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Young and aged rats were treated chronically with ethanol or scopolamine. Muscarinic receptors were measured in cerebral cortex, hippocampus and striatum. Following scopolamine treatment muscarinic receptor density in cerebral cortex, hippocampus and striatum of young rats increased by 34, 57 and 27%, respectively; in brains of aged rats the increase was 41% in cerebral cortex, 43% in hippocampus and nil in striatum. Affinity of muscarinic receptors was not changed by scopolamine treatment. Following chronic ethanol administration there was a 48% increase in cortical muscarinic receptor density in young, but not aged rats. The density of muscarinic receptors in hippocampus and striatum of both young and aged rats was not affected by ethanol treatment. Affinity of receptors in hippocampus of aged, ethanol-treated rats was increased compared to age-matched controls. Adaptative responses of the muscarinic receptor/transducer system to neurotransmitter availability are present in both young and aged rats, both the ethanol-induced response is present only in young animals. This suggests differences in the mechanism of action of ethanol and receptor agonists and antagonists in modulating receptor plasticity.

AbstractThe prelimbic (PL) and infralimbic (IL) medial prefrontal cortex (mPFC) are thought to play opposing roles in drug‐seeking behaviour. Specifically, the PL promotes drug‐seeking whereas the IL is necessary for the inhibition of drug‐seeking during extinction. We studied the roles of the PL, IL and dorsal peduncular PFC (DP) in the expression of context‐induced reinstatement, reacquisition and extinction of alcoholic beer‐seeking. In context‐induced reinstatement (renewal), animals were trained to nosepoke for alcoholic beer (context A), extinguished (context B) and then tested in context A and B. In reacquisition, animals received the same instrumental training and extinction without any contextual manipulation. On test, alcoholic beer was again available and responding was compared with naive controls. Just prior to the test, rats received bilateral infusion of baclofen/muscimol into the PL, IL or DP. Reversible inactivation of the PL attenuated ABA renewal but augmented reacquisition. Reversible inactivation of IL had no effect on the reinstatement or reacquisition of alcoholic beer‐seeking and had no effect on extinction expression (ABB and AAA). IL inactivation did, however, increase the latencies with which animals responded on test but only when animals were tested in the extinction context. DP inactivation had no effect on reinstatement or reacquisition. These studies are inconsistent with the view that PL and IL exert opposing effects on drug‐seeking. Rather, they support the view that PL is important for retrieval of drug‐seeking contingency information and that the use of contextual information is enhanced with IL manipulation.

The uptake of [14C]deoxyglucose by brains of rats that were given alcohol in drinking water for 7 months was investigated. There was a general, approximately 50%, increase in deoxyglucose uptake in brains of ethanol-treated rats with areas of the limbic system being particularly affected.

In four experiments we studied the impact of retrieval-extinction training on the extinction and reinstatement of alcoholic beer seeking. Experiment 1 showed that preceding daily extinction sessions with a brief (10 min) extinction session (retrieval-extinction) attenuated the context-induced reinstatement of alcoholic beer seeking, thereby replicating and extending the findings of Xue et al. (2012). Experiment 2 then showed that the retrieval-extinction manipulation could attenuate the reinstatement produced by reversible inactivation of the nucleus accumbens shell prior to test. Experiment 3 showed that a modified extinction protocol that involved a reversed retrieval (i.e., extinction then retrieval) was also able to attenuate context-induced reinstatement. Finally, experiment 4 showed that the extinction-retrieval manipulation facilitated the reacquisition of alcoholic beer seeking as evidenced by increased breakpoints and responses during tests under a progressive ratio schedule. Taken together, these findings show that retrieval-extinction training protocols can alter the propensity to reinstate extinguished drug seeking but that these alterations are not always protective. These findings are inconsistent with accounts of the retrieval-extinction manipulation in terms of memory reconsolidation and deepened extinction. Instead, they are consistent with the notion that this manipulation increases the sensitivity of animals to the contingencies in effect during testing.

