Biomedical subjects

C W Hodge

Publications and source records attributed to C W Hodge.

17 recordsLinked to original sources

PubMed1997

Differential changes in sucrose/ethanol and sucrose maintained responding by independently altering ethanol or sucrose concentration.

Increased reinforcing efficacy of sucrose/ethanol solutions in comparison to sucrose solutions has been previously demonstrated. However, the contribution of the components of the sucrose/ethanol solution is not well defined. The present study used a multiple schedule of reinforcement to evaluate the differential changes in reinforcer presentations as sucrose or ethanol concentrations were altered. Male Long-Evans rats were trained to press a lever on a multiple fixed ratio 4-fixed ratio 4 schedule which was composed of alternating 2-min components. During one component, 5% sucrose/10% ethanol was presented as the reinforcer and, in the second component, 5% sucrose was presented. Independent manipulations of the ethanol concentration (0, 5, and 20%) in the sucrose/ethanol solution or sucrose concentration (0, 10, and 20%) in the sucrose solution were then performed. Increasing the ethanol concentration in the sucrose/ethanol solution resulted in decreases in reinforcer delivery but increases in ethanol intake (grams per kilogram) and total session caloric intake. Increasing the sucrose concentration in the sucrose solution resulted in significant increases in sucrose reinforcer delivery and total session caloric intake. During the concentration manipulations, the number of reinforcers presented of the unchanged reinforcer was not affected. Differential changes in the pattern of reinforcer presentation after ethanol and sucrose concentration manipulations during successive access periods suggest that sucrose and sucrose/ethanol maintained responding are differentially regulated. Changes in sucrose maintained responding after increases in the sucrose concentration were observed early in the session suggesting a strong influence of taste in regulating intake. Changes in sucrose/ethanol maintained responding after increases in the ethanol concentration occurred later in the session and suggest that postingestive effects (i.e., pharmacology) play a major role in the regulation of sucrose/ethanol intake. In addition, the differential patterns of sucrose/ethanol and sucrose maintained behavior suggest that the ethanol component of the sucrose/ethanol solution plays an important role in maintaining sucrose/ethanol reinforced behavior.

Alcohol Drinking↗

PubMed1996

Effects of ventral tegmental microinjections of the GABAA agonist muscimol on self-administration of ethanol and sucrose.

Two groups of Long-Evans rats were trained to lever press on a fixed-ratio 4 (FR4) schedule of reinforcement with ethanol (10% v/v) or sucrose (75% w/v) presented as the reinforcer. After implantation of guide cannulae aimed at the ventral tegmental area (VTA), weekly bilateral injections of muscimol (10, 30, and 100 ng) were tested. During control conditions, response patterns for both groups were characterized by high rates that began shortly after the start of the session and terminated after approximately 10 min. Muscimol (10 ng) administration in the VTA increased the number of sucrose- but had no effect on the total number of ethanol-reinforced responses. Muscimol (30 ng) shifted the response patterns of both groups from high initial rates with early termination to slow initial rates with delayed termination, suggesting the possibility of nonspecific locomotor effects. These data suggest that ethanol- and sucrose-reinforced response totals are differentially sensitive to changes in GABAergic transmission in the VTA. The similar muscimol-induced changes in response patterns with the two reinforcers supports the hypothesis that GABAA receptors in the VTA are involved similarly in the maintenance of ethanol- and sucrose-reinforced responding. However, the failure of muscimol to increase ethanol-reinforced responding suggests that GABAergic systems in other brain regions may also be involved in the changes in ethanol intake seen following peripheral administration of GABAmimetic drugs.

Alcohol Drinking↗

PubMed1996

Discriminative stimulus function of ethanol: role of GABAA receptors in the nucleus accumbens.

