EXTending availability of self-management structured EducatioN programmes for people with type 2 Diabetes in low-to-middle income countries (EXTEND)-a feasibility study in Mozambique and Malawi.

BACKGROUND: Globally, there are estimated 425 million people with type 2 diabetes (T2D) with 80% from low-middle income countries (LMIC). Diabetes self-management education (DSME) programmes are a vital and core component of the treatment pathway for T2D. Despite LMIC being disproportionally affected by T2D, there are no DSME available that meet international diabetes federation criterion. METHODS: The aims were to test the feasibility of delivering a proven effective and cost-effective approach used in a UK population in two urban settings in Malawi and Mozambique by; (1) developing a culturally, contextually and linguistically adapted DSME, the EXTending availability of self-management structured EducatioN programmes for people with type 2 Diabetes in low-to-middle income countries (EXTEND) programme; (2) using a mixed-method approach to evaluate the delivery of training and the EXTEND programme to patients with T2D. RESULTS: Twelve healthcare professionals were trained. Ninety-eight participants received the DSME. Retention was high (100% in Mozambique and 94% in Malawi). At 6 months HbA1c (-0.9%), cholesterol (-0.3 mmol/L), blood pressure (-5.9 mm Hg systolic and -6.1 mm Hg diastolic) improved in addition to indicators of well-being (problem areas in diabetes and self-efficacy in diabetes). CONCLUSION: It is feasible to deliver and evaluate the effectiveness of a culturally, contextually and linguistically adapted EXTEND programme in two LMIC. The DSME was acceptable with positive biomedical and psychological outcomes but requires formal testing with cost-effectiveness. Challenges exist in scaling up such an approach in health systems that do not have resources to address the challenge of diabetes.

Use of the socio-ecological model to explore factors that influence the implementation of a diabetes structured education programme (EXTEND project) inLilongwe, Malawi and Maputo, Mozambique: a qualitative study.

BACKGROUND: Diabetes Self-Management Education and Support (DSMES) programmes are vital for type 2 diabetes mellitus (T2DM) management. However, they are limited in Sub-Saharan Africa (SSA). To address this gap, a DSMES, namedEXTEND was developed in Lilongwe (Malawi) and Maputo (Mozambique). This qualitative study aimed to explore factors that influence the implementation of DSMES in these settings. METHODS: The Socio-ecological model was applied to explore factors influencing the implementation of DSMES in SSA. Data was analysed using the Framework method and constant comparative techniques. Sixty-six people participated in the study: people with T2DM who participated in the EXTEND programme; healthcare professionals (HCPs), EXTEND educators, EXTEND trainers, and stakeholders. RESULTS: Our findings indicate that there is a need to develop an integrated and dedicated diabetes services in SSA healthcare systems, incorporating culturally adapted DSMES and tailored diabetes training to all professions involved in diabetes management. Traditional media and the involvement of community leaders were proposed as important elements to help engage and promote DSMES programmes in local communities. During the design and implementation of DSMES, it is important to consider individual and societal barriers to self-care. CONCLUSION: Findings from this study suggest that multi-faceted factors play a significant role to the implementation of DSMES programmes in LICs. In the future, EXTEND could be incorporated in the development of diabetes training and dedicated diabetes services in SSA healthcare systems, acting as an educational tool for both people with T2DM and HCPs. This project was supported by the Medical Research Council GCRF NCDs Foundation Awards 2016 Development Pathway Funding.

Self-monitoring of blood glucose versus self-monitoring of urine glucose in adults with newly diagnosed Type 2 diabetes receiving structured education: a cluster randomized controlled trial.

