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In old age there is evidence of waning motivation, and possibly lowering of mood. Physiologically there is a decline in the levels of brain neurotransmitters such as acetylcholine and dopamine, and loss of myelin. These changes might be expected to impair the functioning of brain circuitry for reinforcement, and to lead to impaired motivation. To evaluate the function of brain reinforcement mechanisms during aging we examined brain stimulation reward and its modulation by dopaminergic drugs in BN F344F1 rats aged from young adult (5 months) to old (37 months). Brain stimulation directly activates the neural circuitry for reinforcement, and the response rate-frequency tradeoff can be used to characterize the functioning of the system. Both young and old subjects readily learned to lever press for 0.6 s trains of 0.15 ms brain stimulation pulses, and there was no difference in the number of pulses per train required to maintain responding at 50% of the maximum rate (M50). Amphetamine (0.5 mg/kg) significantly reduced the M50, and the dopamine synthesis inhibitor alpha-methyl-p-tyrosine (100 mg/kg) increased the M50, but these effects were not influenced by the age of the subjects. The results suggest that in healthy animals dopaminergic modulation of reinforcement is functionally intact in old age.

The analgesic properties of the catecholamine uptake inhibitor nomifensine were investigated in the tail immersion, hot plate and formalin tests. Systemic administration of nomifensine produced analgesia only in the formalin test. The analgesia was dose-dependent (0.625-5 mg/kg), and the highest dose completely abolished nociceptive behaviors induced by 2% formalin. The analgesia was not affected by the opioid antagonist naltrexone (2.5-40 microg s.c.) but was dose-dependently reversed by the D2 antagonist eticlopride (181.3-270 microg/kg i.p.). Neither naltrexone nor eticlopride affected formalin pain scores. Nomifensine analgesia appears to be dopamine-mediated but independent of opioid mechanisms.

Electrolytic lesions of the pedunculopontine tegmental nucleus (PPTg) have been previously reported to increase anxiety-like behavior in rats. The aim of the present study was to compare these behavioral changes with those produced by an anxiogenic compound, the partial inverse agonist at benzodiazepine receptors, β-CCE. Three groups of rats, sham-lesioned treated with vehicle, sham-lesioned treated with 10 mg/kg of β-CCE, and PPTg-lesioned rats treated with vehicle, were tested in the elevated plus-maze, the social-interaction test, and for spontaneous locomotion. Histology showed that lesions were concentrated on the caudal half of the PPTg. Measures of both the PPTg-lesioned and β-CCE–treated rats indicated increased anxiety-like behavior in the elevated plus-maze and in the social-interaction test. Spontaneous locomotion, measured in the open- field arena, did not differ between sham controls and PPTg-lesioned rats, but was decreased in rats treated with β-CCE. Our results confirmed that electrolytic lesions of the caudal PPTg produce increased anxiety-like behavior. This behavior is quantitatively and qualitatively similar to that produced by 10 mg/kg of β-CCE.

The rewarding effects of brain stimulation and drugs are believed to depend on a common neural system. However, the pattern of responding produced by drug reinforcers is different from the pattern produced by conventional brain stimulation. Furthermore, pharmacological antagonists of reinforcement increase the rate of drug self-administration but depres self-stimulation. To test the hypothesis that the differences in the characteristics of brain stimulation and drugs as reinforcers are due to differences in the kinetics of drugs and brain stimulation, we modelled drug kinetics with frequency-modulated trains of brain stimulation. We report that animals will self-administer such brain stimulation in a manner that resembles drug self-administration and that, under these conditions, dopamine antagonists can increase the rate of self-stimulation.

Tolerance to morphine analgesia was examined using the Formalin test in which pain lasting about 2 hrs associated with minor tissue injury is produced by subcutaneous injection of dilute Formalin. To distinguish behavioral from pharmacological tolerance, different groups of rats received their daily morphine injection (7 mg/kg) in the test environment or in their home environment for 5 days. Another group of rats was given morphine for 15 days in the home cage followed by 5 days in the test environment. None of the morphine injected groups differed from saline injected control groups in the amount of analgesia. These findings add to previous evidence that the Formalin test measures a type of pain which is different from that assessed in withdrawal reflex tests, and which more closely resembles clinical pain in man. Moreover, the fact that analgesia in the Formalin test shows little tolerance while analgesia in withdrawal tests shows rapid tolerance suggests that the underlying neural mechanisms are different.

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 reinforces, 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.

Naloxone (0.1 to 10 mg/kg) caused a dose-dependent depression of self-stimulation of the medial prefrontal cortex (PFC) lateral hypothalamus (LH) and a region in the dorsal tegmentum lateral to the central gray (DT). The DT contains many enkephalin fibers and is a site for stimulation-produced analgesia, while the PFC contains little enkephalin and does not support stimulation-produced analgesia. However, self-stimulation rates of the PFC, DT and LH were all equally depressed by naloxone. In order to study possible opiate-dopamine interactions, we examined the effects of naloxone on the facilitatory effects of D- and L-amphetamine (1.0 mg/kg) on self-stimulation of the DT and PFC. If amphetamine mildly facilitated self-stimulation (L-amphetamine on DT self-stimulation and D-amphetamine on PFC self-stimulation) then the addition of naloxone was without effect. If amphetamine greatly increased self-stimulation (D-amphetamine on DT self-stimulation), naloxone caused a depression of the amphetamine effect. It is argued that naloxone's effects in this and other reports reviewed is related to the level of self-stimulation performance, and not to the level of enkephalin at the self-stimulation site, nor to amphetamine's effects on dopamine activity.

Rats stopped responding for electrical stimulation of the brain following pretreatment with the dopamine antagonist pimozide, as well as following truncation of brain stimulation trains. In either case the extinguished responding was temporarily reinstated on presentation of a light if the light had previously signalled reward but not if the light had had no such significance. These results indicate that pimozide reduces self-stimulation by abolishing the rewarding effect of brain stimulation rather than by interfering with motor ability.