Because the subjective effects of drugs may be related to abuse potential, this study was conducted to assess the involvement of GABAA receptor systems in the nucleus accumbens (N Acc) in the discriminative stimulus effects of ethanol. Male Long-Evans rats were trained to discriminate between intraperitoneal (IP) injections of ethanol (1 g/kg) and saline under a fixed-ratio 10 schedule of sucrose (10% w/v) reinforcement. When performance during training sessions met the accuracy criteria (> 80% correct responding for five consecutive days), an ethanol generalization curve was determined. The rats were then surgically implanted with bilateral stainless-steel guide cannulae aimed at the N Acc. Intra-accumbens (IA) substitution test sessions were conducted during which the direct GABAA agonist muscimol (0.01, 0.04, 0.10, and 0.40 micrograms/microliter; IA) was administered in combination with saline (IP). The direct GABAA antagonist bicuculline (0.03, 0.10, and 0.30 micrograms/microliter; IA) was administered in combination with the training dose of ethanol (1 g/kg, ip). At 10-min postinjection, IA muscimol partially substituted for IP ethanol. However, at 15-min postinjection, muscimol (0.10 microgram/microliter; IA) fully substituted for IP ethanol. Bicuculline attenuated the discriminative stimulus properties of IP ethanol, but only at doses that significantly decreased response rate. At 10-min postinjection, muscimol (0.01 and 0.04 micrograms/microliter) potentiated (> 80% ethanol lever responding) the discriminative stimulus properties of a dose of ethanol (0.5 g/kg) that alone produced only partial generalization. These data suggest that ethanol discrimination is mediated centrally and demonstrate that infusions of the GABAA agonist muscimol in the N Acc are sufficient to produce the stimulus effects corresponding to a 1.0 g/kg training dose of ethanol. When taken together with data showing that GABAA receptor activation in the N Acc potentiates the termination of ethanol self-administration, these data suggest that ethanol's discriminative stimulus function may influence its reinforcement function.

Alcohol Drinking↗

PubMed1996

Dopamine receptors in the medial prefrontal cortex influence ethanol and sucrose-reinforced responding.

This study tested the role of dopamine receptors in the medial prefrontal cortex (mPFC) in the onset, maintenance, and termination of ethanol and sucrose-reinforced responding. Two groups of Long Evans rats were trained to lever press on a fixed-ratio 4 schedule of reinforcement with 10% ethanol (n = 10) or 5% sucrose (n = 5) presented as the reinforcer. After implantation of injector guide cannulae, the D2/3 agonist quinpirole and the D2 antagonist raclopride were administered bilaterally into the mPFC before behavioral sessions. During control conditions, sucrose reinforcement maintained a 2-fold greater number of responses per session than did ethanol reinforcement. Quinpirole (10.0 micrograms/microliter) reduced total ethanol-reinforced responses by delaying response onset and decreasing the duration of responding, but had no effect on response maintenance (i.e., response rate). A higher dose of quinpirole (20.0 micrograms/microliter) decreased total sucrose responses by simultaneously decreasing duration and response rate, without altering response latency. Thus, the effects of quinpirole on ethanol and sucrose-reinforced responding were similar on response total and duration, but differential on response latency and rate. Raclopride (0.05 and 1.0 microgram/microliter) decreased total ethanol responding and rate, but doses as much as 400-fold greater (20.0 micrograms/microliter) did not alter sucrose response totals. Raclopride alone had no effect on response latency or duration measures in either reinforcement condition. Coadministration of raclopride blocked the quinpirole-induced increase in response latency (ethanol reinforcement) and decrease in response rate (sucrose reinforcement), but had no effect on other response measures. These data are consistent with the interpretation that D2 and D3 receptors in the mPFC are differentially involved in ethanol and sucrose response onset and maintenance, but similarly involved in response termination. However, differences in baseline response parameters and group size may have contributed to the observed effects.

Animals↗

PubMed1996

Norepinephrine and serotonin receptors in the paraventricular nucleus interactively modulate ethanol consumption.