AIMS: To compare the effectiveness and acceptability of self-monitoring of blood glucose with self-monitoring of urine glucose in adults with newly diagnosed Type 2 diabetes. METHODS: We conducted a multi-site cluster randomized controlled trial with practice-level randomization. Participants attended a structured group education programme, which included a module on self-monitoring using blood glucose or urine glucose monitoring. HbA1c and other biomedical measures as well as psychosocial data were collected at 6, 12 and 18 months. A total of 292 participants with Type 2 diabetes were recruited from 75 practices. RESULTS: HbA1c levels were significantly lower at 18 months than at baseline in both the blood monitoring group [mean (se) -12 (2) mmol/mol; -1.1 (0.2) %] and the urine monitoring group [mean (se) -13 (2) mmol/mol; -1.2 (0.2)%], with no difference between groups [mean difference adjusted for cluster effect and baseline value = -1 mmol/mol (95% CI -3, 2); -0.1% (95% CI -0.3, 0.2)]. Similar improvements were observed for the other biomedical outcomes, with no differences between groups. Both groups showed improvements in total treatment satisfaction, generic well-being, and diabetes-specific well-being, and had a less threatening view of diabetes, with no differences between groups at 18 months. Approximately one in five participants in the urine monitoring arm switched to blood monitoring, while those in the blood monitoring arm rarely switched (18 vs 1% at 18 months; P < 0.001). CONCLUSIONS: Participants with newly diagnosed Type 2 diabetes who attended structured education showed similar improvements in HbA1c levels at 18 months, regardless of whether they were assigned to blood or urine self-monitoring.

Nicotine-induced changes of brain ß-endorphin.

A consensus has emerged that endogenous opioid peptides and their receptors play an important role in the psychoactive properties of nicotine. Although behavioral studies have shown that ß-endorphin contributes to the rewarding and emotional effects of nicotine, whether the drug alters the function of brain endorphinergic neurons is not fully explored. These studies investigated the effect of acute, 1mg/kg, sc, and chronic, daily injection of 1mg/kg, sc, for 14 days, administration of free base nicotine on brain ß-endorphin and its precursor proopiomelanocortin (POMC). Acute and chronic treatment with nicotine decreased ß-endorphin content in hypothalamus, the principal site of ß-endorphin producing neurons in the brain, and in the endorphinergic terminal fields in striatum and hippocampus. The acute effect of nicotine on ß-endorphin was reversed by the nicotinic antagonist mecamylamine and the dopamine antagonist haloperidol, indicating pharmacological specificity and involvement of dopamine D2-like receptors. Similar observations were made in prefrontal cortex. POMC mRNA in hypothalamus and prefrontal cortex was unchanged following acute nicotine, but it decreased moderately with chronic treatment. The nicotine treatments had no effect on pituitary and plasma ß-endorphin. Taken together, these results could be interpreted to indicate that nicotine alters the synthesis and release of ß-endorphin in the limbic brain in vivo. Altered endorphinergic function may contribute to the behavioral effects of acute and chronic nicotine treatment and play a role in nicotine addiction.

GM1 enhances dopaminergic markers in the brain of aged rats.

A number of presynaptic markers are compromised in the dopaminergic neurons of aged Sprague-Dawley rats (22 months old) compared with young rats (3 months old). Indeed, in the striatum of the aged rats there is a diminished capacity to transport dopamine (DA), to bind the dopamine transporter (DAT) marker mazindol, to bind the vesicular monoamine transporter 2 (VMAT2) marker dihydrotetrabenazine, and to release DA under basal conditions or after induction by K(+) or amphetamine. Furthermore, the expression of DAT and VMAT2 mRNA in the midbrain is suppressed. GM1 ganglioside, 30 mg/kg ip daily, administered for 30 days, restores the afore-mentioned markers to values approaching those for young rats. Taken together with our published observations that GM1 partially restores tyrosine hydroxylase activity and DA metabolism in aged nigrostriatal and mesoaccumbal neurons and improves their morphology, our work suggests that GM1 might act as a dopaminergic neurotrophic factor in the aged brain and be a useful adjuvant for treating age-associated dopaminergic deficits.

Motoric behavior in aged rats treated with GM1.

Aging is associated with impaired motor function. Nigrostriatal dopaminergic neurons, in part, regulate motoric behavior, and undergo degenerative changes during aging. GM1 ganglioside partially restores pre-synaptic dopaminergic markers and the number and morphology of dopaminergic neurons in the midbrain and striatum of Sprague--Dawley aged rats. These studies investigated whether GM1 treatment, 30 mg/kg, i.p. daily for 36 days, affects locomotor and stereotypic activity, as well as coordination, balance, and strength in aged rats. Under the treatment conditions used, GM1 did not improve the reduced locomotor and stereotypic behavior of the aged rats. While it partially improved performance on a square bridge test, GM1 had no effect on inclined screen and rod suspension tests. Although GM1 restored the decreased content of dopamine and homovanillic acid in the nigrostriatal neurons of the aged rats, it had no effect on the reduced D1 and D2 dopamine receptor binding and mRNA in the striatum. It appears, that despite the morphological and metabolic restoration of aged nigrostriatal neurons, GM1 has limited ability in improving age-associated motor deficits.