Baroreflex sensitivity (BRS) is reduced in humans during snoring, however the mechanisms are unknown. We used an anaesthetised rabbit induced snoring (IS) model, to test: (1) whether IS was associated with reduced BRS; and (2) if snoring related vibration transmission to peri-carotid tissues influenced BRS levels. BRS was quantified using the spontaneous sequence technique. During IS, BRS fell by 40%, without any associated change in blood pressure (BP) but accompanied by an increase in heart rate (HR). Direct application of a snore frequency and intensity matched vibratory stimulus to the peri-carotid tissues of non-snoring tracheostomised rabbits had no effect on BRS, HR or BP. In conclusion, IS induced depression of BRS is likely mediated via a HR driven change in BRS operating point that is unrelated to snoring-related vibration transmission to carotid baroreceptors. The anaesthetised IS rabbit provides a model in which mechanistic interactions between snoring and BRS can be further explored.

AbstractAlcohol taken regularly over a lengthy period of time has been claimed to cause to loss of neurons in both the adult and developing brain. However, it remains uncertain whether acute, as opposed to chronic, exposure to alcohol at specified periods can also cause disruption in the neuronal population of the developing brain. This question was investigated by exposing Wistar rat pups to 7.5 g/kg body weight of ethanol administered as a 10% solution via an intragastric cannula over an 8 hour period either on the 5th (PND5) or the 10th (PND10) postnatal day of age. Gastrostomy controls received a 5% sucrose solution substituted isocalorically for the ethanol. Another set of pups raised by their mothers was used as “suckle controls”. All surgical procedures were carried out under halothane vapour anaesthesia. After the artificial feeding regimes, all pups were returned to the lactating dams and weaned at 21 days of age. Between 52 and 54 days of age, the rats were anaesthetised with an intraperitoneal injection with Nembutal and killed by intracardiac perfusion with 3% glutaraldehyde in 0.1 M phosphate buffer. The relatively unbiased stereological procedure known as the “fractionator” method was used to estimate the total number of Purkinje cells in the cerebellum of each animal. The Purkinje cell nucleolus was used as the counting unit; it was assumed that each Purkinje cell contained only one nucleolus. PND10 ethanol‐treated rats and gastrostomy and suckle controls had between about 210,000‐232,000 Purkinje cells in the cerebellum. However, the PND5 ethanol‐treated rats had only about 137,000 Purkinje cells. Two‐way analysis of variance procedures revealed significant main effects of age at time of alcohol exposure and groups as well as a significant interaction between them. It is concluded that the Purkinje cell population numbers can be disrupted by acute exposure to alcohol on the 5th, but not the 10th, postnatal day of age. © 1995 Wiley‐Liss, Inc.

Glutamate-mediated neurotransmission may be involved in the range of adaptive changes in brain which occur after ethanol administration in laboratory animals, and in chronic alcoholism in human cases. Excitatory amino acid transmission is modulated by a complex system of receptors and other effectors, the efficacy of which can be profoundly affected by altered gene or protein expression. Local variations in receptor composition may underlie intrinsic regional variations in susceptibility to pathological change. Equally, ethanol use and abuse may bring about alterations in receptor subunit expression as the essence of the adaptive response. Such considerations may underlie the regional localization characteristic of the pathogenesis of alcoholic brain damage, or they may form part of the homeostatic change that constitutes the neural substrate for alcohol dependence.

This study focused on the DNA-binding activity and protein expression of the transcription factors Egr-1 and Egr-3 in the rat brain cortex and hippocampus after chronic or acute ethanol exposure. DNA-binding activity was reduced in both regions after chronic ethanol exposure and was restored to the level of the pair-fed group at 16 h of withdrawal. Cortical Egr-1 protein levels were not altered by chronic ethanol exposure but increased 16 h after withdrawal, thus mirroring DNA-binding activity. In contrast, Egr-3 protein levels did not undergo any change. There was no change in the level of either protein in the hippocampus. Immunohistochemistry revealed a region-selective change in immunopositive cells in the cortex and hippocampus. Finally, an acute bolus dose of ethanol did not affect Egr DNA-binding activity and ethanol treatment did not alter the DNA-binding activity or protein levels of the transcription factor Sp1. These observations suggest that chronic exposure to ethanol has region-selective effects on the DNA-binding activity and protein expression of Egr-1 and Egr-3 transcription factors in the rat brain. These changes occur after prolonged ethanol exposure and may thus reflect neuroadaptive changes associated with physical dependency and withdrawal. These effects are also transcription factor-selective. Clearly, protein expression is not the sole mediator of the changes in DNA-binding activity and chronic ethanol exposure must have effects on modulatory agents of Egr DNA-binding activity.