DA content was collected for analysis through a microdialysis probe inserted into the AcbSh. During the initial four sessions, neither CE nor N rats self-infused artificial cerebrospinal fluid (aCSF) or 0.1 mM cocaine into the AcbSh. CE, but not N, rats self-administered 0.5 mM cocaine into the AcbSh, whereas both groups self-infused concentrations of 1.0, 2.0, 4.0, or 8.0 mM cocaine. When cocaine access was restored in Session 8, CE rats responded more on the active lever and obtained more infusions of 0.5, 1.0, 2.0, or 4.0 mM cocaine compared to N rats. Microinjection of aCSF into the pVTA did not alter AcbSh DA levels in N, CE, or Ab rats. Microinjections of 0.25 mM cocaine into the pVTA did not significantly alter AcbSh DA levels in N animals, moderately increased DA levels in CE rats, and greatly increased DA levels in Ab rats. Microinjections of 0.5 mM cocaine into the pVTA modestly increased AcbSh DA levels in N animals, robustly increased DA levels in CE rats, and did not significantly alter DA levels in Ab rats. Microinjections of 1.0 or 2.0 mM cocaine into the pVTA modestly increased AcbSh DA levels in N animals but decreased DA levels in CE and Ab rats. Overall, long-term continuous ethanol drinking by P rats enhanced both the reinforcing effects of cocaine within the AcbSh and the stimulatory and inhibitory effects of cocaine on pVTA DA neurons. Alterations in the stimulatory and inhibitory effects of cocaine on pVTA DA neurons were not only enduring, but also enhanced, following a period of protracted abstinence from ethanol exposure. Translationally, prevention of chronic and excessive alcohol intake in populations with a genetic risk for substance abuse may reduce the likelihood of subsequent cocaine use.