Buspirone, gepirone, ipsapirone, and zalospirone have distinct effects on the differential-reinforcement-of-low-rate 72-s schedule when compared with 5-HTP and diazepam.

The effects of four serotonin (5-HT)-1A compounds (buspirone, gepirone, ipsapirone and zalospirone) were compared with 5-hydroxytryptophan (5-HTP) [a 5-HT precursor with antidepressant (AD) efficacy], and diazepam (a benzodiazepine anxiolytic), on a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule. Past research has shown that AD and anxiolytic compounds each have distinct effects on the DRL 72-s interresponse time (IRT) distribution profile. In the present paper, the profile of the IRT distribution was quantitatively characterized by three metrics: burst ratio, peak location and peak area. 5-HTP shifted the IRT distribution peak toward longer IRT durations, increased reinforcement rate and decreased response rate. The profile of the IRT distribution was not disrupted by 5-HTP. Diazepam disrupted the IRT distribution and increased bursting. In general, the arylpiperazine, 5-HT1A compounds increased reinforcement rate, decreased response rate and disrupted the profile of the IRT distribution. The effects of the four arylpiperazine 5-HT1A compounds on the IRT distribution profile were different from the AD profile of 5-HTP and the benzodiazepine anxiolytic profile of diazepam. Disruption of the IRT distribution by buspirone, gepirone, ipsapirone and zalospirone may result from decreased 5-HT transmission mediated by the presynaptic, somatodendritic 5-HT1A receptor.

Comparison of the effects of mianserin and its enantiomers and metabolites on a behavioral screen for antidepressant activity.

The behavioral effects of racemic mianserin, its (+) and (-) enantiomers, and its metabolites desmethylmianserin and 8-hydroxymianserin were evaluated on the differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule, a screen known to be sensitive to and specific for the antidepressant properties of drugs. Racemic mianserin produced the antidepressant-like effect (increased reinforcement rate, decreased response rate) at 5 and 10 mg/kg. The mianserin enantiomers showed the antidepressant-like effect beginning at lower doses [(+) mianserin; 0.6 mg/kg; (-) mianserin: 2.5 mg/kg]. The mianserin metabolites showed no clear dose-related effect at doses up to 10 mg/kg. It is concluded that the antidepressant-like effects of mianserin are due to the activity of the parent compound rather than to its metabolites, and that they may be primarily attributable to the (+) enantiomer. The greater potency of (+)-mianserin may be related to its higher affinity for the 5-HT2 receptor.

Antidepressant-like effects of trazodone on a behavioral screen are mediated by trazodone, not the metabolite m-chlorophenylpiperazine.

Trazodone is an atypical antidepressant drug (i.e. blocks neither monoamine uptake nor monoamine oxidase) which tests as an antidepressant drug on the differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule of reinforcement by increasing the reinforcement rate and decreasing the response rate. m-Chlorophenylpiperazine (m-CPP) is a 5-HT1B and 5-HT1C agonist, weak 5-HT2 antagonist, and trazodone metabolite. It has been suggested that formation of m-CPP is responsible for the antidepressant action of trazodone. Administration of m-CPP (1-10 mg/kg i.p.) 60, 30 or 10 min before the behavioral session did not mimic the reinforcement rate-increasing effects of trazodone (10-20 mg/kg i.p.) on rats performing under the DRL 72-s schedule of water reinforcement. Pretreatment with proadifen (50 mg/kg i.p.), an inhibitor of trazodone metabolism, caused a greater than 30-fold leftward shift in the dose-response curve for both the reinforcement rate and the response rate. These results suggest that the parent compound and not the trazodone metabolite m-CPP, mediates the antidepressant-like effects of trazodone on DRL 72-s behavior.

Differential mechanisms in the acquisition and expression of heroin-induced place preference.

These experiments examined the neurochemical mechanisms involved in the development and expression of place conditioning produced by heroin. Conditioned place preferences (CPP) lasting up to 8 weeks were obtained with doses of 50-1000 micrograms/kg heroin, using a regimen shown not to produce physical dependence. Naloxone pretreatment (50 micrograms/kg) during conditioning prevented the acquisition of heroin-induced CPP, but when given only on the test day, naloxone (50 or 1000 micrograms/kg) did not prevent the expression of heroin CPP. Clonidine disrupted the establishment of heroin CPP at 20 micrograms/kg, but disrupted its expression only at debilitating doses (100 and 200 micrograms/kg). Pimozide attenuated the acquisition (100 micrograms/kg) and expression (250 micrograms/kg) of heroin CPP. Together, these results support a role for opioid and catecholamine systems in the acquisition of heroin reinforcement, but they suggest that once heroin CPP is established, its expression in opiate-free subjects is not opiate receptor mediated and is relatively refractory to pharmacological treatments which disrupt acquisition. The data challenge the notion that the conditioned effects of opiates in drug-free animals are related to the release of endogenous opioids, and they also may help to explain why naloxone and clonidine are ineffective in the treatment of opiate addiction.

