Baclofen attenuates the reinforcing effects of cocaine in rats.

The effect of the GABAB agonist baclofen on cocaine self-administration in the rat was investigated. In the first experiment, rats trained to self-administer i.v. cocaine (1.5 mg/kg/inj) on a progressive ratio (PR) schedule were pretreated with various doses of baclofen (1.25, 2.5, or 5.0 mg/kg). Baclofen produced a dose-dependent decrease in the break points. In the second experiment, baclofen (2.5 mg/kg) was found to decrease significantly break points across a series of unit injection doses of cocaine (0.18, 0.37, 0.75, 1.5 mg/kg/inj). Baclofen produced only modest effects on food-reinforced responding even at the largest dose tested (5.0 mg/kg). These data suggest that baclofen may produce a specific attenuation of cocaine reinforcement. Baclofen produced no significant change in the rate of i.v. cocaine intake on a fixed ratio (FR 1) schedule. These data support a number of recent observations that rate of drug intake may be an insensitive measure of changes in the motivation to self-administer cocaine.

The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats.

Although it has been demonstrated that many of the behavioral responses to psychomotor stimulants are gender dependent and hormonally sensitive, few studies have examined the possibility that the estrous cycle interacts with drug reinforcement in laboratory animals. The present experiment assessed the effect of the estrous cycle on two aspects of cocaine self-administration behavior: the breaking point on a progressive ratio (PR) schedule and the rate of cocaine intake on a fixed ratio one (FR1) schedule. On the PR schedule, the first lever response produced a drug infusion. Subsequent response requirements escalated with each injection until the behavior extinguished. Breaking points were defined as the final ratio completed. On a FR1 schedule, the estrous cycle had no effect on the rate of drug intake. On a PR schedule, female rats reached higher breaking points during estrus than during other stages of the estrous cycle. Furthermore, female rats displayed higher breaking points than male rats. It appears that the estrous cycle influences an animal's motivation to self-administer cocaine.

Failure to replicate the dorsal bundle extinction effect: telencephalic norepinephrine depletion does not reliably increase resistance to extinction but does augment gustatory neophobia.

Depletion of telencephalic noradrenaline (Ne), caused by lesion of the dorsal tegmental bundle, has been reported to increase persistence of non-reinforced responding in various operant tasks. This has been referred to as the dorsal bundle extinction effect (DBEE). In an effort to reproduce this effect, rats receiving 6-hydroxydopamine lesions of the dorsal Ne bundle (DB-6-OHDA) were compared to controls during extinction of a continuous food rewarded (CRF) lever-press response. While the lesion group showed an increase in responding during initial extinction, no significant difference in resistance to extinction using a 2-min non-response criterion was obtained. Moreover, no differences in reinforced response rates were observed with CRF, fixed ratio (FR-15, FR-30, FR-60) or variable interval (VI-30, VI-60, VI-120 s) schedules of reinforcement. In order to test the hypothesis that the DBEE is dependent on time of behavioral testing after surgery, subsequent experiments were performed where rats began CRF operant training 5, 17, 31 or 110 days post-lesion. No differences in resistance to extinction were observed between lesion and control rats at any post-lesion interval. Neonatal treatment with 6-OHDA which permanently lesions forebrain Ne terminals also failed to prolong extinction. Finally, when both DB-6-OHDA and neonatal rats were given a choice between water and saccharin the lesioned animals exhibited a neophobic reaction whereby they drank significantly less saccharin. We conclude that while the DBEE is not a reliably reproducible phenomenon other effects of forebrain Ne lesions, such as neophobia, appear to be robust.

Increased self-administration of cocaine following haloperidol: effect of ovariectomy, estrogen replacement, and estrous cycle.

Rats which have been trained to self-administer cocaine intravenously show a dose-dependent increase in drug intake when pretreated with dopamine antagonists. This neuroleptic-induced increase in cocaine intake may be related to the antipsychotic potency and suggests that self-administration behavior may provide a useful model for evaluating neuroleptic activity. The present study examines the influence of ovarian hormones on the potency of the neuroleptic haloperidol using the cocaine self-administration model. It was found that the potency of haloperidol fluctuated across the estrous cycle with subjects in diestrus self-administering more cocaine than animals tested in estrus or proestrus. It was also demonstrated that the potency of haloperidol was reduced significantly following ovariectomy (OVX), however this OVX-induced attenuation could not be reversed with a number of estrogen or catechol-estrogen treatments. To the extent that the self-administration model can reflect the potency of antipsychotic drugs, these data indicate that ovarian function can affect neuroleptic activity, although the hormone(s) involved remain unclear. The clinical implications of these data underscore the need to further examine the influence of female sex hormones on the therapeutic efficacy of antipsychotic drugs.

Increased self-administration of cocaine following haloperidol: sex-dependent effects of the antiestrogen tamoxifen.

Intravenous self-administration of cocaine is extremely sensitive to the effects of antipsychotic drugs, making this behavior a useful screen for neuroleptic potency. A possible interaction between female sex hormones and antipsychotic activity was investigated, using increased rates of cocaine self-administration as a measure of neuroleptic action. We found that female rats were more sensitive to haloperidol than were male rats. Female rats treated with a single injection of the antiestrogen tamoxifen 24 hr prior to test showed a significantly reduced response to haloperidol. The normal response was found to have recovered by one week following the tamoxifen treatment. Tamoxifen had no significant effect in male rats. These data, along with previous observations, indicate that ovarian function can greatly influence the behavioral response to antipsychotic drugs. To the extent that the self-administration model may reflect the potency of an antipsychotic drug, these data may indicate that female rats are more sensitive to the activity of neuroleptic drugs. Secondly, pretreatment with tamoxifen results in a significant attenuation of the activity of haloperidol.