Behavioural profile of partial D2 dopamine receptor agonists. 1. Atypical inhibition of d-amphetamine-induced locomotor hyperactivity and stereotypy.

The effects of partial D2 dopamine (DA) receptor agonists on the behavioural activation produced by 1.5 and 8.0 mg/kg d-amphetamine were compared with the changes produced by the classical DA antagonist haloperidol. Alterations in behaviour were assessed in standard activity monitoring cages by direct observation of the rats using a rapid time sampling procedure. Haloperidol blocked d-amphetamine (1.5 mg/kg)-induced increases in photocell counts, ambulation, rearing and sniffing up, and after the highest dose of the DA antagonist the animals were mainly inactive. The partial D2 DA agonist SDZ 208-911 was equipotent to haloperidol in blocking the increase in photocell counts and rearing produced by d-amphetamine. However, even high doses of the drug did not reduce the incidence of sniffing or induce inactivity, but qualitative changes in the form of sniffing did occur. Although considerably less potent, preclamol exerted similar effects to SDZ 208-911. The profiles of SDZ 208-912 and terguride were intermediary to those of SDZ 208-911 and haloperidol. All compounds blocked the repetitive sniffing down produced by 8.0 mg/kg d-amphetamine. After a low dose of haloperidol, these stereotyped behaviours were replaced by a behavioural syndrome similar to that observed with low dose d-amphetamine, but inactivity was observed following a further small increase in antagonist dose. The blockade of stereotypy by SDZ 208-911, preclamol and terguride was accompanied only by the low dose d-amphetamine behavioural syndrome; no inhibition of sniffing or induction of inactivity occurred. SDZ 208-912 exhibited a profile with features very similar to that noted with haloperidol. These findings suggest that partial D2 agonists exert similar, but not identical, behavioural effects to classical DA antagonists when dopaminergic function in increased by d-amphetamine. The differences in behavioural profile are discussed in relation to variations in the intrinsic efficacy of the dopaminergic compounds and to differences in the response capability of D2 receptor populations underlying the different behaviours produced by d-amphetamine.

Substance P release from rat nucleus accumbens and striatum: an in vivo study using antibody microprobes.

Antibody-coated microprobes have provided evidence for the release of neuropeptides in localized regions of the cat spinal cord. We have applied this method to study the release of substance P (SP) from different regions of the rat brain. Anti-SP microprobes were inserted (to a depth of 8 mm) through cortex, striatum, and nucleus accumbens of halothane anaesthetised rats and remained in situ for 10 min. Microprobes (4 control and 10 post-treatment, per rat) were then incubated with 125I-SP and an autoradiographic image produced. In the region of the nucleus accumbens immunoreactive (ir) SP was detected during the first 30 min after intraperitoneal injection of d-amphetamine (4 mg/kg, P < 0.05) but not following saline (P > 0.05). During this time, no release of ir SP was seen over areas of the probes that corresponded to the striatum. At later time intervals (1-4 h) after amphetamine, binding of ir SP was detected along the whole length of the microprobes. Release of SP is thought to be due to the action of dopamine on postsynaptic cells containing this peptide. The later spread of the peptide requires further study.

In vivo detection of immunoreactive neurokinin A release within rat substantia nigra and its dependency on a dopaminergic input.

In the striatum, the tachykinin peptide neurokinin A (NKA) is thought to coexist with substance P in the gamma-aminobutyric acid-containing spiny neurones which project to the substantia nigra. We have used in vivo antibody-coated microprobes to directly monitor the release of NKA-like immunoreactivity (NKA-LI) within substantia nigra during various pharmacological manipulations. The data clearly illustrates a basal or resting extracellular presence of NKA-LI restricted to substantia nigra reticulata which was found to be largely dependent on a dopaminergic input. Acute administration of haloperidol (0.1-0.2 mg/kg i.p.) considerably reduced this basal NKA-LI whereas depot administration (14 mg/kg i.m. released over 2 weeks) produced a less substantial reduction. Lesion of nigro-striatal dopamine neurones with the neurotoxic agent 6-hydroxydopamine produced significant reductions in the nigral NKA-LI detected. However, d-amphetamine administration (4 mg/kg i.p.) did not alter the pattern of NKA-LI release for up to 4 h posttreatment. These results indicate that changes in peptide mRNA levels do not necessarily reflect changes in peptide release and suggest that NKA may be the more physiologically relevant tachykinin within the substantia nigra of the rat.

Role of dopamine D1 and D2 receptors in mediating the d-amphetamine discriminative cue.