Changes in plasma nerve growth factor levels in older adults associated with chronic stress.

Evidence indicates that the actions of nerve growth factor (NGF) reach beyond the nervous system and might modulate immune function. Based on reports that blood NGF rises following the acute stress of parachute jumping, we investigated whether exposure to a chronic stressor, caregiving for a cognitively impaired spouse, could alter the levels of blood NGF. High perceived stress and depression in caregivers (vs. well-matched controls) were associated with elevated blood NGF. These data suggest that exposure to this chronic stressor can alter the concentrations of circulating NGF, and that psychological stress can induce changes in NGF concentrations in older adults.

Boron neutron capture therapy of brain tumors: functional and neuropathologic effects of blood-brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine.

Sodium borocaptate (BSH) and boronophenylalanine (BPA) are two drugs that have been used clinically for boron neutron capture therapy (BNCT) of brain tumors. We previously have reported that hyperosmotic mannitol-induced disruption of the blood-brain barrier (BBB-D), followed by intracarotid (i.c.) administration of BPA or BSH, either individually or in combination, significantly enhanced tumor boron delivery and the efficacy of BNCT in F98 glioma bearing rats. The purpose of the present study was to determine the short-term neuropathologic consequences of this treatment and the long-term effects on motor and cognitive function, as well as the neuropathologic sequelae 1 year following neutron capture irradiation. BBB-D was carried out in non-tumor bearing Fischer rats by infusing a 25% solution of mannitol i.c. followed by i.c. injection of BPA or BSH, either individually or in combination, immediately thereafter. Animals were euthanized 2 days after compound administration, and their brains were processed for neuropathologic examination, which revealed sporadic, mild, focal neuronal degeneration, hemorrhage, and necrosis. To assess the long-term effects of such treatment followed by neutron capture irradiation, non-tumor bearing rats were subjected to BBB-D after which they were injected i.c. with BPA (25 mg B/kg body weight (b.w)) or BSH (30 mg B/kg b.w.) either individually or in combination (BPA 12.5 mg and BSH 14 mg B/kg b.w.). Two and a half hours later they were irradiated at the Medical Research Reactor, Brookhaven National Laboratory, Upton, NY, with the same physical radiation doses (5.79, 8.10 or 10.06 Gy), delivered to the brain, as those that previously had been used for our therapy experiments. The animals tolerated this procedure well, after which they were returned to Columbus, Ohio where their clinical status was monitored weekly. After 1 year, motor function was assessed using a sensitive and reliable locomotor rating scale for open field testing in rats and cognitive function was evaluated by their performance in the Morris water maze, the results of which were similar to those obtained with age matched controls. After functional evaluation, the rats were euthanized, their brains were removed, and then processed for neuropathologic examination. Subtle histopathologic changes were seen in the choroid plexuses of irradiated animals that had received BPA, BSH or saline. Radiation related ocular changes consisting of keratitis, blepharitis, conjunctivitis and cataract formation were seen with similar frequency in most rats in each treatment group. Based on these observations, and the previously reported significant therapeutic gain associated with BBB-D and i.c. injection of BSH and BPA, the present observations establish its safety in rats and suggest that further studies in large animals and humans are warranted.

Nerve growth factor (NGF) and NGF mRNA change in rat uterus during pregnancy.

During pregnancy, the uterus undergoes a profound sympathetic denervation. To explore whether this is associated with changes in neurotrophic factors, we assayed nerve growth factor (NGF) and NGF mRNA in the uterus of non-pregnant and pregnant rats. In the uterine horn, the concentration of NGF and its mRNA decreased during middle and late pregnancy. However, when values were corrected for the increase of uterine weight and total RNA yield during pregnancy, NGF content and mRNA per horn increased during middle and late pregnancy. Similar, but less pronounced, changes were observed in the cervix. By seven days postpartum, both parameters returned to near normal.

Retinal cholinergic and dopaminergic deficits of aged rats are improved following treatment with GM1 ganglioside.

Selected cholinergic and dopaminergic markers were compared in the retina of aged (20-22-months-old) and young (3-months-old) rats before and after treatment with GM1 ganglioside. The dopaminergic markers, tyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid were comparable in the young and aged animals and GM1 treatment did not alter them. In contrast, mazindol binding, a marker for the dopamine transporter, was diminished in the aged retina and treatment with GM1 restored binding to values found in the young animals. The cholinergic markers choline acetyltransferase and hemicholinium-3 binding, a marker for the high-affinity choline transport, were depressed in aged rats and GM1 corrected the deficits.

