Rats were given powdered diet containing L-DOPA (together with the peripheral decarboxylase inhibitor carbidopa) for a period of 6 months. The estimated daily intake was in the range 20-30 mg/kg. Initially, at 1 week and 1 month, L-DOPA-fed rats exhibited enhanced spontaneous locomotor activity, but this fell to within the control range by 3 and 6 months, although (+)-amphetamine-induced hyperactivity was greater at 6 months in L-DOPA-treated animals than in control rats. Six months after receiving L-DOPA in their diet rats showed enhanced stereotypy scores to a series of dopamine agonists administered acutely including (+)-amphetamine, nomifensine, L-DOPA, apomorphine and piribedil compared with the control animals. In another behaviour test L-DOPA administration reduced the cataleptic potency of both fluphenazine and haloperidol was increased. Biochemically 6 months treatment of rats with L-DOPA was associated with significantly increased plasma concentrations of L-DOPA, enhanced striatal levels of L-DOPA, dopamine and dopamine metabolites, enhanced specific binding (as indicated by increased Bmax values) of [3H] spiroperidol, [3H] ADTN and [3H] 5-HT to striatal membranes, and increased basal and dopamine-stimulated striatal adenylate cyclase activity. The results are discussed in the light of changes of sensitivity of cerebral dopamine receptors, an increase in receptor numbers, and the tolerance to L-DOPA which often develop in the treatment of Parkinson's disease.

The possible interaction of the benzodiazepine diazepam with synaptic mechanisms of the central neurotransmitter 5-hydroxytryptamine (5-HT) has been studied in the rat using the superfusion in vitro release technique. The effect of diazepam (1-100 microM) on the spontaneous and potassium-induced release of radioactivity from superfused slices preloaded with [3H]5-HT prepared from cerebral cortex (fronto-parietal) and midbrain raphe region was monitored and compared. The results demonstrate a differential action of diazepam on the release of cortical and raphe 5-HT. In cerebral cortex diazepam significantly reduces both spontaneous and potassium-evoked release of [3H]5-HT. Conversely in raphe slices diazepam significantly enhances both spontaneous and potassium-evoked release of [3H]5-HT. In both tissues the effect of diazepam on K+-stimulated neurotransmitter release was abolished in the presence of picrotoxin. The experiments suggest that the effects of benzodiazepines on 5-HT mechanisms may be manifested at least in part through gamma-aminobutyric acid receptors.

Different classes of neuroleptic drugs have been tested for their potencies in producing behavioural responses and in displacing agonist and antagonist ligand binding to striatal dopamine receptors in rats exposed chronically (6–8 months) to the phenothiazine drug trifluoperazine. Higher doses of haloperidol and trifluoperazine were required to induce cataleptic states in the chronic trifluoperazine-treated animals compared to control rats. Similarly, higher doses of haloperidol, trifluoperazine and sulpiride were required to reduce the enhanced stereotyped behaviour to apomorphine (2 mg/kg) seen in chronic trifluoperazine-treated animals compared to control rats. In both behavioural tests a 50–100 fold increase in dosage of trifluoperazine was required in the chronic neuroleptic rats, but only a 5-fold increase was needed for haloperidol. In binding studies, a 10–15 fold increased concentration of trifluoperazine was required to displace either [3H]ADTN (8 nM) or [3H]spiperone (0.25 nM) from striatal binding sites prepared from chronic neuroleptic animals than from the controls. The reverse situation was observed with haloperidol; less of the butyrophenone was required to displace the 3H-ligands from binding sites prepared from chronic neuroleptic animals than from control rats, although in the case of haloperidol statistical significance was not reached. Sulpiride failed to displace convincingly [3H]spiperone or [3H]ADTN from striatal binding sites, although significantly less sulpiride was required to displace [3H]ADTN from membranes prepared from neuroleptic animals than from control rats. Chronic neuroleptic treatment increased the sensitivity of cerebral dopamine receptors. These supersensitive sites showed a differential response to neuroleptics of different chemical classes;; the receptors now appearing to have a lowered affinity for trifluoperazine. The possible interpretation in terms of different populations of cerebral dopamine receptors is discussed.

3H-Glycine was released by 50 mM K+ in a calcium-dependent manner from rat substantia nigra slices. This release was abolished by GABA (0.1-1 mM) and muscimol (0.1 mM). Taurine and beta-alanine were without effect on evoked 3H-glycine release. The effect of GABA (0.5 mM) was reversed picrotoxin (50 micro M). These results support the hypothesis that GABA receptors may be present on glycinergic interneurones in the substantia nigra.

The effects of GABA and glycine on the release of tritiated dopamine from prelabelled slices of rat striatum have been compared. Both GABA (>50 μM) and glycine (>200 μM) released tritiated dopamine, but had no effect on the release of radiolabelled 5-hydroxytryptamine and GABA. The GABA antagonist picrotoxin (50 μM) markedly reduced the ability of GABA to release [3H]dopamine, but had no effect on the glycine response. Conversely strychnine (0.5 μM), a specific glycine receptor antagonist at low concentrations, abolished both the GABA and the glycine response on [3H]dopamine release. Two other ω-amino acids, β-alanine and taurine, both at 500 μM, had no effect on [3H]dopamine release from rat striatal slices.