The homeostatic function of the hypothalamus has long been recognized. In particular, the role of the paraventricular nucleus (PVN) in regulating ingestive behavior has been of interest. Infusions of serotonin and norepinephrine into the PVN are correlated with nutrient selective decreases and increases in consumatory behavior, respectively. Given the wide range of homeostatic functions of the hypothalamus, it is plausible that similar hypothalamic mechanisms may also be involved in the regulation of ethanol intake. This study examined the effects of PVN infusions of serotonin (5-HT) and norepinephrine (NE) on ethanol intake in a 1-hr limited-access two-bottle paradigm. When intake of 6% (v/v) ethanol versus water stabilized, male Wistar rats were implanted with stainless steel guide cannulae aimed at the PVN. After recovery, NE (20, 50, and 100 nmol), 5-HT (5 and 25 nmol), and their combination (NE 50 nmol + 5-HT 5 nmol) were microinjected into the PVN in a volume of 0.5 microliter/side over 1 min. Baseline ethanol intake was approximately 1.0 g/kg and ethanol preference (milliliters ethanol per total milliliters) was approximately 60%. Both 20 and 50 nmol of NE significantly increased absolute ethanol intake by 50% and relative ethanol intake by approximately 30%. Corresponding decreases were observed in water intake. Neither dose of 5-HT when administered alone altered ethanol or water consumption, but the 5-nmol dose of 5-HT attenuated the increase observed after NE (50 nmol) administration. These data demonstrate that NE and 5-HT receptors in the PVN interact in the modulation of ethanol ingestion. This finding suggests that homeostatic regulatory functions of the hypothalamus are involved in ethanol intake, and a perturbation of this system may influence excessive drinking.

Alcohol Drinking↗

PubMed1995

Morphine induced changes in ethanol-and water-intake are attenuated by the 5-HT3/4 antagonist tropisetron (ICS 205-930).

The opiate agonist morphine has been shown to increase ethanol intake and mesolimbic dopamine (DA) levels. Conversely, the 5-HT3/4 antagonist tropisetron has been shown to decrease ethanol intake and morphine-induced increases in mesolimbic DA levels. This study was designed to test the effects of acutely administered tropisetron on morphine-induced changes in ethanol (6% v/v) and water intake in a two-bottle test procedure. Ten water restricted male rats were injected with combinations of morphine (0.0, 0.56, 1.0, 1.5, 10.0, and 17.0 mg/kg, SC) and tropisetron (0.0, 1.0, 10.0, and 17.0 mg/kg, SC) prior to test sessions. Morphine (1.0 and 1.5 mg/kg) significantly increased absolute (g/kg) and relative ethanol intake (ethanol/total fluid). Tropisetron alone did not affect ethanol or water intake. When tropisetron (10.0 and 17.0 mg/kg) was administered in combination with morphine (1.5 mg/kg), the increase in ethanol intake induced by morphine was attenuated. Tropisetron (1.0 mg/kg) reversed a decrease in ethanol intake induced by morphine (17.0 mg/kg). The two highest doses of tropisetron partially attenuated a significant decrease in water intake produced by morphine (17.0 mg/kg). These data suggest that opiate and 5-HT3 mechanisms could interact in the regulation of ethanol intake. However, the doses of tropisetron tested were high and, therefore, the potential involvement of 5-HT4 receptors or other neurotransmitter systems in regulating ethanol intake is discussed.

Alcohol Drinking↗

PubMed1995

GABAergic transmission in the nucleus accumbens is involved in the termination of ethanol self-administration in rats.

Long-Evans rats (n = 12) were trained to lever-press on a fixed-ratio 4 schedule of reinforcement with ethanol (10% v/v) presented as the reinforcer. After implantation of bilateral stainless-steel guide cannulae aimed at the nucleus accumbens, site-specific microinjections of muscimol (1-30 ng) and bicuculline (1-10 ng) were tested for effects on ethanol-reinforced responding. Baseline response patterns were characterized by initial high rates that terminated abruptly after approximately 20 min. Muscimol administration in the nucleus accumbens decreased the total number of ethanol-reinforced responses and obtained reinforcers. Bicuculline also decreased ethanol-reinforced responses and reinforcers at the highest dose tested. When a dose of bicuculline (1 ng) that was ineffective by itself was coadministered with an effective dose of muscimol (10 ng), the muscimol-induced decreases in responding were blocked. Analysis of response patterns showed that muscimol decreased ethanol self-administration by terminating responding, normally lasting 20 min, after approximately 10 min with no changes in local response rate. Bicuculline decreased total responding by producing parallel, but nonsignificant, changes in time course and response rate. These data suggest that GABAergic transmission in the nucleus accumbens is involved in the termination, but not the onset or maintenance of ethanol self-administration. The specificity of this effect gives emphasis to the importance of measuring behavioral parameters, as well as products of behavior (such as intake volume) in the study of ethanol self-administration.