Glutamate receptors participate in the nicotine-induced changes of met-enkephalin in striatum.

A single dose of nicotine given to mice induces first a rapid decrease (presumed release/enhanced degradation) and then a rise (presumed synthesis/enhanced accumulation) of met-enkephalin (Met-Enk) in dorsal and ventral striatum observed at 30 and 60 min post-treatment, respectively. These studies investigated whether the nicotine effect on Met-Enk was mediated indirectly, in part, via other neurotransmitters known to be released by nicotine. Based on the ability of selective antagonists of dopamine (Sch 23390, D1; Sulpiride, D2), glutamate (CPP, competitive NMDA; dizocilpine, non-competitive NMDA; NBQX, AMPA) and GABA (bicuculline, GABA(A); Sch 50911, GABA(B)) receptors, to inhibit or enhance the response to nicotine, we conclude that nicotine alters striatal Met-Enk, in part, via glutamate NMDA and AMPA receptors. These findings further support the notion that glutamate might play a role in the pharmacology of nicotine.

Phosphorylation and activation of brain aromatic L-amino acid decarboxylase by cyclic AMP-dependent protein kinase.

Aromatic L-amino acid decarboxylase (AAAD), an enzyme required for the synthesis of catecholamines, indoleamines, and trace amines, is rapidly activated by cyclic AMP-dependent pathways in striatum and midbrain in vivo, suggesting enzyme phosphorylation. We now report that the catalytic subunit of cyclic AMP-dependent protein kinase (PKA) directly phosphorylated AAAD immunoprecipitated from homogenates prepared from the mouse striatum and midbrain in vitro. Under the same phosphorylation conditions, the catalytic subunit of PKA also phosphorylated a recombinant AAAD protein expressed in Escherichia coli transfected with an AAAD cDNA isolated from the bovine adrenal gland. The PKA-induced AAAD phosphorylation of immunoprecipitates from striatum and midbrain was time and concentration dependent and blocked by a specific PKA peptide inhibitor. Incubation of the catalytic subunit of PKA with striatal homogenates increased enzyme activity by approximately 20% in a time- and concentration-dependent manner. Moreover, incubation of the catalytic subunit of PKA with recombinant AAAD increased activity by approximately 70%. A direct phosphorylation of AAAD protein by PKA might underlie the cyclic AMP-induced rapid and transient activation of AAAD in vivo.

GM1 ganglioside restores abnormal responses to acute thermal and mechanical stimuli in aged rats.

We investigated the effect of aging on the responses to thermal and mechanical stimuli in rats. Young (3-5 months old) and aged (22-24 months old) male Sprague-Dawley rats were tested in the hot plate, high- and low-intensity radiant heat tail flick, and von Frey hair assays. Compared to young rats, aged rats displayed longer latencies in the hot plate and the high-intensity tail flick assays (hypoalgesia), but there was no difference in the low-intensity tail flick assay. In addition, aged rats had decreased thresholds to mechanical stimuli produced by von Frey hairs compared with young rats (mechanical allodynia). Administration of GM1 ganglioside, 30 mg/kg, i.p., once daily for 30 days, to aged rats partially restored the responses in the hot plate and von Frey hair assays. GM1 had no effect on the altered responses in the tail flick test in aged rats, and in general, had no effect on any sensory modality tested in young rats.

SCH 23390 enhances exogenous L-DOPA decarboxylation in nigrostriatal neurons.

Exogenous L-DOPA enhances dopamine metabolism in the intact and denervated striatum, and is the treatment of choice for Parkinsonism. Aromatic L-amino acid decarboxylase (AAAD) converts L-DOPA to dopamine. Blockade of dopamine D1-like receptors increases the activity of AAAD in both intact and denervated striatum. A single dose of SCH 23390, a dopamine D1-like receptor antagonist, increases the activity of AAAD in the striatum and midbrain and induces small changes in dopamine metabolism. When L-DOPA is administered after SCH 23390, there is a significant increase in the formation of 3,4-dihydroxyphenylacetic acid and dopamine turnover in striatum and midbrain compared to L-DOPA alone, suggesting further enhancement of dopamine metabolism. When the studies are repeated in the MPTP mouse model of Parkinson's disease, there is significantly more dopamine metabolism in the striatum of lesioned mice pretreated with SCH 23390 than in a comparison group treated with L-DOPA alone. These studies suggest that it may be possible to enhance the conversion of L-DOPA to dopamine in Parkinson's disease patients by administering substances that augment brain AAAD.