The effects of l- and d-baclofen were studied on two dopamine-dependent behaviours in rats, namely the hyperactivity response after bilateral injection of 12 μg dopamine into the nucleus accumbens and the state of catalepsy produced after an intraperitoneal injection of 0.6 mg/kg of the neuroleptic fluphenazine. Both l- and d-baclofen (0.5–50 μg) injected bilaterally into the nucleus accumbens septi 60 min after the bilateral injection of dopamine strongly antagonized hyperactivity in a dose-dependent manner. Significance was achieved for both isomers at 5, 10 and 50 μg doses. This effect was rapid in onset and lasted longer than 2 hr. Both l- and d-baclofen produced a highly significant potentiation of fluphenazine's ability to produce catalepsy at 10 mg/kg and 25 mg/kg, the effect of d-baclofen was also significant at 5 mg/kg. In a further experiment the effect of dl-, d- and l-baclofen on motor co-ordination was tested with animals on a rotarod. Whilst d-baclofen had no effect in this system, l-baclofen severely impaired the performance at all doses above 5 mg/kg. In all experiments animals receiving d-baclofen showed no perceptible loss in muscle tone. Animals receiving l-baclofen displayed great reduction in muscle tone with marked sedation and analgesia. Such muscle hypotonia and sedation would explain the effect of l-baclofen in both the motor coordination and dopamine-dependent behaviours. The effect of d-baclofen would however be apparently more specific to an interaction with cerebral dopamine systems.

The effect of ethanolamine- O -sulphate induced elevation of cerebral GABA concentrations on monoamine and their metabolites levels has been studied in various regions of the rat brain. Increased GABA concentrations were associated with a decrease in turnover of dopamine in limbic regions: striatal dopamine was not significantly affected. An increased turnover of 5-hydroxytryptamine was also observed in other brain areas. Increased cerebral GABA concentrations had no effect on regional noradrenaline turnover. The possible sites of interaction between the neurotransmitters are discussed.

The effect of systemically administered centrally-acting cholinergic and anticholinergic drugs on circling behaviour induced by the dopamine agonists apormorphone and amphetamine in mice with unilateral 6-hydroxydopamine lesions of nigro-neostriatal dopamine terminals has been studied. The anticholinergic drugs, scopolamine and benztropine, both caused circling towards the side of the lesion when administered alone to this animal model. Scopolamine and benztropine also significantly potentiated the ipsiversive circling behaviour induced by amphetamine, but had no consistent effect on apomorphine-induced contraversive turning. The cholinergic agents, physostigmine, arecoline and pilocarpine, produced no circling activity when given alone, but depressed the rates of circling induced by both amphetamine and apomorphine in these lesioned mice.

Mice with a 6-hydroxydopamine induced unilateral nigro-striatal lesion received (+)-amphetamine sulphate (2.5–20 mg/kg) over a 3-month period by daily incorporation into the drinking water. During this period the circling response to apomorphine hydrochloride (0.01–0.5 mg/kg, s.c.) was increasingly suppressed in comparison to control animals, while spontaneous locomotor activity increased. Following drug withdrawal the circling response to apomorphine remained suppressed two months later. However, spontaneous locomotor activity was also reduced up to 1 month following drug removal.

BEDARD, P. & PYCOCK, CJ. (1977). 'Wet-dog' shake behaviour in the rat: A possible quantitative model of central 5-hydroxy-tryptamine activity. Neuropharmacology, 16, 663-670. DOUGLAS, W.W. (1975). Histamine and antihistamines; 5-hydroxytryptamine and antagonists. In The Pharmacological Basis of Therapeutics, ed. Goodman, L.S. and Gilman, A., pp. 590629. New York: Macmillan. ELLIOTT, P.N.C., JENNER, P., HUIZING, G., MARSDEN, C.D. & MILLER, R. (1977). Substituted benzamides as cerebral dopamine antagonists in rodents. Neuropharmacology, 16, 333-342. SNYDER, S.H., AXELROD, J. & ZWEIG, M. (1965). A sensitive and specific fluorescence assay for tissue serotonin. Biochem. Pharmac., 14, 831-835.

The rat globus pallidus has been investigated as a possible model in which to study pre-synaptic GABA mechanisms in vitro. (+/-)-Baclofen (300 micrometer-1 mM) significantly enhanced the release of radioactivity from superfused slices of rat globus pallidus prelabelled with 3H-GABA in vitro. This releasing action was specific to the (+)-isomer of baclofen: neither the (-)-isomer nor another neuronal depressant dl-alpha-epsilon-diaminopimelic acid had any significant effect. The releasing effect of baclofen appeared unrelated to the phenethylamine moiety of its structure as neither beta-phenethylamine nor dopamine evoked release of 3H-GABA from pallidal slices. Baclofen increased the efflux of radioactivity from pallidal slices prelabelled with either [3H]-beta-alanine or [3H]diaminobutyric acid in vitro. The use of specific glial and neuronal GABA uptake blocking compounds (beta-alanine and (+/-)-cis-1,3-amino-cyclohexanecarboxylic acid) did not permit resolution of the elements from which baclofen was evoking [3H]GABA release. Baclofen also inhibited uptake of [3H]GABA into pallidal slices with an IC50 value of 6 x 10(-4) m. The GABA-like properties of baclofen may be related to the (+)-isomer while non-specific neuronal depressant actions are an effect of the (-)-isomer. The potential of the (+)-isomer as an antipsychotic agent while (-)-baclofen remains the effective antispastic drug free from unwanted side-effects, is discussed.

Unilateral electrolytic lesions were made in the areas of the dorsal or the ventral noradrenergic bundles in rats to see if the motor and biochemical effects of unilateral electrolytic locus coeruleus lesions could be reproduced. Lesions of the locus coeruleus result in transient contraversive circling in response to systemically administered apomorphine andd-amphetamine, a transient rise in ipsilateral striatal dopamine and a permanent fall in ipsilateral cerebral cortical noradrenaline.

Both 6-hydroxydopamine treatment at birth and bilateral locus coeruleus lesions specifically harmed the ascending dorsal noradrenergic pathway, causing significant decreases in cortical and limbic forebrain noradrenaline concentrations.