Alcohol Drinking↗

PubMed1994

Comparison of the discriminative stimulus function of ethanol following intracranial and systemic administration: evidence of a central mechanism.

Rats were trained using a two-lever drug discrimination procedure to press one lever following systemic administration of ethanol (1.0 mg/kg, IP) and another lever following IP injections of saline. After determination of an ethanol generalization curve (0.25-1.25 g/kg, IP), rats were surgically implanted with bilateral stainless steel guide cannulae that terminated in the lateral ventricles. Following surgery, the generalization curve was redetermined and did not differ from presurgery values. Then, generalization to bilateral intracerebroventricular (ICV) injections of ethanol (600.0 and 900.0 mM, 1.0 microliter/side) were administered alone and in combination with IP injections of ethanol. The ICV ethanol injections produced partial generalization, but the combination of ICV ethanol (600.0 and 900.0 mM) with IP ethanol (0.25 and 0.50 g/kg) injections were two- to threefold more potent then IP injections alone. Response rates were unaffected by any dose of ethanol tested. These data suggest central mediation of ethanol's discriminative stimulus function due to: 1) increased potency of systemically administered ethanol by centrally administered ethanol, and 2) partial generalization between centrally and peripherally administered ethanol.

Animals↗

PubMed1994

Effects of intraaccumbens injections of dopamine agonists and antagonists on sucrose and sucrose-ethanol reinforced responding.

The present experiment tested the effects of intraaccumbens injections of dopamine (DA) agonists and antagonists on operant responding reinforced by sucrose and sucrose/ethanol solutions. The mixed DA agonist d-amphetamine (20.0 micrograms/microliters) significantly reduced responding reinforced by a low concentration sucrose solution (2% w/v) by 48% and 38% compared to no injection and sham control values, respectively. The addition of ethanol (10%) to a low concentration sucrose solution (3%) presented as the reinforcer changed the response pattern from a continuous moderate response rate, over a 30 min session, to an initial high response rate that terminated after approximately 10 min. With sucrose/ethanol reinforcement, d-amphetamine slowed the initial high response rate but extended responding throughout the 30 min sessions. However, no significant changes were observed in number of responses per session. When 75% sucrose (w/v) was presented as the reinforcer, d-amphetamine did not change the total number of responses/session, but response patterns were again altered from high initial rates with early offset to slow steady rates that continued for the duration of sessions. The D2 DA antagonist raclopride (0.1-5.0 micrograms/microliters) resulted in a dose-dependent decrease in responding reinforced by 75% sucrose. The baseline patterns, response totals, and effects of the DA antagonists resemble our previously reported findings with 10% ethanol (v/v) reinforcement. These data support the conclusion that mesolimbic DA activity may be a common mechanism in ethanol reinforced behavior and behavior reinforced by other substances, but suggest that the nature of behavioral change may depend upon the reinforcer.

Animals↗

PubMed1993

Effect of dopamine agonists and antagonists on ethanol-reinforced behavior: the involvement of the nucleus accumbens.

Rats initiated to self-administer 10% ethanol (v/v) in an operant situation using the sucrose-substitution technique received bilateral n. accumbens or caudate nucleus microinjections of d-amphetamine (4, 10, and 20 micrograms/brain), quinpirole (4 micrograms/brain), and/or raclopride (0.1, 0.5, and 1.0 micrograms/brain). Only microinjections into the n. accumbens produced changes in rate and pattern of responding. With d-amphetamine, an increase in total responding and a slowing of initial response rate was seen, whereas with raclopride administration a dose-related decrease in total responding was observed with no alteration in momentary response rates. Drug-dependent behavioral rate and pattern differences suggest that DA activity in the n. accumbens influences ethanol reinforced behavior.

Analysis of Variance↗

PubMed1993

Ventral tegmental microinjections of quinpirole decrease ethanol and sucrose-reinforced responding.