GM1 ganglioside restores dopaminergic neurochemical and morphological markers in aged rats.

The monosialoganglioside GM1 exerts neurotrophic-like activity in vitro and in vivo. In particular, it improves cholinergic neuron morphology and chemistry and learning abilities of cognitively impaired aged rats and young animals with cholinergic lesions, and restores neurochemical, pharmacological, morphological and behavioral parameters in animal models of Parkinson's disease. Our studies present evidence that GM1 reverses dopaminergic deficits in the nigrostriatal neurons of aged rats. GM1 administered to aged Sprague-Dawley rats for 30 days reversed the decreased activity of tyrosine hydroxylase in the midbrain and striatum, elevated the reduced protein content and mRNA levels of the enzyme in the midbrain, and reversed the decrements of dopamine and 3,4-dihydroxyphenylacetic acid content in both the midbrain and striatum. Tyrosine hydroxylase activity of the midbrain, but not of the striatum, remained elevated for 15 days after discontinuing GM1. The count profiles of tyrosine hydroxylase-immunopositive neurons, the size of tyrosine hydroxylase-immunopositive neurons and the number of tyrosine hydroxylase-immunopositive fibers were decreased in the substantia nigra pars compacta and the ventral tegmental area of aged rats. GM1 corrected the morphology of dopaminergic neurons in the substantia nigra pars compacta and partially improved it in the ventral tegmental area. These findings support the notion that the aged striatal dopaminergic neurons respond to GM1, and strengthen the utility of using this compound for combating age-associated neuronal deficits.

Tyrosine hydroxylase, aromatic L-amino acid decarboxylase and dopamine metabolism after chronic treatment with dopaminergic drugs.

Mice were treated with dopamine (DA) receptor agonist and antagonist drugs: Agonists: (+/-)-SKF 38393 ((+/-)-1-phenyl-2,3,4, 5-tetrahydro-(1H)-3-benzazepine-7,8-diol) [DA D1-like]; bromocriptine, [DA D2 selective]; quinpirole, [DA D2/D3 preferring]; (+/-)-7-hydroxy-dipropylamino-tetralin (7-OH-DPAT), [DA D3/D2 preferring], Antagonists: R(+)-SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine), [DA D1-like]; and haloperidol, [DA D2-like]. All drugs were administered intraperitoneally, two injections daily 8 h apart for 30 days. Aromatic L-amino acid decarboxylase (AAAD) and tyrosine hydroxylase (TH) activity, protein and mRNA, as well as DA metabolism were followed with time thereafter in the nigrostriatal neurons. We observed that chronic administration of D1-like agonists had no effect on TH or AAAD activity, while D2-like agonists decreased AAAD, but not TH activity. Additionally, chronic blockade of DA D2-like receptors resulted in prolonged induction of TH and AAAD, while chronic blockade of DA D1-like receptors induced changes of AAAD only. Compared to TH the induction of AAAD was longer lasting. DA metabolism was altered by chronic administration of drugs acting on DA D2-like, but not DA D1-like receptors, and in general the patterns of change did not follow those for TH or AAAD. When studied 48 h after the last dose of the chronic haloperidol schedule TH displayed tolerance to acute drug challenge. At the same time interval, there was tolerance to the enhancing effects of haloperidol and SCH 23390 on DA metabolism. The induction of AAAD by haloperidol or SCH 23990 did not appear to develop tolerance after chronic administration. These observations complement existing knowledge, and provide novel information about AAAD that may have practical importance for Parkinson's patients on L-DOPA therapy.

Low concentrations of cerebrospinal fluid GABA correlate to a reduced response to phenobarbital therapy in primary canine epilepsy.