Aversive properties of opiate receptor blockade: evidence for exclusively central mediation in naive and morphine-dependent rats.

The motivational effects of exclusively peripheral or central opiate receptor blockade were studied using place conditioning. Place aversions were observed with intraventricular (i.c.v.) methylnaloxone (MN) in both naive (200-1000 ng) and morphine-dependent rats (50-500 ng). Subcutaneous MN (0.03-10 mg/kg) was ineffective in naive rats; in dependent rats a small aversion was seen at the highest dose. Place aversions were not necessarily associated with behavioral signs of withdrawal. The data suggest that the aversive properties of opioid receptor antagonism are centrally mediated in both naive and dependent rats, and that their enhancement in morphine-dependent subjects results from a sensitized central mechanism rather than from the recruitment of a peripheral component.

Differential effects of acute clozapine and haloperidol on the activity of ventral tegmental (A10) and nigrostriatal (A9) dopamine neurons.

Extracellular single-unit recording techniques were used to evaluate the effects of acute intravenous (i.v.) clozapine (CLOZ) and haloperidol (HAL) on the activity of dopamine (DA) neurons of the ventral tegmental area (VTA or A10) and the substantia nigra pars compacta (SNC or A9). CLOZ increased the firing rate of A10 but not A9 cells, and drove 9/23 (39%) of A10 cells into an apparent depolarization blockade. HAL, on the other hand, produced a rate elevation and, at higher doses, depolarization inactivation in both subpopulations of DA neurons. Cell firing was restored in inactivated cells with i.v. apomorphine (APO) or iontophoretic GABA. CLOZ always fully reversed APO-induced suppression of A10 DA activity, but in many cases only partially reversed suppression of A9 DA neurons. Scopolamine did not mimic the effects of CLOZ on A10 neurons, and it also failed to block the activating effect of HAL on A9 units, indicating that the selective action of CLOZ cannot be interpreted simply by its anticholinergic properties. After hemi-transections of the diencephalon, which severed the medial forebrain bundle and other feedback pathways to the DA somata, CLOZ was still ineffective in altering A9 DA activity. This suggests that the lack of effect on CLOZ on A9 cells is not due to the inhibitory influence of forebrain feedback pathways. This hemi-transection also left intact the activation of A10 neurons produced by HAL and CLOZ, but it did prevent the excitatory action of HAL on most A9 neurons sampled. This indicates that forebrain feedback pathways are less critical in mediating the action of APDs on A10 DA neurons. Finally, iontophoretic application of CLOZ and HAL into the vicinity of DA cell bodies blocked the rate-reducing effects of locally applied DA, but not those of GABA. This suggests that both APDs block somatodendritic DA autoreceptors. However, HAL was considerably more potent than CLOZ in producing this blockade. It is suggested that the different pharmacological and clinical properties of HAL and CLOZ may be partially explained by a differential mode of action on the A10 and A9 subpopulations of DA cells. The data also provide pharmacological evidence that these 2 groups of DA cells are regulated by different mechanisms.

Effects of acute thioridazine, metoclopramide and SCH 23390 on the basal activity of A9 and A10 dopamine cells.

Extracellular single-unit recording techniques were employed to examine the effects of various dopamine (DA) antagonists on the basal activity of spontaneously active DA cells. Metoclopramide and thioridazine were both effective in reversing apomorphine-induced suppression of A9 and A10 DA cells. SCH 23390 produced only a partial reversal of this suppression. When the antagonists were given without any pretreatment, thioridazine preferentially increased the firing rate of A10 DA cells, and was relatively ineffective in altering A9 activity. Metoclopramide, on the other hand, increased the activity of most A9 DA cells, but was less effective in doing so with A10 cells. SCH 23390 did not significantly affect the basal activity of either cell subpopulation. These data support the hypothesis that the so-called 'atypical' antipsychotic drugs act preferentially on the A10 DA system. Taken together with previous results, they also suggest that the acute effects of DA antagonists on DA cell subpopulations coincide with their chronic effects.

Associative factors in the effects of morphine on self-stimulation.