The effects of microinjections in the ventral tegmental area (VTA) of the dopamine D2/D3 agonist quinpirole on ethanol- and sucrose-reinforced responding were tested. Two groups of Long-Evans rats were trained to lever press on a fixed-ratio 4 schedule with 10% ethanol (v/v) (n = 8) and 75% sucrose (w/v) (n = 10) presented as the reinforcer. Weekly bilateral injections of quinpirole were tested in the ethanol group (0.0, 0.001, 0.01, 0.1, and 1.0 micrograms/microliters) and sucrose group (0.0, 0.01, 0.1, 1.0, and 10.0 micrograms/microliters). Quinpirole dose dependently decreased ethanol- and sucrose-reinforced responding, but the dose-effect curve for sucrose was shifted two orders of magnitude to the right of the ethanol curve. Temporal response patterns during control sessions for both reinforcers were characterized by initial high rates that terminated after approximately 10 min. VTA injections of quinpirole dose dependently delayed the onset of the first response and the initial high rate period, and resulted in an early termination of responding following onset. These data support the hypothesis that dopamine activity in the VTA is involved in the regulation of ethanol-reinforced responding in a manner similar to that of other reinforcers.

Animals↗

PubMed1993

The role of the mesoaccumbens dopamine system in ethanol reinforcement: studies using the techniques of microinjection and voltammetry.

Microinjection of dopamine agonists and antagonists into both the n. accumbens and the ventral tegmental area were shown to alter ethanol reinforced responding. These data support that of others researchers in showning that the mesolimbic pathway is involved in the mechanisms underlying ethanol reinforcement. Studies using microvoltammetry suggest that ethanol's access into this pathway is not by direct stimulation of DA release from the terminal fields in the n. accumbens.

Animals↗

PubMed1992

Alcohol self-administration: role of mesolimbic dopamine.

It appears clear that ethanol reinforcement, like that of many abused drugs, utilizes the mesolimbic DA pathways. From the data presented on microinjection of DA agonists and antagonists, it would seem that only part of the regulatory process controlling ethanol drinking is directly involved with this pathway. Once drinking has begun, the DA antagonist raclopride results in a rapid termination of drinking. This appears to be a blocking effect of what may be conditioned reinforcement resulting from prior ethanol reinforcement initiation procedures. Microinjection of the DA agonists d-amphetamine and quinpirole prolonged drinking, with little signs of normal termination apparent in the 30-min session in many animals. This appeared to be the result of interference with normal termination processes. While it remains to be demonstrated that oral ethanol consumption results in the release of DA in the nucleus accumbens, evidence from prior work and the present studies support a role for the mesolimbic DA system in ethanol reinforcement.

Alcoholism↗

PubMed1992

Microinjections of dopamine agonists in the nucleus accumbens increase ethanol-reinforced responding.

Long-Evans rats (N = 3) were trained to lever press on a fixed-ratio 4 (FR 4) schedule with ethanol (10% v/v) presented as the reinforcer. Each rat received a total of six bilateral nucleus accumbens microinjections, one per week. They were tested with one physiological saline control, three 20.0-microgram/brain d-amphetamine, and two 6.0-microgram/brain quinpirole injections given 10 min prior to operant sessions. Ethanol-reinforced responding terminated after approximately 10 min during control sessions. Microinjections of the D2 agonist quinpirole and the nonspecific dopamine (DA) agonist d-amphetamine increased total responding but produced slowed response rates that continued for 45-60 min. The slowed response rate produced by d-amphetamine resulted in a peak increase in interresponse times (IRTs) between 8-10 s, whereas quinpirole increased IRTs in the 14- to 16-s range, indicating that nonspecific DA activation resulted in higher rates of ethanol-reinforced responding than specific D2 activation although both drugs decreased local response rates. These data indicate that the amount and temporal extent of ethanol-reinforced responding are increased by microinjections of DA agonists in the nucleus accumbens and support the hypothesis that DA activity in this region is involved in the regulation of ethanol-reinforced responding.

Animals↗

PubMedDate not supplied

Effects of morphine on acquisition and maintenance of ethanol and water intake patterns in rats.