The role of D1 and D2 dopamine (DA) receptors in mediating the discriminative cue produced by d-amphetamine (0.5 mg/kg) in rats has been assessed by using compounds which exert strong selectivity for each of these DA receptor subtypes. The D2 agonists quinpirole and RU 24213 substituted completely for d-amphetamine, while the D1 agonists SKF 38393 and SKF 81297 failed to exert such effects. On the other hand, the D2 antagonists raclopride and YM 09151-2, and D1 antagonists SCH 23390 and SKF 83566, all completely blocked d-amphetamine discrimination. The D2 antagonists produced more pronounced inhibitory effects on response rate than did D1 antagonists. Quinpirole substitution for d-amphetamine was blocked by YM 09151-2, but not by SCH 23390, while the locomotor stimulatory effect of quinpirole was inhibited by both drugs. The present findings confirm that D2 receptors play a primary role in the d-amphetamine discriminative cue, while the precise role of D1 receptors remains to be disclosed.

Effects of the dopamine autoreceptor antagonist (-)-DS121 on the discriminative stimulus properties of d-amphetamine and cocaine.

(-)-DS121 [S-(-)-3-(3-cyanophenyl)-N-n-propyl piperidine) is a recently synthesised phenylpiperidine derivative suggested to be a dopamine receptor antagonist acting preferentially at dopamine autoreceptors. The drug exerts 'agonist-like' behavioural effects by enhancing dopamine release, but also shares properties in common with neuroleptics. The ability of (-)-DS121 to both generalise to and antagonise the stimulus effects of psychostimulants was determined in rats trained to discriminate d-amphetamine (0.5 mg/kg) or cocaine (5.0 mg/kg) from saline in a two-lever, food-reinforced, drug discrimination task. (-)-DS121 (3.5-14.0 mg/kg) produced small, but significant, increases in drug lever-appropriate responding in both d-amphetamine and cocaine-trained rats. However, there was no indication of a dose-dependent effect in either case. On the other hand, (-)-DS121 dose-dependently reduced response rate. Caffeine produced a higher level of drug lever-appropriate responding than (-)-DS121 in d-amphetamine-trained rats. (-)-DS121 (7.0-14.0 mg/kg) also weakly antagonised the cueing properties of both d-amphetamine and cocaine. A marked response disruption with the drug combination precluded testing of higher doses of (-)-DS121. A combination of subthreshold doses of (-)-DS121 (3.5 mg/kg) and d-amphetamine (0.0625 mg/kg) produced a significant degree of drug lever-appropriate responding, suggesting a synergistic interaction between these drugs. However, such an interaction was not noted with a higher dose of (-)-DS121, or when this drug was administered with a low dose of cocaine (0.25 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitory effects of partial D2 dopamine receptor agonists on the d-amphetamine discriminative cue.

The ability of partial dopamine (DA) receptor agonists with low relative efficacy to inhibit the d-amphetamine discriminative cue has been determined in rats trained to discriminate 0.5mg/kg d-amphetamine from saline. The classical neuroleptic haloperidol and selective D1 antagonist SCH 23390 potently blocked the cueing properties of d-amphetamine. A complete blockade of d-amphetamine discrimination was also observed with the partial DA agonist terguride. In contrast, preclamol [(-)-3-PPP] and SDZ 208-911 produced only a partial inhibition which was characterized by an asymptotic drug effect across a wide dose range. Clear variations in the sensitivity of individual rats to the inhibitory effects of preclamol on the d-amphetamine cue were observed. Some rats were sensitive to even low doses of preclamol, while others were minimally affected across the dose range. Variations in individual response were also observed with SDZ 208-911 and terguride, but not with haloperidol or SCH 23390. The present findings are discussed in relation to the partial agonist profile of preclamol, SDZ 208-911 and terguride and to possible underlying differences in DA receptor sensitivity between individual rats.

Probing the brain and spinal cord with neuropeptides in pathways related to pain and other functions.

The principles involved in the fabrication and use in vivo of antibody microprobes are described. These devices have shown that immunoreactive (ir)-substance P and ir-neurokinin A are released in the region of the substantia gelatinosa of the spinal cord when impulses arrive in nociceptors. Particularly with ir-neurokinin A, rapid inactivation does not appear to occur, resulting in the released neuropeptides accessing sites relatively remote from sites of release. Microprobes have also provided evidence that the sites accessed by ir-substance P are controlled by spinal cord peptidases and that peptidase inhibition by the endogenous neuropeptide calcitonin gene-related peptide expands the distribution of sites reached. Inflammatory joint disease results in a relatively massive central release of ir-substance P when the damaged joints are flexed or compressed. Antibody microprobe studies of the spinal release of ir-galanin have favored release from intrinsic spinal neurons rather than from primary afferent terminals following peripheral noxious stimuli. Immunoreactive-somatostatin was found to be released following noxious thermal but not noxious mechanical peripheral stimuli but it is uncertain whether this results from release predominantly from primary afferents or intrinsic spinal neurons. Studies using antibody microprobes inserted into the brain have detected the release of ir-substance P in the ventral region of the striatum following administration of amphetamine. Microprobes have also followed peptide release from striatal terminals in substantia nigra and have provided evidence of a basal presence of ir-neurokinin A but not of substance P. Depletion of the dopamine input to the striatum, or blockade of dopamine receptors, caused considerable reduction of ir-neurokinin A released within the substantia nigra.