These experiments tested the hypothesis that the suppressing and facilitating effects of morphine on intracranial self-stimulation (ICS) (measured 1 h and 3 h post-injection, respectively) are influenced by associative, non-pharmacological factors. Experiment 1 confirmed previous demonstrations that the facilitation of ICS by morphine (10 mg/kg) develops with repeated drug exposures. Once ICS facilitation had developed, the effect was mimicked by saline injection in most subjects. In a separate group of animals, previous exposure to morphine in the home cage prevented drug-induced facilitation of ICS. Tolerance to ICS suppression developed after repeated pairings of the drug and the ICS chambers, but not when the drug had previously been received in the home cage. Experiment 2 examined the effect of low (0.3, 1, 3 mg/kg) doses of chronic morphine on ICS. Facilitation was observed with 1 and 3 mg/kg, but only after repeated testing. Naloxone (0.1 and 1 mg/kg) failed to reverse facilitation in a number of these subjects. In Experiment 3, animals receiving their daily injections of morphine were allowed to self-stimulate only at 3 h post-injection (when ICS facilitation is usually maximal), rather than at 1 h and 3 h post-injection. ICS facilitation was not observed, even with repeated testing. These data indicate that the facilitation of ICS by morphine is the outcome of a learned association between drug administration and the ICS procedure, rather than the invariable result of opiate receptor activation. Repeated exposure to morphine is required for the initial establishment of ICS enhancement, but the subsequent expression of this behavior is not directly related to opiate receptor activity.

Lesions of ventral tegmental dopamine neurons delay the development of tolerance to morphine catalepsy.

Selective lesions of the dopamine (DA) neurons of the ventral tegmental area (VTA) were found to substantially delay the development of tolerance to morphine-induced catalepsy, in comparison with sham-operated controls receiving morphine. Lesioned subjects receiving vehicle injections showed no catalepsy. The data suggest that tolerance to morphine catalepsy requires intact VTA DA neurons. Furthermore, since the acute cataleptic response was intact in lesioned animals, the data suggest that the mechanisms involved in the cataleptic response to morphine are dissociable from those which bring about tolerance to that response.

6-OHDA lesions of the ventral tegmental area block morphine-induced but not amphetamine-induced facilitation of self-stimulation.

The biphasic effect of morphine on intracranial self-stimulation (ICSS) (suppression followed by facilitation) was examined in rats following injections of 6-OHDA or vehicle into the ventral tegmental area (VTA). During 7 days of chronic administration of morphine, sham-lesioned animals gradually developed tolerance to the rate-reducing effects of the drug and a concurrent sensitization to its rate-enhancing effects (measured 1 and 3 h post-injection, respectively). VTA lesioned rats showed neither tolerance to the rate suppression nor any facilitation of ICSS throughout testing. Amphetamine's facilitation of ICSS remained intact in all subjects. The lesion was restricted to the VTA cell bodies but produced a significant depletion of dopamine (DA) in both the nucleus accumbens and in the striatum. Morphine facilitation of ICSS is suggested to be dependent on an indirect opiate receptor-VTA DA cell interaction. It is also proposed that amphetamine facilitation of ICSS is a 'mass action' effect involving the full DA terminal area of the forebrain rather than a subregion of that area.

The influence of amphetamine on preference for lateral hypothalamic versus prefrontal cortex or ventral tegmental area self-stimulation.

Rats were trained to bar-press for intermittent reinforcement on a concurrent schedule offering self-stimulation (SS) at the animal's choice of one of two different brain loci. On the concurrent schedule, the relative reward value of the two reinforcers is evaluated by the way the subject divides its session time responding for these reinforcers, thus yielding a rate-free measure of reward in addition to response rate data. In animals with electrodes in the lateral hypothalamus (LH) and prefrontal cortex (PFC), amphetamine dose-dependently increased response rates as well as the proportion of time allotted to LH stimulation, demonstrating that the reward value of LH stimulation was increased relative to PFC stimulation. This finding supports the hypothesis that DA systems modulate the rewarding value of LH but not PFC SS, and it suggests that differing neural mechanisms underlie these two behaviors. In animals with LH/ventral tegmental area (VTA) implants, amphetamine had no effect on preference, although it produced an overall increase in rate. This suggests that the drug elevates the rewarding value of LH and VTA stimulation to a similar degree, and that the two regions may have a common DA-related reward substrate. Finally, it was found that when the two reinforcers were equally preferred (50% session time allotted towards each reinforcer), response rates for the two rewards were not necessarily equal. This confirms that SS response rate is not a simple function of reward magnitude.