Two experiments were conducted to assess the effects of chronic subcutaneous injections of morphine (1.0 mg/kg) or saline on the pattern and amount of sweetened ethanol and water intake in fluid restricted Long-Evans rats. Following daily injections, 2-h two-bottle choice tests were conducted with water and an ethanol solution (15% ethanol v/v in 5% sucrose w/v). During a 20-day acquisition phase (Experiment 1), ethanol intake patterns and amounts did not differ between saline (n = 6) and morphine (n = 6) groups. Both groups exhibited ethanol intake patterns that decreased exponentially throughout the session suggesting control by fluid restriction procedures. Morphine decreased water intake during initial periods of each session and increased intake during later periods. In Experiment 2, morphine and saline injections were reversed across three phases with the same rats. Morphine increased total ethanol consumption during the first few days of each 15-day phase, but the groups did not differ thereafter, and the initial increases produced no statistically significant group differences. Additionally, morphine augmented ethanol intake in early portions of sessions, while water intake was decreased and increased during early and later portions of each session, respectively. Analysis of the data from the last 5 days of each phase indicated that, when injected with morphine, the group which received saline during acquisition consumed significantly more ethanol solution than the group injected with morphine during acquisition. The effect on patterns of water and ethanol intake were observed, regardless of the drug injected during acquisition.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗

PubMedDate not supplied

Specific decreases in ethanol- but not water-reinforced responding produced by the 5-HT3 antagonist ICS 205-930.

The serotonin 5-HT3 antagonist ICS 205-930 has been shown to block the discriminative stimulus properties of ethanol and decrease voluntary intake, suggesting a possible role for 5-HT3 systems in the reinforcing effects of ethanol. ICS 205-930 (0.56, 1.0, 3.0, 10.0, and 17.0 mg/kg i.p.) was examined on ethanol and water self-administration in an operant paradigm. Following a sucrose-fading procedure, two groups of nondeprived rats responded on either a concurrent fixed ratio 4 schedule for ethanol (10% v/v) and water (CONC FR4 FR4), or a single FR4 schedule for ethanol (10% v/v). ICS 205-930 dose-dependently decreased ethanol-reinforced responding in the concurrent condition without decreasing water-reinforced responding, suggesting a specific effect on ethanol. Ethanol-reinforced responding was also dose-dependently decreased in the single FR4 condition, but the dose effect curve was shifted to the left. These data support the conclusions that 5-HT3 systems may play a specific role in ethanol self-administration that is independent of general appetitive and motor processes, and that 5-HT3 antagonists may have therapeutic efficacy in the treatment of alcohol abuse when multiple reinforcers are available.

Alcohol Drinking↗

PubMedDate not supplied

Dopaminergic and opiate agonists and antagonists differentially decrease multiple schedule responding maintained by sucrose/ethanol and sucrose.

Similar neurobiological mechanisms are hypothesized to influence ethanol- and food-related reinforcement processes. This study examined the ability of compounds with dopaminergic or opiate activity to selectively alter responding maintained by a sucrose/ethanol solution in comparison to a sucrose solution. Long-Evans rats were trained to press a lever using 5% sucrose/10% ethanol and 5% sucrose as the reinforcers on a multiple Fixed Ratio 4 Fixed Ratio 4 schedule of reinforcement. When stable responding was established, the effects of intraperitoneally administered amphetamine (0.0-3.0 mg/kg), haloperidol (0.0-1.0 mg/kg), morphine (0.0-10.0 mg/kg), and naloxone (0.0-10.0 mg/kg) were examined on total session reinforcer presentation and presentation of each reinforcer within individual multiple schedule components. Prior to drug treatment, the total number of reinforcer presentations of the sucrose/ethanol solution was significantly greater than sucrose reinforcer presentations, suggesting the sucrose/ethanol solution was a more efficacious reinforcer. All agents administered decreased responding maintained by sucrose/ethanol and sucrose. The dose-effect curves for sucrose/ethanol were shifted to the left compared to sucrose, suggesting that although the compounds did not selectively impact sucrose/ethanol-maintained responding, sucrose/ethanol-maintained responding was more sensitive to the effects of these compounds.

Amphetamine↗