In this study, we investigated whether pretreatment cerebrospinal fluid (CSF) neurotransmitter concentrations of gamma-aminobutyric acid (GABA) and glutamate (GLU) were correlated with response to phenobarbital treatment in dogs with primary epilepsy. Eleven untreated dogs, 6 males and 5 females, with a median age of onset of seizures of 3 years (range: 0.5-5 years) were selected for therapy based on progressive or serious seizure patterns. The median interval between the first observed seizure and start of phenobarbital therapy was 485 days (range: 101-1,765 days). All dogs were purebred, with the exception of I male dog. Oral phenobarbital was started at 2.5 mg/kg every 12 hours. Trough serum phenobarbital concentrations were measured at 15, 45, 90, 180, 360, 540, and 720 days after the start of treatment. There was no difference in the mean trough serum concentration or in the mean number of seizures recorded between each time period of phenobarbital measurement over the 2-year evaluation. No correlation was found between CSF GLU, GABA, or GLU: GABA ratio and the total number of seizures recorded before or after initiation of phenobarbital therapy. Lower CSF GABA concentration, however, was correlated with a lower seizure frequency difference (the total number of seizures before phenobarbital therapy minus the total number of seizures after phenobarbital therapy for an identical time period of evaluation) and lower percentage reduction in seizures: ([total number of seizures before phenobarbital therapy minus the total number of seizures after phenobarbital therapy] divided by the total number of seizures before phenobarbital therapy) x 100. There was no correlation between CSF GLU and the seizure frequency difference and percentage reduction in seizures. A negative correlation between the CSF GLU:GABA ratio and seizure frequency difference was found. Thus, dogs with an initial lower CSF GABA concentration before phenobarbital therapy did not respond as well as did dogs with a higher CSF GABA concentration.

Decreased neuropeptide content in the spinal cord of aged rats: the effect of GM1 ganglioside.

This study investigated the status of substance P (SP), methionine-enkephalin (Met-Enk) and dynorphin A(1-13) (Dyn A) in the spinal cord of aged Sprague-Dawley rats and the effect of GM1 ganglioside on these neuropeptides. SP and Met-Enk, but not Dyn A, were decreased in both dorsal and ventral horns of the aged spinal cord. Treatment with GM1 ganglioside (30 mg/kg i.p., daily for 30 days) restored, in part, the neuropeptide deficits in the ventral horns, but not in the dorsal horns. This information might be important for understanding the sensory and motor deficits associated with ageing, and how the spinal cord neuropeptides might be amplified in the aged spinal cord.

Nicotine abstinence in the mouse.

We present evidence that intermittent administration of nicotine, 2 mg/kg s.c., four times daily to mice for 14 days produces a somatic abstinence syndrome after discontinuing treatment. The nicotine abstinence was mild and protracted, lasting more than 92 h. The constellation of abstinence signs was characterized by rearing, jumping, shakes, abdominal constrictions, chewing, facial tremor and scratching. No autonomic symptomatology was observed. Nicotine abstinence was attenuated with a single dose of nicotine administered at 24 or 48 h into withdrawal. The nicotinic antagonist mecamylamine, 3 mg/kg, induced a small increase in the total abstinence score when given 60 min after the last nicotine injection. Nicotine-abstinent mice displayed reduced locomotor activity. Finally, mice lost weight during the nicotine treatment which was not recovered during the withdrawal. Along with the rat nicotine abstinence model, the mouse model of intermittent nicotine administration and abstinence might be useful for studying the pharmacological and biochemical mechanisms of nicotine addiction and tobacco use.

Parallel modulation of striatal dopamine synthetic enzymes by second messenger pathways.

The activity of tyrosine hydroxylase and aromatic L-amino acid decarboxylase in the striatum and their mRNA content in the midbrain were assayed in mice following the intracerebroventricular injection of forskolin or phorbol-12,13-myristic acid (PMA). Control and 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned animals were studied. Both forskolin and PMA induced a rapid and transient increase of tyrosine hydroxylase and aromatic L-amino acid decarboxylase activity in the striatum that lasted less than 45 and 60 min, respectively. A second belated increase of striatal tyrosine hydroxylase and aromatic L-amino acid decarboxylase activities was seen only after forskolin, and it was accompanied by a rise of tyrosine hydroxylase and aromatic L-amino acid decarboxylase mRNA in the midbrain. In the MPTP-lesioned mouse, the rise of tyrosine hydroxylase and aromatic L-amino acid decarboxylase following forskolin appeared exaggerated, while the response to PMA was not. These studies suggest that tyrosine hydroxylase and aromatic L-amino acid decarboxylase of striatum can be modulated in parallel by protein kinase A and protein kinase C, and that exaggerated responsiveness to protein kinase A is observed in the partially denervated striatum.